Pathophysiology, clinical features, and diagnosis of migraine in children

INTRODUCTION — Migraine is the most common disabling primary headache disorder that occurs in children and adolescents. It is characterized by headache that is often throbbing in character and accompanied by symptoms such as photophobia, phonophobia, nausea, vomiting, and movement sensitivity.

The epidemiology, pathophysiology, clinical features, and diagnosis of migraine headaches in children are reviewed here. Other aspects of migraine in children are discussed separately.

●(See "Types of migraine and related syndromes in children".)

●(See "Acute treatment of migraine in children".)

●(See "Preventive treatment of migraine in children".)

An approach to the general evaluation of headaches in children is discussed elsewhere. (See "Headache in children: Approach to evaluation and general management strategies".)

PATHOPHYSIOLOGY — Migraine is thought to have a polygenetic and multifactorial etiology [1]. Despite the strong genetic underpinnings of migraine, the specific genes underlying migraine have not been fully delineated, with the exception of the rare subform of familial hemiplegic migraine. (See "Hemiplegic migraine", section on 'Familial hemiplegic migraine'.)

No single theory or hypothesis has yet explained all of the phenomena that occur with migraine [2]. The once-popular vascular theory of migraine, which suggested that the headaches were caused by the dilatation of blood vessels while the aura resulted from vasoconstriction, has been discredited. In spontaneous migraine attacks imaged with magnetic resonance angiography, there is no extracranial artery dilation and only minimal intracranial artery dilation [3]. Successful treatment of the attacks with sumatriptan did not cause intracranial vasoconstriction. The throbbing nature of migraine head pain does not represent perception of one's own arterial pulse, as the throbbing percept rhythm and the arterial pulse rhythm are distinct from and out of phase with one another [4]. A central oscillation in nociceptive processing may underlie the throbbing percept of migraine head pain.

The mechanism appears to be a primary neuronal dysfunction that leads to an increased sensitivity to a broad range of stimuli. A genetic predisposition can make individuals susceptible to an acute migraine attack, depending upon the balance between excitation and inhibition at various levels of the nervous system [5-7]. Both genetic and environmental factors are likely to be important [8].

A primary event may occur in the hypothalamus and/or brainstem to initiate a migraine attack. Support for the role of the brainstem is derived from studies that used positron emission tomography to examine changes in regional cerebral blood flow as an index of neuronal activity in the human brain during spontaneous migraine attacks. In one study, increased blood flow was found in the cerebral hemispheres in the cingulate, auditory, and visual association cortices and in the brainstem [6]. In another study of adults with migraine attacks triggered by nitroglycerin infusion, the hypothalamus and brainstem regions activated during the premonitory phase (ie, migraine phase preceding the headache) [9].

Antidromic stimulation of the trigeminal nerve results in the release of substance P, calcitonin gene-related peptide (CGRP), and other vasoactive peptides that cause pain and vasodilatation in experimental models and lead to the sequence of events labeled as "neurogenic inflammation." Locus ceruleus projections to the cerebral cortex may initiate cortical hypoperfusion and spreading depression, which can explain the aura of migraine. One group of investigators has established a causal link between the aura and headache by providing evidence that cortical spreading depression, a wave of neuronal depolarization that spreads across the cerebral cortex and is thought to cause aura, activates trigeminal nerve afferents that, through central and peripheral reflex mechanisms, cause changes in the pain-sensitive meninges to generate the headache [10]. A second group has also reported temporary sensitization of central trigeminal neurons during acute migraine attacks [11].

Cortical spreading depression — Cortical spreading depression (CSD) is thought to be the underlying cause of migraine aura [12]. CSD is a self-propagating wave of neuronal and glial depolarization that spreads across the cerebral cortex. CSD appears to:

●Cause the aura of migraine

●Activate trigeminal nerve afferents

●Alter blood-brain barrier permeability by matrix metalloproteinase (MMP) activation and upregulation [13]

The activation of trigeminal afferents by CSD could contribute to the headache of migraine through central and peripheral reflex mechanisms [10].

