Clinical manifestations

Presentation and course

Diagnosis of migraine. Migraine is a disabling neurovascular disease. The third edition of the International Classification of Headache Disorders (ICHD-3) provides criteria for the formal diagnosis of migraine and subdivides the disease into migraine without aura and migraine with aura (21). Notably, however, non-nociceptive psychological, gastrointestinal, neurologic or autonomic, and constitutional symptoms that constitute migraine are not detailed in the formal diagnostic criteria.

Table 1. Diagnostic Criteria for Migraine Without Aura

(A) At least five attacks fulfilling criteria B through D (B) Headache attacks lasting 4 to 72 hours (untreated or unsuccessfully treated) (C) Headache has at least two of the following four characteristics:
	(1) unilateral location (2) pulsating quality (3) moderate or severe pain intensity (4) aggravation by or causing avoidance of routine physical activity (eg, walking or climbing stairs)
(D) During headache at least one of the following:
	(1) nausea or vomiting (2) photophobia and phonophobia
(E) Not better accounted for by another ICHD-3 diagnosis
From (21).

Table 2. Diagnostic Criteria for Migraine With Aura

(A) At least two attacks fulfilling criteria B and C (B) One or more of the following fully reversible aura symptoms:
	(1) visual (2) sensory (3) speech or language (4) motor (5) brainstem (6) retinal
(C) At least three of the following six characteristics:
	(1) at least one aura symptom spreads gradually over 5 or more minutes (2) two or more aura symptoms occur in succession (3) each individual aura symptom lasts 5 to 60 minutes (4) at least one aura symptom is unilateral (5) at least one aura symptom is positive (6) the aura is accompanied, or followed within 60 minutes, by headache
(D) Not better accounted for by another ICHD-3 diagnosis
From (21).

A simplified, self-administered, three-item migraine screener can supplement the formal diagnostic ICHD-3 criteria and aid in the diagnosis of migraine in the primary care setting (30). This screener asks the patient if, during the previous 3 months, he/she had three specific symptoms associated with their headaches. The yes/no questions are as follows: (1) have you felt nauseated or sick to your stomach, (2) has light bothered you (a lot more than when you don’t have headaches), (3) have your headaches limited your ability to work, study, or do what you needed to do for at least 1 day. Affirmation of two of the three associated symptoms matched with a positive screen for migraine (sensitivity of 0.81, 95% CI, 0.77-0.85; specificity of 0.75, 95% CI, 0.64-0.84; positive predictive value of 0.93, 95% CI, 89.9-95.8) (30).

Chronic versus episodic migraine. The ICHD-3 further subdivides migraine into episodic and chronic by frequency of headache days. One percent to 2% of people with migraine have chronic migraine, or headache occurring on 15 or more days per month for more than 3 months (28; 33; 21). For chronic migraine, patients should have migrainosus headache features on at least 8 days per month or more (21). The remainder of people with migraine have episodic migraine or headache occurring fewer than 15 days per month. Similar to chronic migraine, episodic migraine can be debilitating. Nearly a third of patients have episodic migraine more than once a week, whereas 8% experience high-frequency episodic migraine occurring 10 to 14 days per month (60; 61). The frequency of episodic migraine can decrease, increase, or remain unchanged over time.

Migraine clinical manifestations and phases

Migraine is a disease that is present whether an individual is experiencing symptoms or not. For this reason, migraine is divided into two distinct states: the ictal state and the interictal state. The interictal state describes times of relatively normal function that occur between recurrent attacks of headache and associated symptoms. The ictal state includes attacks of head pain, which are the key characteristic of migraine. However, the clinical features of migraine extend to an array of non-nociceptive psychological, gastrointestinal, neurologic or autonomic, and constitutional symptoms that are not specified in the ICHD-3 diagnostic criteria. In the clinical setting, assessment of non-nociceptive ictal symptoms are as important as assessment of head pain.

Ictal state. The ictal state of migraine can be subdivided into four phases: (1) premonitory or prodrome, (2) aura, (3) headache, and (4) postdrome (09). These phases, although typically chronological, can have some overlap. Not every phase will be present for any given patient or for any given attack. Identifying and explaining these ictal phases of migraine can help patients recognize symptoms associated with migraine and guide treatment.

The premonitory or prodromal phase. The premonitory, or prodromal, phase occurs in up to 88% of patients with migraine (18; 24; 53; 27). Premonitory symptoms include yawning, changes in energy level (lethargy or increased energy), mood changes (euphoria, irritability, depression, mental slowness, hyperactivity, restlessness, and anxiety), food cravings, concentration difficulty, stiff neck, nausea and other gastrointestinal symptoms, photophobia, and photophobia. These symptoms can continue into the headache and postdromal phases (18). One 3-month multicenter prospective study and a large population retrospective cross-sectional study found that premonitory symptoms could be a reliable predictor of head pain up to 12 hours prior to the attack, especially in patients with poor function during this phase (18; 27). Head pain generally follows premonitory symptoms within 72 hours.

