Continuing Education Activity

Migraine is one of the most common headache disorders affecting approximately 12% of the general population. A timely diagnosis is essential to avoid debilitating consequences. Migraine auras are the sensory symptoms (neurologic, gastrointestinal, and autonomic) that can occur before or during a migraine episode. These symptoms can include flashes of light, blind spots, or tingling in the hands or face. This activity describes various types, pathophysiology, evaluation, and treatment of migraine headaches with aura and highlights the role of the healthcare team in evaluating and managing patients with this condition.

Objectives:

• Identify the etiology of migraine headache with aura.
• Review the appropriate evaluation of migraine headache with aura.
• Outline the management options available for migraine headaches with aura.
• Describe interprofessional team strategies for improving care coordination and communication to identify migraine headaches with aura and improve outcomes.

Introduction

Migraine is one of the common types of headache disorder that can present with a wide variety of symptoms. The word migraine derives from the Latin word ‘hemicrania,’ meaning ‘half skull.’ The term ‘migraine’ was first used by the Greek physician, Galenus of Pergamon. Migraine auras are the sensory symptoms (neurologic, gastrointestinal, and autonomic) that can occur before or during a migraine episode. These symptoms can include flashes of light, blind spots, or tingling in the hands or face. Migraine without aura accounts for 70% of patients with migraine headaches.

Etiology

The exact etiology of various aspects of migraine is not completely understood. It is believed that a primary neuronal dysfunction leads to a sequence of changes intracranially and extracranially, which causes migraines. The aura of migraine is thought to be due to neuronal and glial depolarization that spreads across the cerebral cortex.[1] This, in turn, activates trigeminal afferents, which cause inflammatory changes in the pain-sensitive meninges that generate the migraine headache through central and peripheral reflex mechanisms.

Genetics and Inheritance

Migraine has a strong genetic component. The risk of migraines in ill relatives is three times greater than that of relatives of non-ill subjects, but no inheritance pattern was identified. The genetic basis of migraine is complex, and it is uncertain which loci and genes are the ones implicated in the pathogenesis; it may be based on more than one genetic source at different genomic locations acting in tandem with environmental factors to bring susceptibility and the characteristics of the disease in such individuals.[2][3] Identifying these genes in an individual with migraines could predict the targeted prophylactic treatment.

Triggers

Withdrawn or exposure to several factors contribute to the development of migraine headaches. A retrospective study found that 76% of the patients reported triggers.[4] Some of the precipitating factors for migraine headaches include:

• Certain food items like aged cheese, food additives like nitrates (as used in hot dogs), and monosodium glutamate (MSG) can be responsible in a few patients.
• High-stress levels and anxiety
• Caffeine: High intake of coffee or withdrawal from coffee can precipitate migraines.
• Weather changes: Storm fronts, strong winds, or changes in altitude can sometimes trigger a migraine.
• Sleep disturbances: Lack of adequate sleep or too much sleep can trigger a migraine.
• Menstrual period: Many women can have migraine episodes during their menstrual periods and be symptom-free otherwise.
• Exposure to bright lights, loud noise, or strong odors[5]

Epidemiology

Migraine affects about 12% of the general population. Women are affected more compared to men. The prevalence of migraines is two to three times in women compared to men.[6] Migraine tends to run in families. It is consistently the fourth or fifth most common reason for emergency visits accounting for an annual 3% of all emergency visits.[7] Its prevalence increases in puberty but continues to increase until 35 to 39 years of age, decreasing later in life, especially after menopause.[8] Moreover, it is considered the second major cause of disability after back pain with respect to years of life lived with disability.

Pathophysiology

Multiple mechanisms are believed to be involved in the pathophysiology of migraines. 

Cortical Spreading Depression

Neuronal and glial depolarization spreading across the cerebral cortex is thought to cause the aura of the migraine.[1] This activates the trigeminal afferents, which cause inflammatory changes in the meninges, leading to pain. 