Role of serotonin — Serotonin (released from brainstem serotonergic nuclei) may also play an important role in the pathogenesis of migraine; this is probably mediated via its role in central pain control pathways and through cerebral cortical projections of brainstem serotonergic nuclei [14]. The exact mechanism of serotonin action is obscure. A decline in serotonergic function has been noted during acute migraine attacks in adults, resulting in vasodilation of cranial vessels and sensitization of meningeal afferents of the trigeminal nerve [15]. Between attacks, patients who have migraine without aura appear to have increased brain serotonin synthesis [16].

Preventive migraine treatments may act via centrally modulating serotonergic neuronal networks [17], while abortive medications such as triptans terminate migraine attacks through agonist activity at certain serotonin receptors [18]. Beta-blocking drugs used for migraine prevention may regulate serotonin synthesis through action at the serotonin receptor [16].

Role of CGRP — CGRP is thought to play a central role in migraine pathophysiology. CGRP is a 37 amino acid neuropeptide that is expressed in trigeminal ganglia nerves and is enriched in dural nerves [19-21].

CGRP is involved in pain signaling both within the peripheral and central nervous systems [22,23]. An infusion of CGRP can trigger a migraine attack in those with migraine [24]. CGRP levels have been reported to be elevated during migraine attacks in both adults and children [22,25] and higher in adults with chronic migraine compared with those who have episodic migraine [26]. An elevated CGRP level during a migraine attack may predict response to triptans [27].

Elevated CGRP levels are normalized in migraine patients following administration of the serotonin 1B/1D receptor agonist sumatriptan [23], suggesting that triptans may act to control migraine at least in part by reducing CGRP levels. Monoclonal antibodies to the CGRP ligand or receptor are effective for the preventive treatment of migraine in adults. (See "Preventive treatment of episodic migraine in adults", section on 'CGRP antagonists'.)

Right to left cardiac shunt — A few studies in adults [28-30] and children [31,32] have suggested that migraine with aura is associated with right-to-left cardiac shunts, usually in the setting of a patent foramen ovale or, much less often, an atrial septal defect. It may simply be that this is generally an association without causation, as there is no compelling evidence that closure of a patent foramen ovale or atrial septal defect is effective treatment for migraine. (See "Preventive treatment of episodic migraine in adults", section on 'Other interventions not recommended'.)

EPIDEMIOLOGY — Migraine is a major cause of disability in children [33]. Migraine occurs at all ages and may even begin in infancy [34,35]. The prevalence of migraine increases throughout childhood and in particular during adolescence [36-38]. By age 10, the prevalence of migraine is approximately 5 percent. The prevalence of migraine may be as high as 2.5 percent in children less than seven years of age. Prior to puberty, females and males are affected equally; during puberty, migraine starts to affect more females more than males [36]. There is a family history of migraine in the majority of patients [39,40].

Chronic migraine, meaning migraine occurring at least 15 days per month for at least three months, affects approximately 1 to 2 percent of adolescents aged 12 to 17 years and <1 percent of schoolchildren 5 to 12 years old [41,42]. Chronic migraine is associated with more missed school and poorer performance in school. Children from socioeconomically disadvantaged backgrounds are at higher risk of developing chronic migraine [41].

CLINICAL FEATURES — Migraine is a disorder of recurrent attacks; chronic migraine is the term used for headaches that occur ≥15 days per month for ≥3 months, with ≥8 days per month meeting criteria for migraine. Migraine attacks unfold through a cascade of events that occur over the course of hours to days. A typical attack of migraine without aura progresses through three phases: the premonitory phase, the headache phase, and the postdrome phase [43,44]. In an attack of migraine with aura, the aura is an additional phase that may occur before or with the headache, as at least in adults the headache is already present during aura in the majority of attacks. (See "Pathophysiology, clinical manifestations, and diagnosis of migraine in adults", section on 'Migraine aura'.)