To determine the underlying pathophysiological mechanism to premonitory symptoms, patients with episodic migraine without aura who habitually experienced premonitory symptoms underwent a PET scan after being given nitroglycerin to trigger migraine (34). Imaging showed activations in several significant brain regions. Notably, there is increased activation in the posterolateral hypothalamus, which could explain premonitory homeostatic changes, as well as the periaqueductal gray (PAG), locus cerulus, and dorsal raphe regions, which could explain changes in sensory processing (ie, photophobia) (34; 09).

The premonitory phase is also thought to be dopaminergically mediated, with excitatory symptoms of migraine prodrome resulting from dopaminergic excess due to dopaminergic dysregulation (40). Excitatory symptoms suggestive of dopaminergic excess include yawning, mood changes, nausea, gastrokinetic changes, hypotension, vomiting, and dyskinesias. Further supporting this theory is the efficacy of dopamine receptor antagonists, such as metoclopramide, promethazine, and prochlorperazine, for migraine treatment. Domperidone, a peripheral dopamine antagonist, has also been shown to prevent migraine attacks if taken at the time of the nonevolutive warning symptoms (72).

Clinically, recognition of migraine premonitory symptoms can help guide the diagnosis and management of migraine. In addition, an understanding that symptoms can occur before the onset of the pain phase may prevent misinterpretation of premonitory symptoms, such as food cravings, as migraine triggers (22).

A multicenter, randomized, double-blind, placebo-controlled, crossover trial in patients with low-frequency episodic migraine showed that calcitonin gene-related peptide (CGRP) receptor antagonist, ubrogepant, can be used to improve common migraine prodromal symptoms, such as sensitivity to light, fatigue, neck pain, sensitivity to sound, and dizziness (07).The trial also showed that it prevented the development of moderate/severe headache for 24 and 48 hours post-dose (07).

The aura phase. About a third of patients with migraine have aura, or focal neurologic symptoms that occur before or during an attack of head pain (54). Unlike premonitory symptoms, auras are of shorter duration with a more defined proximal relationship to head pain; headache generally occurs during or within 60 minutes of the end of the aura. The ICHD-3 criteria stipulate that typical aura symptoms develop over 5 minutes and last no more than 60 minutes (21). However, migraine auras have been found to last more than 1 hour (26% of patients), with 5% of auras lasting more than 4 hours (70). Occasionally, aura can occur without the development of head pain (23), and patients can have both migraine with and without aura (54).

Auras encompass a range of symptoms, including changes in vision, sensation, motor function, language, thoughts, or mood (09; 20). Aura is thought to be secondary to cortical spreading depression, which is a propagation of brief neuronal excitation followed by neuronal inhibition that spreads slowly across the cortex. This pattern of cortical spreading depression may explain the aura pattern of positive symptoms followed by negative symptoms (ie, flashing lights followed by scotomas) and gradual progression of symptoms from the occipital cortex anteriorly to the frontal cortices (20). Visual auras are the most common (09; 20).

Table 3. Aura and Pattern of Manifestation

Aura (percentage of people with aura)	Pattern of manifestation
(1) Visual (99%)	Dots, flashing lights, tunnel vision, blind spots or scotomas, wavy or jagged lines, fortification spectrum, shimmering, oscillation, or rotation of objections. Binocular. Can move across the visual field.
(2) Visual distortions or hallucinations	Metamorphopsia, micropsia, macropsia, zoom vision, mosaic vision
(3) Paresthesias (30% to 33%)	Typically, paresthesias will start in the hand, followed by migration up the arm. Paresthesias will then jump to the ipsilateral face and tongue. The ipsilateral leg is occasionally involved. Can be followed by numbness. Paresthesias can occur unilaterally or bilaterally. They typically follow visual aura.
(4) Motor symptoms (18%)	True weakness is rare and always unilateral. Hyperkinetic movements including chorea can occur. Characteristics of nonfamilial migraine with unilateral motor symptoms (MUMS) (76): motor symptoms begin with onset of pain and worsen with pain, typically associated with sensory symptoms. Weakness of the arm (subjectively), both arm and leg (objectively), with give-way character. In patients with MUMs, facial weakness (17%) and interictal weakness (58%) can occur. Symptoms are typically ipsilateral to headache (66%).
(5) Language (17% to 20%)	Dysarthria, aphasia
(6) Olfactory changes (19%)
(7) Changes in touch or taste (14%)
(6) Other	Body apraxia and agnosia, déjà vu, multiple consciousness or trance-like states
From (09; 20)

Occasionally, patients may have typical aura without headache in which aura is neither accompanied nor followed by headache (21).

Migraine with brainstem aura distinguishes a specific subset of aura originating from the brainstem. Characteristics of this aura include dysarthria, vertigo, tinnitus, hypacusis, diplopia, ataxia, or decreased level of consciousness (21). This subset excludes motor weakness and retinal symptoms.