Trigeminovascular System

Activation of the trigeminovascular system is also believed to be involved in the pathophysiology of migraine. The trigeminovascular system consists of sensory neurons originating from the trigeminal ganglion and upper cervical dorsal roots: these sensory neurons project to innervate large cerebral vessels, dura mater, and dial vessels. The convergence of these projections at the trigeminal nucleus caudalis explains the distribution of migraine pain that involves anterior and posterior regions of the head and the upper neck. Trigeminal ganglion stimulation leads to the release of vasoactive neuropeptides like substance P, neurokinin A, and calcitonin-gene-related peptide (CGRP), which in turn leads to neurogenic inflammation.[9]

Role of Serotonin

Serotonin, released from the brainstem serotonergic nuclei, may play a role in migraine; however, the exact role of its mechanisms remains a matter of controversy.[10] Most likely, serotonin levels are low between attacks because it may cause a deficiency in the serotonin pain inhibition system, therefore helping the activation of the trigeminal system. It could mediate by acting directly over the cranial vessels or in central pain control pathways, or by cortical projections of brainstem serotonergic nuclei.[11][12] Serotonin is thought to be involved in the pathogenesis of migraines due to its direct action on the cranial vasculature and its role in central pain control pathways. 

Role of CGRP

Calcitonin gene-related peptide (CGRP) plays an essential role in the pathogenesis of migraines. CGRP is a neuropeptide that has a vasodilatory effect on the cerebral and the dural vessels.[13][14] It mediates pain transmission to the central nervous system from the intracranial vessels. It is also involved in the vasodilatory component of neurogenic inflammation.[15]

Sensitization

The process of neurons becoming increasingly sensitive to nociceptive and non-nociceptive stimulation is called sensitization. Sensitization in primary afferent neurons, the second-order neurons in the trigeminal nucleus caudalis, and higher-order neurons in the central nervous system play a role in migraine attacks. Sensitization also explains the throbbing quality of migraine pain, hyperalgesia, and worsening pain with coughing and sudden head movements.

Genetic Basis

The genetic basis of migraines is complex. Some migraine disorders are believed to be caused due to mutations in a single gene, while others are caused due to polymorphisms in many genes.[16] Mutations in three different ion channel genes, CACNA1A, SCN1A, and ATP1A2, are found to be causal in migraine disorders in family studies. Also, hemiplegic migraine (migraine with motor weakness) is believed to be dominantly inherited.[17]

History and Physical

Migraine is a disorder that usually occurs as recurrent attacks. A migraine attack can last from hours to days. A typical migraine attack passes through 4 phases: the prodromal phase, the aura phase, the headache phase, and the postdromal phase.

Prodromal Phase

This involves symptoms usually occurring 24 to 48 hours before the headache onset. Some of the common prodromal symptoms are irritability, depression, increased yawning, neck stiffness, and craving for specific foods.

Aura Phase

Aura is seen in about 25% of patients with migraines. Aura can precede the headache, or sometimes headaches start along with aura. A typical aura can present with positive or negative symptoms and is completely reversible.[2] Active discharge from the central nervous system neurons leads to positive symptoms. Absence or loss of function leads to negative symptoms. 

Aura can be visual, auditory, somatosensory, or motor. Visual aura can be a flickering, jagged arc of light, bright lines, or a blind spot in the visual field.[18] An auditory aura may be in the form of tinnitus, music, or noises. Sensory aura can present as tingling, numbness, or paresthesias. Language aura is rare and can present as word-finding difficulty or trouble understanding words. Motor aura can present as a weakness of one side of the face or one side of the body. This very rare form is classified as a "hemiplegic migraine."

Some patients experience isolated aura without the development of migraine headaches. This is called 'migraine equivalent' or 'acephalgic migraine.' 

Headache Phase

A migraine headache can be unilateral or bilateral. The pain is usually described as throbbing or pulsatile. Headaches can be accompanied by nausea or vomiting. Intensity can vary from moderate to severe. Many patients report phonophobia or photophobia during the attacks. They get relief from sleeping in a dark, quiet room. 

Postdromal Phase

In this phase, patients can report transient headaches on sudden head movements. Patients can also experience extreme tiredness and exhaustion.

Evaluation

Migraine is a clinical diagnosis. A good history and physical examination are necessary to diagnose.