Premonitory phase — The premonitory phase of migraine consists of affective, vegetative, and sensitivity symptoms that appear hours to even a day prior to the onset of the headache phase [44-46]. Frequently reported premonitory symptoms include euphoria, fatigue, irritability, social withdrawal, food cravings, urinary or bowel changes, neck stiffness, and increased yawning. The prevalence of premonitory symptoms in pediatric migraine needs further investigation, but one study of children with migraine noted that at least one premonitory symptom was reported by 67 percent [47]. The most commonly experienced symptoms were fatigue, irritability, and face changes such as pallor or shadows under the eyes.

Migraine aura — Aura, when it occurs, is most often visual. A slowly enlarging scotoma, scintillations, and fortification spectra (ie, a jagged line, typically black and white and crescent shaped) are the most common manifestations. Other forms of aura include sensory, language, motor, brainstem-type, and retinal.

As cortical spreading depression is thought to underlie aura, key clinical features of aura are spread and progression. The slow spread of positive symptoms (scintillations or tingling) followed by negative symptoms (scotoma or numbness) is quite characteristic of migraine aura [48]. The aura symptom should spread over at least five minutes and/or there should be progression from one symptom to the next (eg, from visual to sensory) [49]. Therefore, the patient who simply sees a flash of light for a few seconds would not be considered to have aura. The most typical duration of aura is 5 to 60 minutes. However about one-quarter of adults with migraine with aura will experience aura symptoms that last longer than an hour with at least some of their attacks [50].

●A sensory aura usually begins as a tingling in one limb or on one side of the face. As the tingling sensation migrates across one side of the face or down the limb, numbness is left in its wake and may last up to an hour. The sensory aura may also move inside the mouth, affecting the buccal mucosa and half the tongue.

●Language aura may range from mild word finding difficulties to frank dysphasia with paraphasic errors. This symptom can sometimes be challenging to distinguish from concentration problems that begin in the premonitory phase. In motor aura, the limbs and possibly the face on one side of the body become weak. Motor aura is separated out from the other forms of aura and classified as hemiplegic migraine. (See "Hemiplegic migraine".)

●Atypical auras associated with variant forms of migraine and related syndromes are discussed separately. (See "Types of migraine and related syndromes in children".)

While aura can precede headache, headache is most often already present during aura [51]. In fact, the headache can begin before, during, or after the aura [50]. Therapeutically, sumatriptan response rates appear to be slightly lower in adults with migraine with aura [52]. As stroke risk is slightly elevated in young women who have migraine with aura, and the risk is increased further with use of higher-dose estrogen-containing contraceptives, there should be careful counseling about potential risks and benefits of estrogen-containing treatments in adolescent females who have migraine with aura [53].

Children should be asked specifically if they see anything unusual at the beginning of their headache. Some are embarrassed to mention their experience spontaneously or do not associate it with their headache.

Migraine headache phase — The headache of migraine tends to have a throbbing or pulsatile quality, especially as the intensity increases. However, the symptoms of migraine vary with age. In toddlers, who may be unable to effectively describe their symptoms, symptoms appreciated by caregivers include pallor, decreased activity, and vomiting [35,54]. In children, the headache is most often bifrontal, bitemporal, or generalized rather than unilateral [44]; bifrontal headache is more common in younger children, while bitemporal headache is more common in the early teenage years [55]. The migraine attack is often accompanied by nausea and sensitivity to light and noise. Many children have vomiting that occurs once or repetitively.

Patients typically want to lie down in a dark, quiet room and may obtain relief with sleep.

Cranial autonomic symptoms occur with headache in up to 70 percent of children and adolescents with migraine [56]. These symptoms include one or more of the following:

●A sense of aural fullness

●Forehead and facial sweating and/or flushing

●Lacrimation

●Conjunctival injection

●Ptosis and/or miosis

●Nasal congestion and/or rhinorrhea

●Periorbital edema

It is important to be aware of the frequency of cranial autonomic symptoms in migraine to avoid an erroneous diagnosis of "sinus headache," which is one of the most common misdiagnoses given to people with migraine [57]. (See "Evaluation of headache in adults", section on 'Sinus symptoms'.)