If retinal symptoms are present with migraine headache, the patient would be diagnosed with retinal migraine (21). These symptoms include attacks of monocular visual disturbance, such as scintillations, scotomata, or blindness. Underlying pathology should be excluded.

If motor symptoms are present with migraine headache, the patient may have hemiplegic migraine, which constitutes fully reversible motor weakness and fully reversible visual, sensory, or speech and language symptoms (21). This diagnosis is further subdivided into familial hemiplegic migraine and sporadic hemiplegic migraine.

A diagnosis of familial hemiplegic migraine is made when at least one first- or second-degree relative has had migraine aura with motor weakness (21). Three familial hemiplegic migraine subtypes are associated with identified gene mutations whereas a fourth subtype has unidentified genetic loci. Familial hemiplegic migraine is important to distinguish clinically as it is associated with significant other features. During familial hemiplegic migraine attacks, disturbances of consciousness, including coma, confusion, fever, and CSF pleocytosis can occur. Some attacks can be triggered by mild head trauma. In addition, in about half of cases, a syndrome of chronic progressive cerebellar ataxia occurs independently of migraine attacks.

A syndrome of nonfamilial migraine with unilateral motor symptoms can also present as motor aura (76). This syndrome is characterized by motor symptoms that begin with onset of pain and worsen with pain and are typically associated with sensory symptoms. Weakness of an arm ipsilateral to the pain (66% of cases) can occur subjectively, or both arm and leg weakness can occur objectively. This weakness is characterized by a give-way character on physical examination (76). Facial weakness occurs in 17% of cases, and there is interictal weakness in 58% of cases (76).

Headache phase. Head pain caused by migraine is described as unilateral with a throbbing quality and has at least a moderate severity with pain exacerbations caused by routine physical activity (21). In the clinical setting, it is important to note that these features can vary widely. For example, migraine headache can also be bilateral or nonthrobbing and vary in intensity from moderate to severe (09). About 40% of individuals with migraine can have short-lived jabs of pain between characteristic attacks. The location can also move around the head and radiate from the neck to the shoulder. Pain can extend to the maxillary or mandibular areas of the face (11). Tenderness of the scalp and neck also often occurs during or after a headache. Cranial autonomic ocular symptoms (eyelid edema, conjunctival injection, and lacrimation) and nasal symptoms (nasal congestion, rhinorrhea) during the headache phase are also common (67).

Pain is typically gradual in onset and can occur at variable times throughout the day, but in many individuals occurs on waking up in the morning (09). Lying down in a dark, quiet room often alleviates pain.

Migraine postdrome. The postdrome phase occurs as the pain attack diminishes. This phase defines the period following pain and before normal function is regained (17). Postdromal symptoms include poor concentration, fatigue, and feeling washed out or listless. Other symptoms include feelings of euphoria, muscle weakness, anorexia, yawning, or food cravings (53). One study of 827 patients with migraine showed that postdrome occurred in about 69% of patients with an average duration of 25.2 hours (24).

Interictal state. The interictal state describes times of relatively normal function that occurs between recurrent attacks of headache and associated symptoms. It is important to note that even during the interictal state of migraine, the brain can be in a state of hyperexcitability. This results in an enduring predisposition to migraine attacks. There are two important factors that can initiate or prevent an attack during the interictal state: triggering factors and protective factors.

Migraine triggers. Questions about migraine triggers are common in the clinical setting as trigger identification and avoidance, or preemptive therapy with behavioral modification, could theoretically reduce the risk of transitioning from the interictal state to the ictal state (32).

A trigger is a measurable endogenous or exogenous exposure associated with an increased probability of an attack over a relatively brief period (32). Triggers can be subdivided into endogenous factors, such as menses, or exogenous factors, such as changes in barometric pressure, dietary factors, or light and sound exposure (32). They can also be further subdivided into “low-intensity” triggers and “high-intensity” triggers (32). Low-intensity triggers are factors that do not result in symptoms among healthy individuals without migraine; examples include sleep changes, dietary factors, or stress. Among individuals with migraine, these low-intensity triggers can disrupt sensory, homeostatic or autonomic, and affective networks, leading to transition to the migraine ictal state. “High-intensity” triggers lead to secondary headache in people with and without migraine (32). Examples of “high-intensity” triggers include subarachnoid hemorrhage or meningitis. Headaches initiated by high-intensity triggers are referred to as secondary headache because of the direct causal link between the trigger and headache occurrence. These high‐intensity triggers may activate the same pathways as low‐intensity triggers, which explains the symptomatic overlap between migraine and secondary headache (32).

Triggers, however, may not be individually sufficient to trigger a migraine attack or may be inconsistent. For example, in one study, the following 15 common triggers were self-identified by patients: menstruation, weather, stress, red wine, smoking, hunger, alcohol, skipping meals, noise, change in sleeping habits, glare, “stress let-down” or relaxation after stress, exhaustion, odors, and physical activity (74; 65). Among these triggers, only menstruation was statistically significant in consistency.