The necessary information that has to be gathered consists of these simple questions:

• Demographic features of the patient: age, gender, race, profession
• When did the headache start?
• Where does it hurt? Location, irradiation.
• What is the intensity of the pain?
• How is the pain? Which are the qualitative characteristics of pain?
• How long does the pain last?
• In which part of the day does the pain appear?
• How has it evolved since it started?
• What is the frequency of appearance?
• What are the triggering situations?
• Simultaneous symptoms?
• Is it related to sleep?
• How does it get better or worse?
• Which medications do you take to make it better? What is the frequency of this medication?

Following are certain criteria specified by the International Classification of Headache Disorders, 3rd edition (ICHD-3), which can help in diagnosing migraine with aura:

• A. At least two attacks that fulfill criteria B and C
• B. One or more of the following aura symptoms that are reversible:
  • Visual, retinal, sensory, brainstem, motor, speech, or language
• C. At least three of the six characteristics below:
  • At least one aura symptom that spreads gradually over greater than 5 minutes
  • Two or more symptoms in succession
  • At least one unilateral aura symptom
  • At least one positive aura symptom
  • Each aura symptom lasts 5 to 60 minutes
  • Aura accompanied by or followed by headache within 60 minutes[18]

• D. No other ICHD-3 diagnosis accounting for the symptoms

Patients should also be inquired about somatosensory disturbances, such as spreading unilateral numbness or tingling in the face and arm, as well as about disturbances in speech or thinking. Some aura symptoms, as described below, could indicate uncommon types of migraine:

• Motor weakness
• Dysarthria
• Hypacusis
• Diplopia
• Ataxia
• Vertigo
• Tinnitus
• Decreased level of consciousness

There is no diagnostic test for migraines. Hence, most patients do not need any neuroimaging. Neuroimaging may be indicated in the following situations:

• Sudden onset of severe headache
• New neurological symptom or sign-on examination
• Headache not responding to treatment
• Headache lasting > 72 hours
• New-onset headaches in patients greater than 50 years of age
• A significant change in the frequency, pattern, or severity of headaches
• Severe headache pain ("worst headache of life") or headache causing awakening from sleep
• New-onset headache in patients with HIV infection or cancer
• Associated symptoms or signs suggestive of meningitis or stroke[19]

Treatment / Management

Migraine treatment involves abortive and prophylactic therapy. Abortive treatment is to stop a headache that has already started from progressing further. Prophylactic therapy aims to reduce the frequency or severity of headaches, thereby improving patients' quality of life.