A sense of grit in the eye may be a cranial autonomic symptom that occurs with migraine in children [56].

The duration of migraine headache tends to be shorter in younger compared with older children or adults [58]. However, the duration needs to be at least two hours untreated or unsuccessfully treated to meet criteria for migraine in children [49].

Migraine postdrome — Once the migraine headache resolves, the child may experience a postdromal phase, during which patients often feel drained or exhausted, although some report a feeling of mild elation or euphoria [44]. In a survey of 100 children and adolescents with migraine, the most frequently reported symptoms that began before migraine headache cessation and persisted after were asthenia, cognitive difficulties, pallor, anorexia, somnolence, and nausea [59]. The most frequently reported symptoms that began after headache cessation were thirst, somnolence, visual disturbances, food craving, paraesthesia, and ocular pain.

MIGRAINE VARIANTS — Migraine headaches may occur with or without aura. Variant forms of migraine with aura that occur in children include:

●Migraine aura without headache

●Hemiplegic migraine

●Migraine with brainstem aura

●Retinal migraine

●Estrogen-associated migraine

In addition, other episodic pediatric syndromes are associated with or are precursors to other types of migraine. These include:

●Vestibular migraine of childhood

●Benign paroxysmal vertigo of childhood

●Infantile colic

●Cyclic vomiting syndrome

●Abdominal migraine

●Alternating hemiplegia of childhood

●Benign paroxysmal torticollis

Types of migraine and related syndromes occurring in children are discussed in detail separately. (See "Types of migraine and related syndromes in children".)

DIAGNOSIS — The diagnosis of migraine is made on the basis of a careful clinical history and neurologic examination. The diagnosis may be more challenging in young children, whose ability to describe their symptoms may be limited, or in patients with atypical symptoms.

Diagnostic criteria — The International Classification of Headache Disorders, 3^rd edition (ICHD-3) diagnostic criteria (table 1) note that certain features of migraine in children may differ from typical features in adults [49].

●Migraine attacks may last 2 to 72 hours.

●Migraine headache is often bilateral in children, and an adult pattern of unilateral pain usually emerges in late adolescence or early adulthood.

●Photophobia and phonophobia may be inferred from behavior in young children.

The ICHD-3 criteria provide a reasonable guide to migraine headache characteristics in children (table 1). However, because the ICHD-3 criteria require at least five attacks to fulfill the diagnosis of migraine, they may have suboptimal sensitivity in the setting of the emergency department, where children may be more likely to present with a first episode of moderate to severe headache. In the emergency department setting, diagnostic emphasis is usually on ruling out dangerous secondary causes of headache.

Clinical evaluation — Headache drawings may be a useful adjunct to the history and physical examination in differentiating migraine from nonmigraine headaches. In one study, pediatric neurologists masked to the clinical history evaluated pictures drawn by 226 children, ages 4 to 19 years, illustrating how their headache felt [60]. Drawings with features consistent with migraine (eg, pounding pain, nausea/vomiting, photophobia) had a sensitivity and specificity of 93.1 and 82.7 percent, respectively, and a positive predictive value of 87.1 percent for migraine.

The child should have no abnormalities on general physical and neurologic examinations related to migraine.

Indications for diagnostic testing — Children with an established history (at least three months) of typical intermittent headaches and a normal examination usually do not need neuroimaging. Imaging should be performed if there are abnormal neurologic examination findings or features of the history concerning for elevated intracranial pressure such as diplopia, ataxia, or worsening of headache when supine.