In the clinical setting, it is important to counsel patients that (1) triggers are hard to identify as they can be confused with premonitory symptoms, and (2) there are triggers that cannot be avoided or modified (37). Examples of triggers noted to be commonly confused with premonitory symptoms include stress and foods rich in vasoactive biogenic amines, such as chocolate. A double-blinded study with chocolate and carob showed that chocolate was not more likely to provoke headache than was carob in any of the chronic headache groups (36). A study showed that stress is inconsistent as a trigger (71). Associated behavioral changes with stress, such as changes in sleep and dietary factors, could predispose an individual to transition to the ictal state or impact neurophysiological processes, including decreased descending inhibition of trigeminovascular nociceptive neurons (71). Alternatively, instead of precipitating an attack, stress may be perceived more intensely during the premonitory phase (71). To study triggers and protective factors more rigorously, web-based platforms, such as Curelator Headache, are now being used to identify associations between triggers and headaches and test behavioral modification (65).

Patient-led identification of triggers should focus on factors or triggers that are most important or worthwhile to the patient (37). A headache journal could lead to identification of previously unrecognized triggers or conditions that can be modified or treated, such as caffeine withdrawal or menstrual migraine (37). An overemphasis on trigger identification, however, can be harmful. This can result in an increase in anxiety or lead to anticipation of attacks and does not address the underlying cause of the disorder (38). For this reason, overemphasis on trigger identification and avoidance is not recommended.

Protective factors. Instead of trigger emphasis, it is recommended that healthcare professionals shift from focusing on triggers to focusing on protective factors, such as healthy weight maintenance, consistent and adequate sleep, and participating in regular exercise (37). Studies have indicated that physical exercise may be equivalent to some preventive medications. Learning strategies to cope with unavoidable triggers, such as stress, and building tolerance to other perceived triggers, such as noise, can also lead to an increase in functionality (50; 73; 37).

Cephalgiaphobia, or the fear of having migraine symptoms, may also emerge in the interictal state (49). Clinical history should assess for activity-avoidance or restriction in the interictal state due to fear of migraine. Providing an effective acute treatment plan can help improve confidence, reduce anxiety, and prevent migraine chronificiation (31; 37).

Prognosis and complications

Migraine is typically a lifelong disease, although severity and frequency of symptoms can naturally fluctuate over time. Appropriate preventive and acute treatments can increase time in the interictal state and also mitigate symptoms.

Clinically, it is important to understand and recognize the following complications associated with migraine: (1) status migrainosus, (2) persistent aura without infarction, (3) migrainous infarction, and (4) migraine aura-triggered seizure.

Status migrainosus is defined as a debilitating migraine attack lasting for more than 72 hours (21). It may be secondary to medication-overuse headache, and these disorders should be differentiated in the clinical setting.

Rarely, an individual may have persistent aura symptoms without underlying infarction (01). This complication is defined by aura symptoms lasting 1 week or more. Symptoms can be persistent for months or years and are generally bilateral.

Migrainous infarction is defined as one or more migraine aura symptoms correlating with an ischemic brain lesion in a corresponding vascular territory as demonstrated by neuroimaging (21). The infarct occurs during a typical migraine with aura attack. This complication occurs rarely, with an incidence of only 0.2% to 0.5%. When it does happen, it typically affects young women older than 40 years of age on oral contraceptive pills and occurs in posterior circulation territories. Although people with migraine with aura have a twofold increased risk of ischemic stroke as compared to the general population (57), uncorrelated infarcts outside the timeframe of a typical migraine with aura attack are not categorized as migrainous infarctions.

Migralepsy or a seizure triggered by an attack of migraine with aura is another complication of migraine (21). Because migraine occurs prior to the seizure for this diagnosis, migralepsy differs from the headache typically seen in the postictal period of patients with epilepsy.

In addition to physical complications, migraine is associated with individual, family, and socioeconomic costs. Healthcare costs for those with migraine are estimated to be $2916 greater annually as compared to those without migraine (55). Individuals are also burdened with high out-of-pocket medication costs (16). Recent findings showed that the emotional burden of migraine is significant, and more present in those with chronic migraine as compared to episodic migraine (16). People with migraine are impacted by poor sleep quality, negative anticipation of migraine exacerbation, and reliance on family for help. Individuals on two or more preventive treatment failures had the most severe impact (16).

Clinical vignette

A 23-year-old woman presented to an outpatient headache medicine clinic complaining of increased headache frequency. She described her headache as a “pounding” pain, initially starting over the left temple but spreading to the right side of her head if the pain severity escalated. The pain severity was initially moderate, about a 4 to 5 out of 10 on a scale where 0 is no pain and 10 is the worst pain. However, she reported the severity could escalate to a 6 to 10 out of 10.