Abortive Therapy

• Acute treatment aims to stop the progression of a headache. It has to be treated quickly and with a large single dose. Oral agents can be ineffective in patients with migraine-induced gastric stasis. Therefore, parenteral medication could be the rule for some patients, especially those with nausea or vomiting.[20][21][22] Therapy consists of stratified options:
  • NSAIDs (nonsteroidal anti-inflammatory drugs): ibuprofen (400 to 600 mg), naproxen (275 to 825 mg), diclofenac (65 mg), aspirin (900 to 1000 mg), or acetaminophen (1000 mg).[23] Usually, in mild to moderate attacks without nausea or vomiting. If one NSAID is ineffective, another class of drug should be used.
  • Triptans (the first line in patients with allodynia): sumatriptan (administered as a subcutaneous injection of 6 mg, a nasal spray of 20 to 40 mg over 24 hours, a nasal powder of 10 to 30 mg over 24 hours, or orally 50 to 100 mg once), zolmitriptan 10 mg per 24 hours (nasal 2.5 to 5 mg as a single dose and oral 2.5 mg as a single dose), eletriptan, rizatriptan, almotriptan. With or without naproxen for moderate to severe attacks. Unlike NSAIDs, patients who do not respond well to one triptan may respond to another; therefore, therapy may be individualized.
    • To avoid medication overuse, triptans should be limited to less than ten days of use within a month.
    • Because of the activation of the 5-HT(1B) and 5-HT(1D) receptors on coronary arteries and cerebral vessels, there are recommendations against its use in patients with ischemic stroke, ischemic heart disease, poor-controlled hypertension, angina, pregnancy, hemiplegic or basilar migraine. In these patients with cardiovascular risks, the best-suited medication is a selective serotonin 1F receptor agonist that does not produce vasoconstriction; lasmiditan.
    • It is recommended to monitor therapy if the patient takes selective serotonin reuptake inhibitors or selective serotonin-noradrenaline reuptake inhibitors because of the risk of serotonin syndrome.
    • The combination of nonsteroidal anti-inflammatory drugs (NSAID) with triptan appears more effective than using either drug class alone. Sumatriptan succinate 85 mg and naproxen sodium 500 mg in a single tablet may be prescribed as initial therapy.[24]
    • The use of triptans should be limited to no more than ten days of use per month to avoid medication overuse headaches.
  • Antiemetics: metoclopramide, chlorpromazine, prochlorperazine. They are generally used as adjunctive therapy with NSAIDs or triptans to decrease nausea and vomiting, especially in the emergency department. Diphenhydramine can also be added to prevent dystonic reactions (mostly with metoclopramide).
  • Calcitonin-gene-related peptide antagonists: These include rimegepant (75 mg as a single dose) and ubrogepant. It could be considered in patients who don't respond to conventional treatment or those with coronary artery disease.[25] The use of rimegepant for both migraine treatment and prevention concurrently has not been studied.
  • Selective serotonin 1F receptor agonist: US Food and Drug Administration (FDA) approved lasmiditan oral tablets in October 2019 for the acute treatment of migraine in adults. The initial dose of lasmiditan is 50 or 100 mg, particularly effective for patients who cannot use triptans due to cardiovascular risks. The dose may be increased to 100 or 200 mg per requirement, but no more than one dose should be taken over 24 hours. However, one significant side effect is dizziness. So patients should not engage in potentially hazardous activities or drive a motor vehicle for at least eight hours after each dose of lasmiditan. Some other adverse effects are nausea, fatigue, and paresthesia.[26]
  • Ergots: ergotamine and dihydroergotamine (intravenous (IV), intramuscular (IM), subcutaneous, and intranasal use), recommended for acute attacks as a parenteral administration and effective as bridge therapy for medication overuse headache and status migrainosus. Ergotamine has not demonstrated particular effectiveness yet, and it can present significant side effects, including cerebrovascular, cardiovascular, and peripheral ischemic complications.
  • Dexamethasone can reduce the recurrence of early headaches but does not provide immediate relief of headaches.[27][28]
  • Transcutaneous supraorbital nerve stimulation can reduce intensity.[29]
  • Transcranial magnetic stimulation is proved effective as a second-line treatment, with no serious side effects. It can also be offered as an option to treat chronic migraines. It is contraindicated in patients with epilepsy.[30][31]
  • Nonpainful remote electric neurostimulation could be considered a first-line treatment in some patients.[32]
  • Peripheral nerve blocking (occipital plexus and sphenopalatine ganglion).[33][34]

Migraine Treatment in the Emergency Setting

Patients presenting to an emergency room with severe migraine headaches associated with nausea and vomiting can be managed with:

•  Sumatriptan
•  Antiemetics/dopamine receptor blockers like metoclopramide, prochlorperazine, or chlorpromazine
•  Dihydroergotamine with metoclopramide
•  Ketorolac

It is recommended to add dexamethasone in patients treated with the above therapies to reduce the risk of early headache recurrence. 

Prophylactic Therapy

• Prophylactic therapy is indicated in patients with frequent or long-lasting migraine headaches, headaches causing significant disability and affecting the quality of life, or when acute therapies are contraindicated.[35]
• The drugs for prophylactic therapy are usually started at a low dose and gradually titrated up until the patient gets the therapeutic benefit.
• Some of the agents used in prophylactic therapy are:[36]
  • Beta-blockers like metoprolol or propranolol
  • Antidepressants like amitriptyline or venlafaxine
  • Anticonvulsants like valproate or topiramate
  • Calcium channel blockers like verapamil or flunarizine

Certain noninvasive neuromodulatory approaches, such as supraorbital or vagal nerve stimulation, are emerging as a part of prophylactic methods for migraines.[37] Injection of botulinum neurotoxin A (BoNT-A) is also effective in chronic refractory migraines.[38]

Lifestyle Measures

Lifestyle measures to control migraine headaches include routine meal schedules, regular exercise, good sleep hygiene, and managing migraine triggers.