The ICHD-3 states that occipital headache in children is rare and calls for diagnostic caution [49]. This concern about occipital headache location is related to the risk of structural brain lesions in children who present to the emergency department with acute headache. However, even in emergency settings, several studies found that all children who had intracranial mass lesions also had abnormal neurologic examination findings at presentation, such as papilledema or ataxia [61,62]. Thus, it is the neurologic examination that is the most important test in sorting out secondary from primary headache, not neuroimaging tests. In the outpatient clinic setting, occipital headache location is present in about 6 to 16 percent of children and adolescents, and multiple studies have found no increased risk of intracranial structural lesions [63-65]. Thus, occipital headache in the outpatient setting is neither rare nor suggestive of an increased risk of pathology.

Neuroimaging — There are no specific neuroimaging findings associated with migraine in children. In a retrospective case-control study, incidental white matter lesions were slightly more common among pediatric patients who had migraine with aura compared with controls (10 versus 4 percent), but the difference was not statistically significant [66].

Most patients with a history of migraine headaches and no signs or symptoms of neurologic dysfunction or increased intracranial pressure do not need neuroimaging.

The American Academy of Neurology, American Academy of Family Physicians, American College of Physicians–American Society of Internal Medicine, and four other groups formed a consortium that took an evidence-based approach to evaluating the need for brain imaging in patients with headache [67]. This report noted that the odds of finding a significant abnormality on neuroimaging in patients with nonacute headache were increased by the following symptoms:

●Rapidly increasing headache frequency

●History of lack of coordination

●History of localized neurologic signs or subjective numbness or tingling

●History of headache causing awakening from sleep (although this can occur with migraine headache)

However, the odds of finding a significant abnormality were not lowered by the absence of these symptoms [67].

The consortium recommended that neuroimaging is usually not warranted in patients whose history is consistent with migraine and who have a normal neurologic examination [67]. In addition, data were insufficient to make a specific recommendation regarding the relative sensitivity of magnetic resonance imaging (MRI) compared with computed tomography (CT) in patients who have an imaging study performed. However, given the potential radiation risks of CT, MRI is generally preferable in the nonemergent imaging of children with headache.

Laboratory evaluation and other testing — Laboratory testing rarely is helpful in the evaluation of childhood headache [68-71].

Lumbar puncture (LP) may be necessary to diagnose an intracranial infection or abnormal cerebrospinal fluid pressure. (See "Lumbar puncture in children", section on 'Indications'.)

Children with episodic syndromes that may be associated with migraine, such as cyclic vomiting syndrome or abdominal migraine, may require more testing to be able to come to a diagnosis than those who experience typical migraine headaches. (See "Types of migraine and related syndromes in children", section on 'Episodic syndromes that may be associated with pediatric migraine'.)

Electroencephalography (EEG) is not indicated in the routine evaluation of headache [72]. An EEG is performed if seizures are suspected.

DIFFERENTIAL DIAGNOSIS — The differential diagnosis of migraine headache is broad and includes other types of primary headaches, such as tension-type headache and trigeminal autonomic cephalalgias such as cluster headache, as well as secondary headaches (ie, headache caused by another disorder such as head or neck trauma, cerebrovascular disorders, intracranial lesions, disorders of face, skull or adjacent structures, or infection).

The differential diagnosis for migraine aura includes other conditions that may produce acute focal neurologic deficits. These include:

●Transient ischemic attack (TIA)

●Seizure

●Syncope

●Electrolyte disturbances

●Vestibular disorders

Useful features for distinguishing these various types of transient neurologic attacks include the nature of the symptoms, their progression, duration and timing, associated symptoms during and after the attacks, and presence of focal or nonfocal symptoms. The symptoms of TIA and migraine are fully reversible, and neuroimaging is often unrevealing in both conditions. However, both a TIA and an ischemic stroke typically have a sudden onset of symptoms rather than a gradual progressive spread of one aura symptom after another. Ischemic events are also less likely to have positive symptoms such as visual scintillations or paresthesia and are less likely to have migrainous symptoms such as nausea, vomiting, photophobia, and phonophobia. (See "Differential diagnosis of transient ischemic attack and acute stroke".)

SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Migraine and other primary headache disorders".)