She had exacerbations in headache severity about 4 to 5 days per week. These exacerbations were associated with sensitivity to light and sound as well as with sensitivity to smells, such as to certain perfumes. She also occasionally experienced “aura” with her head pain exacerbations. She described seeing flashing lights in the left visual field, which remained present even when her eyes were closed. This aura started along with head pain and resolved in 60 minutes. She did not always experience aura with head pain. During exacerbations of pain, the patient was confined to her bed. The pain could last for 2 to 3 days if untreated. Pain was worsened by exercise; it was improved by lying down in a dark quiet room.

Prior to or during head pain exacerbations, she occasionally experienced increased yawning, drowsiness, neck stiffness, decreased appetite, and difficulty concentrating.

Due to head pain, she missed work about 1 to 2 days per month and family activities about 3 to 4 days per month.

Migraine symptoms started at the age of 18 years. She initially attempted to treat her head pain with over-the-counter medications, but this was not effective. Her family physician eventually prescribed almotriptan, which has been effective in acutely treating head pain exacerbations.

She had no relevant medical history. Her family history was notable for migraine; her mother developed migraine at age 20 years. Her physical examination did not show any neurologic deficits.

Discussion. This patient meets diagnostic criteria for chronic migraine with and without aura. She had untreated pain attacks lasting 4 to 72 hours. The location was initially unilateral and of moderate or severe pain intensity, although could spread bilaterally. Additionally, the pain caused her to avoid routine physical activity. She also had accompanying photophobia and phonophobia. Characteristics of her migraine aura are typical: symptoms lasted up to 60 minutes and then spontaneously resolved; symptoms were “positive” (flashing lights) and were accompanied by headache. She also had other typical prodromal features of migraine, such as yawning and neck stiffness, that are not categorized in the formal ICHD-3 criteria.

Given the disease’s impact on her functionality, she was started on a preventive migraine medication. As her features were characteristic of migraine without change in pattern, and she did not have any other “red flag” symptoms or medical history, she did not meet criteria for further diagnostic testing.

Biological basis

Genetics

Migraine likely has a genetic component. Studies show that there is an increased risk (1.9 to 3.8 times) for migraine in first-degree relatives of people with migraine (52). Twin studies show a significantly higher pair-wise concordance rate in monozygotic (0.28 to 0.34) twins versus dizygotic (0.12 to 0.18) twins, with environmental factors taken into account (15; 69). Analysis of genome-wide association studies (GWAS) suggested a possible protective benefit of longer length of fatty acids against migraine and a causual influence of high levels of lysophosphatidylethanolamine, LPE(20:4), on migraine (66). However, migraine has nongenetic, environmental components as well. Currently, the genes and environmental components resulting in migraine are not known. It is possible there are many migraine genetic “subtypes” leading to the spectrum of symptoms and presentations seen clinically.

Pathophysiology

The pathogenesis of migraine headache is complex. The hypothalamus, which has hypothalamic projections to and regulatory effects on the thalamus, interacts with the brainstem to cause the brain to become “hyperexcitable” and vulnerable to migraine attacks in the early phase of migraine (40; 59).

Onset of headache and associated symptoms involves activation of nociceptive fibers innervating the cranial blood vessels and meninges and reflex connections between the cranial parasympathetic pathway and the trigeminal nucleus caudalis pathway (09). Activation of parasympathetic pathways may occur through mechanisms such as stress or changes in homeostasis, with subsequent activation of the superior salivatory nucleus and peripheral nociceptors (03). Dysfunction of signals transmitted from the trigeminal nucleus caudalis to its pathways in the CNS may also provoke activation of nociceptive fibers. Maintenance of the headache phase is largely secondary to central sensitization of neurons in the trigeminal nucleus caudalis.

Dysregulation of central nervous system-mediated pain modulation, which typically inhibits pain signals, also plays a role in pain activation. Brain imaging has shown the dorsal raphe nucleus, locus ceruleus, and nucleus raphe, structures that play key roles in modulating trigeminal sensory transmission, are linked to migraine (09).

There are pathophysiological differences between the various ictal states of migraine as discussed below. These differences factor into the clinical symptoms perceived by patients as a migraine attack progresses.

Prodrome. H₂¹⁵O-PET, or positron emission tomography with a radioisotope of labeled water imaging, measures cerebral blood flow as a marker for neuronal activity; it has been used to study brain structures activated during migraine prodrome. In one study, migraine prodromal symptoms and headache were induced using nitroglycerin in patients with episodic migraine without aura who often experienced prodromal symptoms during spontaneous migraine attacks (34). Results confirmed activation of the posterolateral hypothalamus, midbrain tegmental area, periaqueductal grey, dorsal pons, and various cortical areas, including the occipital, temporal, and prefrontal cortex (34). A similar H₂¹⁵O-PET implicated the rostral dorsal medulla, including the nucleus tractus solitarius, dorsal motor nucleus of vagus, and nucleus ambiguus, and periaqueductal gray, as important central mediators of nausea (35).

