Continuing Education Activity
Migraine is one of the common types of headache disorders affecting approximately 12% of the general population. Timely diagnosis is essential to avoid debilitating consequences. This activity describes various types, pathophysiology, evaluation, and treatment of migraine headaches with aura. It highlights the role of the healthcare team in evaluating and managing the patients with this condition.
- Identify the etiology and epidemiology of migraine headache with aura.
- Review the appropriate history, physical, and evaluation of migraine headache with aura.
- Outline the treatment and 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.
Migraine is one of the common types of headache disorders that can present with a wide variety of symptoms. The word ‘migraine’ is derived 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 that can occur before or during a migraine episode. These symptoms can include flashes of light, blind spots or tingling in hand or face.
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. 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.
Some of the precipitating factors for migraine headache 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 change 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
Migraine affects about 12% of the general population. Women are affected more compared to men. The prevalence of migraine is two to three times in women compared to men. The most common type of migraine is the migraine without aura, seen in about 75% of the patients. Migraine tends to run in families, and it usually affects the population aged 30 to 39 years. In general, migraine is known to be most active between the third and fourth decades of life.
Multiple mechanisms are believed to be involved in the pathophysiology of migraine.
Cortical spreading depression
Neuronal and glial depolarization spreading across the cerebral cortex is thought to cause the aura of the migraine. 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 that originate from 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 lead to neurogenic inflammation.
Role of serotonin 
Serotonin is thought to be involved in the pathogenesis of migraine 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 migraine. CGRP is a neuropeptide, which has a vasodilatory effect on the cerebral and the dural vessels. It mediates pain transmission to the central nervous system from the intracranial vessels. It is also involved in the vasodilatory component of the neurogenic inflammation.
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 migraine is complex. Some of the migraine disorders are believed to be caused due to mutations in a single gene, while some others to be caused due to polymorphisms in many genes. 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.
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: prodromal phase, aura phase, headache phase, and the postdromal phase.
This involves symptoms that usually occur 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 is seen in about 25% of patients with migraine. Aura can precede the headache, or sometimes headaches start along with aura. Typical aura can present with positive or negative symptoms and have complete reversibility. 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 in the form of a flickering, jagged arc of light, bright lines, or a blind spot in the visual field. 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 is a very rare form and is classified as "hemiplegic migraine."
Some patients experience isolated aura without the development of migraine headaches. This is called 'migraine equivalent' or 'acephalgic migraine.'
A migraine headache can be unilateral or bilateral. The pain is usually described as throbbing or pulsatile. Headache can be accompanied by nausea or vomiting. Many patients report photophobia or photophobia during the attacks. They get relief on sleeping in a dark, quiet room.
In this phase, patients can report transient headaches on sudden movements of the head. Patients can also experience extreme tiredness and exhaustion.
Migraine is a clinical diagnosis. A good history and physical examination are necessary to diagnose.
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 2 attacks which 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 3 of the 6 characteristics below:
- At least 1 aura symptom that spreads gradually over greater than 5 minutes
- 2 or more symptoms in succession
- At least 1 unilateral aura symptom
- At least 1 positive aura symptom
- Each aura symptom lasting 5 to 60 minutes
- Aura accompanied by or followed by headache within 60 minutes
- D. No other ICHD-3 diagnosis accounting for the symptoms
There is no diagnostic test for migraine. 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
- New-onset headache in patients greater than 50 years of age
- A significant change in frequency, pattern or severity of headaches
- New-onset headache in patients with HIV infection or cancer
- Associated symptoms or signs suggestive of meningitis or stroke
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 is aimed at reducing the frequency or severity of headaches, thereby improving the quality of life of patients.
- Patients with mild to moderate migraine headaches, not associated with nausea or vomiting, can benefit from non-steroidal anti-inflammatory drugs (NSAIDs) like aspirin, naproxen, ibuprofen, or diclofenac.
- Patients with moderate to severe attacks usually require treatment with triptans or with the combination of triptans with NSAIDs. Triptans inhibit the release of vasoactive peptides, block pain pathways in the brainstem, and also promote vasoconstriction. It is recommended to avoid triptans in patients with hemiplegic migraine, ischemic stroke, basilar migraine, Prinzmetal angina, ischemic heart disease, pregnancy, and uncontrolled hypertension.
- Lasmiditan is a selective serotonin 1F receptor agonist. Its role in clinical practice is not yet defined. It can probably be used in patients with cardiovascular risk factors who have relative contraindications to triptans. Some of the adverse events associated with lasmiditan are somnolence, nausea, fatigue, and paresthesia.
- CGRP antagonists: Randomized controlled trials have described the benefits of CGRP antagonists rimegepant and ubrogepant, compared to placebo in a single migraine attack. However, their efficacy compared to triptans is not yet known.
Migraine Treatment in the Emergency Setting
In patients presenting to an emergency room with severe migraine headache, associated with nausea and vomiting can be managed with:
- Antiemetics/dopamine receptor blockers like metoclopramide, prochlorperazine or chlorpromazine
- Dihydroergotamine with metoclopramide
It is recommended to add dexamethasone in patients treated with the above therapies, to reduce the risk of early headache recurrence.
- 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.
- 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:
- 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 as supraorbital or vagal nerve stimulation are emerging as a part of prophylactic methods for migraines. Injection of botulinum neurotoxin A (BoNT-A) is also effective in chronic refractory migraine.
Lifestyle measures to control migraine headaches include routine meal schedules, regular exercise, good sleep hygiene, and managing migraine triggers.
Tension-type headache is usually bilateral, compared to migraine headaches, which are unilateral in about 60% to 70% of the 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 is usually unilateral, and the pain begins around the eye. The pain is severe and reaches 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 respond 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 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.
Migraine is a fairly benign disorder, though it can affect the quality of life in some patients. With increasing age, the frequency and the 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 severity of symptoms and frequency of headaches. Patients who follow lifestyle changes, including meal schedules and good sleep hygiene, have a good prognosis.
This is a debilitating migraine attack that tends to last for more than 72 hours. Some patients with status migrainous 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 that is 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 it can sometimes be debilitating and affect the quality of life. Patients should be educated about the different phases of migraine headache 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 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 team. A good history and physical examination can rule out other differentials and help in the diagnosis of migraine. An interprofessional approach is necessary for the management of patients with migraines. When a primary care provider is unsure of the diagnosis, neurologists should be involved in patient care. With proper management, the majority of 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 need to review prescriptions, can consult with the prescriber on optimal agent selection, check for drug-drug interactions, and inform patients about usage and side effects. These interprofessional efforts will help drive better outcomes for patients with migraine headaches. [Level 5]