INFORMATION FOR PATIENTS — UpToDate offers two types of patient education materials, "The Basics" and "Beyond the Basics." The Basics patient education pieces are written in plain language, at the 5^th to 6^th grade reading level, and they answer the four or five key questions a patient might have about a given condition. These articles are best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more sophisticated, and more detailed. These articles are written at the 10^th to 12^th grade reading level and are best for patients who want in-depth information and are comfortable with some medical jargon.

Here are the patient education articles that are relevant to this topic. We encourage you to print or email these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on "patient info" and the keyword(s) of interest.)

●Basics topics (see "Patient education: Migraines in children (The Basics)" and "Patient education: Headaches in children (The Basics)")

●Beyond the Basics topic (see "Patient education: Headache in children (Beyond the Basics)")

SUMMARY

●Definition – Migraine is a primary headache disorder occurring in children and adolescents that is characterized by headache that is often throbbing in character and accompanied by symptoms such as photophobia, phonophobia, nausea, vomiting, and movement sensitivity. (See 'Introduction' above.)

●Pathophysiology – Migraine is thought to have a polygenetic and multifactorial etiology. The mechanism appears to be a primary neuronal dysfunction that leads to an increased sensitivity to a broad range of stimuli. A primary event may occur in the hypothalamus and/or brainstem to initiate a migraine attack. Antidromic stimulation of the trigeminal nerve results in the release of substance P, calcitonin gene-related peptide (CGRP), and other vasoactive peptides that cause pain and vasodilatation. (See 'Pathophysiology' above.)

●Epidemiology – Migraine is the most common disabling headache disorder in children. The prevalence of migraine increases throughout childhood with a prevalence by age 10 years of approximately 5 percent. Prior to puberty, females and males are affected equally; during puberty, migraine starts to affect females more than males (figure 1). (See 'Epidemiology' above.)

●Clinical features – A migraine attack may be classified by distinct clinical phases (see 'Clinical features' above):

•Premonitory phase – The premonitory phase of migraine consists of affective, vegetative, and sensitivity symptoms that appear hours to even a day prior to the onset of the headache. (See 'Premonitory phase' above.)

•Migraine aura – Aura may occur with some migraine attacks. Key clinical features of aura are spread and progression of positive neurologic symptoms (eg, scintillations or tingling) followed by negative symptoms (scotoma or numbness), typically over at least five minutes. Symptoms most commonly consist of visual symptoms; sensory or language symptoms may also occur. (See 'Migraine aura' above.)

•Headache – The headache of migraine tends to have a throbbing or pulsatile quality and is most often bifrontal, bitemporal, or generalized rather than unilateral. The migraine attack is often accompanied by nausea and sensitivity to light and noise. Cranial autonomic symptoms occur with headache. (See 'Migraine headache phase' above.)

•Postdrome phase – During the transient postdrome phase following cessation of the headache children often feel drained or exhausted, although some report a feeling of mild elation or euphoria. (See 'Migraine postdrome' above.)

●Variant forms of migraine and related conditions – Several variant forms of migraine with aura occur in children. In addition, other episodic pediatric syndromes are associated with or are precursors to other types of migraine. (See "Types of migraine and related syndromes in children".)

●Diagnosis – The diagnosis of migraine is made on the basis of a careful history and neurologic examination in children whose symptoms fulfill diagnostic criteria (table 1). (See 'Diagnosis' above.)

Children with an established history (at least three months) of typical intermittent headaches and a normal examination usually do not need neuroimaging. Imaging should be performed if there are abnormal neurologic examination findings or features of the history concerning for elevated intracranial pressure. (See 'Indications for diagnostic testing' above.)

●Differential diagnosis – The differential diagnosis of migraine headache is broad and includes other types of primary headaches, secondary headaches, and other conditions that may produce acute focal neurologic deficits. (See 'Differential diagnosis' above.)

ACKNOWLEDGMENT — The UpToDate editorial staff acknowledges Robert P Cruse, DO, who contributed to earlier versions of this topic review.