Hypothalamic activation during prodrome is clinically significant as it explains many prodromal symptoms. Peak activation of the hypothalamus within the last 24 hours preceding the onset of migraine pain was shown in a study of a patient with episodic migraine without aura who underwent functional MRI (fMRI) every day for 30 days, including during three untreated spontaneous migraine attacks (58). Another fMRI study found patients with migraine had increased hypothalamic functional connectivity with brain areas involved in regulating autonomic functions (41). The hypothalamus also controls a major dopaminergic pathway in the brain, which explains the many excitatory and inhibitory dopaminergic-related prodromal symptoms (40).

Migraine aura. Understanding of the pathophysiology behind migraine aura has undergone a significant shift over time. Initially explained as caused by vasoconstriction of cerebral blood vessels in the 1940s, migraine aura is now thought to be due to neurovascular processes. Neuronal activity results in a progression of hyperperfusion (increased blood flow) followed by inhibition (reduced blood flow) across the brain correlating with the spread of aura. This is termed cortical spreading depression (46; 44). A study using high-field fMRI with near-continuous recording during visual aura has been able to visualize an increased blood oxygenation level-dependent (BOLD) signal developing within the extrastriate cortex, then progressing contiguously and slowly (3.5 +/- 1.1 mm/min) over the occipital cortex, congruent with where neurons map perceived visual aura onto the retina (19).

Headache phase. Understanding of the headache phase of migraine has undergone a similar shift in thought. Although head pain was initially conceptualized as resulting from dilation of blood vessels, it has subsequently been realized that pain generation has underlying neuronal substrates. It is now thought of as a neurovascular disease.

Migraine head pain results from altered brain excitability of neuronal origin, which results in activation of the trigeminovascular system. Repeated exacerbations may result in vascular, structural, and functional changes. The phases of trigeminovascular system activation are categorized into peripheral sensitization and central sensitization.

Peripheral sensitization. The trigeminal system transmits painful, nociceptive information from nerves that surround the cranial structures, such as pial, arachnoid, and dural blood vessels, cerebral arteries, and large venous sinuses (43). Activation of these nerves results in signals being carried to the brainstem, via the trigeminal ganglion and the trigeminal nucleus caudalis. The trigeminal nucleus caudalis (TNC) extends through the whole of the midbrain, pons, and medulla, and into the high cervical spinal cord (43). Together, with the dorsal horn of the cervical spinal cord, which encompasses C1-C2 fibers, this structure is called the trigeminal cervical complex (TCC). In the trigeminal cervical complex, fibers from the TNC converge with fibers from extracranial structures, including the neck, periorbitial areas, and occipital regions (06). Clinically, activation of the trigeminal cervical complex explains why some patients with migraine initially experience neck, periorbital, and occipital pain. Activation of the trigeminal nucleus caudalis eventually leads to the central release of vasoactive neuropeptides, such as substance P, CGRP (calcitonin gene-related peptide), and neurokinin A (43). Their release results in the process of neurogenic inflammation, which includes vasodilation, plasma protein extravasation, degranulation of mast cells, and platelet aggregation (43). Clinically, neurogenic inflammation is linked to the sensation of throbbing pain and aggravation of pain with exertion.

Central sensitization. If neurogenic inflammation continues, the migraine attack itself will transition from peripheral sensitization to central sensitization (08). This process is mediated by neurochemical disturbances involving N-methyl-D-aspartate (NMDA) receptor and may be maintained by glia surrounding the trigeminal nucleus caudalis. During central sensitization, signals are transmitted to various structures in the brain, including the thalamus, causing dysregulation of sensory signal processing, midbrain, cerebellum, reticular formation, and limbic system. Clinically, central sensitization is linked to refractory pain, along with disturbances in sleep, mood, vestibular function, and sensory processing (08; 43).

Associated symptoms. Clinically, some patients may complain of cranial autonomic symptoms such as lacrimation, conjunctival injection, facial swelling, ptosis, rhinorrhea, and pupillary changes during a migraine attack. These symptoms result from activation of the efferent parasympathetic arm of the trigeminoautonomic reflex (63). Sensitization of thalamic neurons can also result in dysregulation of pain signal processing from the whole body, causing allodynia and hyperalgesia beyond the sites expected of migraine head pain (04).

Postdrome phase. Hypoperfusion resulting from changes in cerebral blood flow during the headache phase is thought to cause symptoms, such as fatigue, that persist beyond the headache phase (05). Clinically, this may lead to patients complaining of a “hangover” like feeling after their migraine attack subsides.

Epidemiology

The 1-year period prevalence for migraine is about 12% (29). It is higher in women (about 17%) than men (about 6%) (29). The prevalence of migraine peaks in middle life. Adolescents and those older than 60 years of age are less likely to have migraine (29). Migraine is a leading cause of global disability-adjusted life-years (DALYs) (14).