Differential Diagnosis

Tension-type Headache

Tension-type headache is usually bilateral, compared to migraine headaches, which are unilateral in about 60% to 70% of adults. Tension headache feels like pressure or tightness around the head, which waxes and wanes. It is not commonly accompanied by photophobia, photophobia, nausea, or vomiting.

Cluster Headache

Cluster headache is usually unilateral, and the pain begins around the eye. The pain is severe and reaches a crescendo within minutes, unlike a migraine headache, where the pain is gradual in onset. Associated symptoms in cluster headaches include ipsilateral redness and lacrimation of the eye, rhinorrhea, stuffy nose, and sweating, and responding well to oxygen therapy. 

Transient Ischemic Attack (TIA)

The differential diagnosis for migraine with aura includes TIA. The symptoms are sudden in onset in a TIA, whereas in a migraine, the symptoms are relatively gradual in onset. Also, positive aura symptoms like visual scintillations or paresthesias and associated symptoms of photophobia, phonophobia, nausea, and vomiting are less likely in a TIA.

Treatment Planning

Table 1. Acute therapy for migraine

*Adverse effects in this section pertain to all the triptans unless specified

Table 2. Preventive therapy for migraine

Prognosis

Migraine is a fairly benign disorder, though it can affect the quality of life in some patients. With increasing age, the frequency and severity of migraine headaches tend to diminish. Though migraine is a chronic disorder, prolonged remissions are common. Menstrual migraine tends to get better after menopause in terms of the severity of symptoms and frequency of headaches. Patients who follow lifestyle changes, including meal schedules and good sleep hygiene, have a good prognosis.

Complications

Status Migrainosus

This is a debilitating migraine attack that tends to last for more than 72 hours. Some patients with status migrainosus require hospitalization due to intense pain.

Migrainous Infarction or Stroke

Patients with migraine with aura have a higher risk of stroke. Migrainous infarction is a migraine attack in patients with aura, wherein the aura symptoms last for more than an hour, and infarction is seen on the neuroimaging. 

Persistent Aura without Infarction

This can be seen in patients where the aura lasts for more than a week after the migraine headache has ended. Patients can have symptoms similar to migrainous infarction, but neuroimaging does not show any infarction.

Migraine-aura Triggered Seizure

This is a seizure triggered by a migraine attack with aura. The seizure typically occurs within an hour after a migraine attack.

Mental Health Issues

Some patients with migraine headaches are at an increased risk of having a major depressive disorder, bipolar disorder, or posttraumatic stress disorder.

Deterrence and Patient Education

Timely diagnosis and management of migraine headaches are essential, as they can sometimes be debilitating and affect the quality of life. Patients should be educated about the different phases of migraine headaches and the benefits of abortive and prevention therapy. Patients should be educated about lifestyle changes, which can help in reducing the frequency and severity of migraine attacks. Patients should also be instructed to go to a doctor in case of worsening symptoms or the occurrence of new neurological symptoms, which might warrant neuroimaging.

Enhancing Healthcare Team Outcomes

As migraine headache is a clinical diagnosis, providers need to be aware of various presentations of migraine, to reduce unnecessary investigations and neuroimaging. Optimal management will require the efforts of an interprofessional healthcare team. A good history and physical examination can rule out other differentials and help diagnose migraine. An interprofessional approach is necessary for the management of patients with migraines. Neurologists should be involved in patient care when a primary care provider is unsure of the diagnosis. With proper management, most patients with migraine headaches have a good prognosis. Neuroscience and pain control nurses can work with patients on lifestyle changes and educate them about the use of medications. Pharmacists must review prescriptions, consult with the prescriber on optimal agent selection, check for drug-drug interactions, and inform patients about usage and side effects. Nurses can help monitor and reinforce medication teaching points and serve as a contact point connecting clinicians and other team members.

All team members must document all observations in the patient's medical record and reach out to the appropriate team members for necessary therapeutic interventions. These interprofessional efforts will help drive better outcomes for patients with migraine headaches. [Level 5]