Prevention

Along with preventive medications, lifestyle modifications focusing on protective factors, such as healthy diet and an exercise regimen as well as establishing regular sleep and meal routine, may help prevent migraine attacks (37). Another important factor for chronic migraine prevention is achieving a healthy BMI. Patients who are overweight or obese have been found to have an association with increased pain attack frequency and progression of episodic to chronic migraine (02).

Differential diagnosis

Confusing conditions

Migraine should be distinguished from other primary headache disorders, such as primary tension-type headache and trigeminal autonomic cephalalgias (21). Other primary headache disorders include: primary cough headache, primary exercise headache, primary headache associated with sexual activity, primary thunderclap headache, cold-stimulus headache, external-pressure headache, primary stabbing headache, nummular headache, and hypnic headache.

Clinical features, including differences in pain location, duration, and extent of disability, as well as triggers (ie, cough) help differentiate these primary headache disorders. However, migrainous features often overlap among headache disorders, and distinguishing between specific disorders can be difficult (75).

Other differential diagnoses to consider are secondary causes of headache. SNOOP4 is a common acronym that describes clinical features for which a person with migraine would need further diagnostic imaging to rule out infections, malignancies, strokes, or vascular or mass lesions (42).

Associated or underlying disorders

Cardiovascular disease, cerebrovascular disease, or risk factors. Cardiovascular and cerebrovascular diseases have been well-studied conditions associated with migraine. Specifically, evidence has emerged for an increased incidence of stroke in young women with migraine with aura and in especially those who smoke or use oral contraceptives (12; 57; 64; 56). Notably, this increased risk is present independently of other known cardiovascular risk factors. A consensus statement determined that quality evidence is still needed to determine the safety of hormonal contraceptives in women with migraine (56).

Congenital heart defects. Patent foramen ovale has been researched in association with migraine with and without aura. However, the causal relationship between patent foramen ovale and migraine remains uncertain. The MIST, PRIMA, and PREMIMUM trials are randomized clinical trials that assessed if patent foramen ovale closure impacted the clinical course of patients with migraine with and without aura (10; 39; 68). In all trials, patent foramen ovale closure did not meet the primary endpoint of reduction of migraine frequency.

Currently, there is no role for routine screening for patent foramen ovale. Current evidence does not suggest that patent foramen ovale closure would impact the clinical course of migraine with aura.

Diagnostic workup

Differentiating migraine, or other primary headache disorders, from secondary headache disorders is a key first step for clinical evaluation of someone presenting with headache. “Red flags” are signs or symptoms that indicate an increased probability of a secondary headache disorder. The presence of red flags increases the need for further investigation. SNOOP4 is a common acronym that describes clinical features for which a person with migraine would need further diagnostic workup, such as blood tests, brain imaging, or lumbar puncture, to rule out infections, malignancies, strokes, and vascular or mass lesions (42).

Acronym	Stands for	Example
S	Systemic symptoms	Fever, weight loss, or fatigue
	Secondary risk factors	Malignancy or immunocompromised state
N	Neurologic symptoms or signs	Focal deficits or changes in mental status
O	Onset	Thunderclap
O	Older	New onset at age older than 50 years
P4	Positional	Change or onset of headache when going from lying down to sitting up or vice versa
	Prior	Change in character from prior baseline headache
	Papilledema
	Precipitated by	Actions that increase intracranial pressure, such as coughing or straining
From (42)

Specific populations, such as those who are elderly, immunosuppressed, pregnant or postpartum, with underlying disease, and of young age (children), may have special considerations for further diagnostic testing (45).

Workup with brain neuroimaging. Clinicians should be aware of the association between migraine and white matter abnormalities. The population-based Cerebral Abnormalities in Migraine, an Epidemiological Risk Analysis (CAMERA I) study assessed individuals with and without migraine and without a reported history of stroke or transient ischemic attack or neurologic examination abnormalities (25). The study showed that although there was no overall difference in the prevalence of clinically relevant infarcts between those with migraine and those without migraine, patients with migraine had a higher prevalence of subclinical infarcts in the cerebellar region of the posterior circulation territory than controls (5.4% vs 0.7%; P = .02; 95% CI, 0.9-55). The highest risk for subclinical infarcts was in patients with migraine with aura with one attack or more per month (OR, 15.8; 95% CI, 1.8-140). Women with migraine were about twice as likely to have deep white matter lesions as those without migraine (OR, 2.1). Again, this increased risk of white matter lesions and subclinical infarcts is present independently of known cardiovascular risk factors.

Patients with migraine have a higher likelihood of subclinical white matter lesions on brain imaging, which may lead to unnecessary patient anxiety or further workup. Therefore, it is important to be judicious about the use of diagnostic neuroimaging in the clinical setting. The American Academy of Neurology guidelines state that “in adult patients with recurrent headaches that have been defined as migraine, including those with visual aura with no recent change in pattern, no history of seizures, and no other focal neurologic signs or symptoms, the routine use of neuroimaging is not warranted” (51). This recommendation has been supported by the American Headache Society, whose guidelines note that there is no strong evidence that routine imaging for migraine meeting ICHD-3 criteria is more likely to reveal meaningful abnormalities compared to the general healthy population in the absence of worrisome features (13). These guidelines do suggest that neuroimaging may be considered for presumed migraine for the following reasons:

• Unusual, prolonged, or persistent aura • Increasing frequency, severity, or change in migraine clinical features • First or worst migraine • Migraine with brainstem aura • Confusional migraine • Hemiplegic migraine • Late-life migrainous accompaniments • Migraine aura without headache • Side-locked migraine • Posttraumatic migraine

Management

Migraine treatment constitutes acute (abortive) therapy and preventive therapy as well as integrative behavioral modifications to reduce triggers, such as stress or sleep disturbances. Acute therapy treats an attack of pain at its onset. Frequent reliance on acute therapy, however, can increase a patient’s risk for medication overuse headache. Preventive therapy is a treatment that works on a daily basis and is used to try to reduce the frequency, duration, or severity of attacks. Further discussion on migraine management is discussed elsewhere on Medlink Neurology and is outside the scope of this review.

Special considerations

Pediatric migraine variants

Patients who have migraine with or without aura have an increased likelihood of developing a specific group of episodic syndromes, including abdominal migraine, cyclic vomiting syndrome, benign paroxysmal vertigo, and benign paroxysmal torticollis. Although these syndromes typically occur in childhood, they may also occur in adults.

One syndrome is recurrent gastrointestinal disturbance, which is further subdivided into cyclic vomiting syndrome and abdominal migraine. Cyclic vomiting syndrome constitutes recurrent episodic attacks of intense nausea and vomiting with complete resolution of symptoms between attacks (21). Within an individual, the episodes are typically the same each time, with predictable timing of episodes. The attacks may be associated with pallor and lethargy. Abdominal migraines are rare recurrent attacks of moderate to severe midline abdominal pain. The pain can be associated with anorexia, nausea, vomiting, and pallor. Typically, symptoms last for 2 to 72 hours and completely resolve. Headache does not accompany these symptoms. If headache does occur concurrently with abdominal symptoms, a diagnosis of migraine without aura should be considered.

Benign paroxysmal vertigo is an episodic syndrome characterized by recurrent attacks of abrupt vertigo in otherwise healthy individuals, accompanied by nystagmus, ataxia, vomiting, pallor, or fearfulness, with full resolution of symptoms between attacks (21). Infants and small children may experience benign paroxysmal torticollis, which is defined as recurrent episodes of head tilt to one side, possibly with slight rotation, with spontaneous resolution.

Additional episodic conditions associated with migraine in the pediatric populations include infantile colic and alternating hemiplegia of childhood (26). Other conditions include motion sickness and periodic sleep disorders such as sleep walking, sleep talking, night terrors and bruxism (21).

Table 4. Group of Episodic Syndromes that May Be Associated with Migraine

Syndrome	Pattern of manifestation
Cyclic vomiting syndrome	Recurrent, stereotyped, predictable episodic attacks of intense nausea and vomiting with complete resolution of symptoms between attacks
Abdominal migraine	Recurrent attacks of moderate to severe midline abdominal pain without headache
Benign paroxysmal vertigo	Recurrent attacks of abrupt vertigo in otherwise healthy individuals
Benign paroxysmal torticollis	Recurrent episodes of head tilt to one side, possibly with slight rotation, with spontaneous resolution
From (21)

Migraine comorbidities. When diagnosing or treating a patient with migraine in the clinic, it is important to acknowledge that migraine is accompanied by several coexisting diseases (62). Cardiovascular comorbidities include low or high blood pressure, Raynaud disease, mitral valve prolapse (in migraine with aura), chest pain, and stroke. People with migraine can also have comorbid psychiatric diseases, including depression and bipolar, generalized anxiety, and substance use disorders. Other neurologic disorders, including essential tremor and epilepsy as well as dysautonomia, restless leg syndrome, and benign paroxysmal positional vertigo, are common. Finally other comorbid diseases, such as irritable bowel syndrome, asthma, and allergies, have been described. These comorbidities can overlap with the symptoms of migraine or impact treatment.

Pregnancy

During pregnancy, migraine will most likely improve in frequency or remit, especially during the second and third trimesters (47). Among women whose migraine does not improve by the end of the first trimester, preventive treatment may be warranted. This treatment should be selected to avoid teratogenic agents. Although generally, migraine should not affect pregnancy or delivery, in women who require acute-setting care for migraine treatment, the pregnancy may require closer surveillance for adverse birth outcomes, and future pregnancies should be monitored for possible worsened headache.