Learning Objectives/Outcomes:After participating in this CME/CNE activity, the provider should be better able to:

1. Describe 2 different types of migraine and the characteristics of each type.

2. List 3 "red-flag" conditions in the examination of patients who present with migraine that should raise consideration of additional diagnostic testing.

3. Explain the main approaches to the treatment of migraine, including nonpharmacologic and pharmacologic options.

Migraine is a common neurologic condition characterized by recurrent (>=5 attacks) moderate-to-severe pain that worsens with routine physical activity and is associated with nausea and vomiting and/or sensitivity to light or sound.1 Migraine headache affects more than 1 billion people worldwide, and is associated with significant levels of disability. The Global Burden of Disease Study in 2015 ranked headache disorders (including migraine, tension-type headache, and medication overuse headache) as the third-leading cause of years of life lost to disability worldwide in the age group of 15 to 49 years.2

Among children and adolescents, the prevalence of migraines is reported to be 7.7% and increases with age.3 Worldwide, migraine affects 1 in 7 people, and is more prevalent than diabetes, epilepsy, and asthma combined.2 With increased recognition that migraine can impact long-term functioning and quality of life, expedient diagnosis and treatment is a priority for improving health outcomes.4 Primary headaches, including migraine and its variants, tension-type headache, and other trigeminal autonomic cephalalgias, occur due to physiologic alterations that directly cause symptoms, whereas secondary headaches include new or preexisting headaches caused by a primary disorder such as trauma or systemic disease.5

Clinical Examination

A thorough medical history and description of headache onset, associated symptoms, current and prior treatments, and familial history should be documented, followed by assessment of vital signs and neurologic examination.6 Specifically in infants, check for bulging fontanelle and, even among older children, measure head circumference to detect abnormal cranial growth.3 Evaluate for signs of neurocutaneous syndromes such as neurofibromatosis and tuberous sclerosis.6

In patients of all ages, palpate the head and neck for tenderness of the sinus, jaw, eye area, or temporomandibular joint, and the neck to detect thyromegaly and nuchal rigidity.6 Use the bell of the stethoscope to auscultate over the orbital, mastoid, frontal, and parietal areas for thrills and bruits that may indicate a vascular anomaly.

Assessment of the optic discs, eye movements, presence of pronator drift, gait, and deep tendon reflexes are essential for detecting any structural neurologic abnormalities.5 Consideration of neuroimaging is based on certain warning signs, such as a recent onset of severe headache, change in headache quality or frequency, abnormal neurologic examination, coexistence of seizures, or other red-flag conditions (Table 1).7

Table 1. Migraine "Red Flags"

Major Primary Headache Types

Differentiating migraine from other primary headaches is based on the characteristics of the headache, including its temporal pattern and associated symptoms (Table 2). The 2 major types of migraine are migraine without aura and migraine with aura. According to the International Classification of Headache Disorders-3rd edition (ICHD-3),5 typical aura symptoms are fully reversible and are categorized as follows:

Table 2. Differentiating Characteristics of Major Primary Headache

* Visual (most common are scintillations)-positive symptom;

* Sensory, such as pins and needles-positive symptom;

* Speech/language disturbances, usually aphasic;

* Motor;

* Brainstem; and

* Retinal.

In addition, aura symptoms must have at least 3 of the following 6 characteristics:

* At least 1 symptom gradually spreads over more than 5 minutes;

* Two or more symptoms occur in succession;

* Each individual aura symptom lasts 5 to 60 minutes;

* At least 1 symptom is unilateral;

* As least 1 symptom is positive; and

* Aura symptoms are accompanied or followed by headache within 60 minutes.

In contrast, brainstem aura includes at least 2 of the following fully reversible symptoms: dysarthria, vertigo, tinnitus, hypoacusis, diplopia, ataxia not attributable to sensory deficit, or decreased level of consciousness.5 Please see full diagnostic criteria at https://www.ichd-3.org.

Patients with migraine may experience prodromal symptoms up to 48 hours preceding other migraine symptoms, and postdromal symptoms after headache resolution. Predromal and postdromal symptoms can include hyperactivity or hypoactivity/fatigue, depression, repetitive yawning, pallor, nausea, neck stiffness, difficulty concentrating, blurred vision, photophobia and/or phonophobia, and cravings for particular foods.

In addition to the headache and aura symptoms, episodic syndromes that may be associated with migraine include recurrent gastrointestinal disturbance (cyclic vomiting syndrome/abdominal migraine), benign paroxysmal vertigo, and benign paroxysmal torticollis. Complications that add complexity to the treatment of migraine include status migrainosus (lasting >=72 hours), persistent aura without infarction, migrainous infarction, and migraine aura-triggered seizure.

Pathophysiology of Migraine

Although once thought to be caused primarily by vascular dysregulation, improved characterization of migraine has provided evidence that vascular changes preceding or associated with the onset of headache are only part of the picture.8,9 Several migraine-associated genes have been identified through genome-wide association studies, although all have small effect sizes.10 Rare migraine syndromes, such as familial hemiplegic migraine and monogenic vasculopathies, have been shown to be associated with single-gene mutations.11-13 Two mutations identified in 2 families are in the gene encoding the enzyme casein kinase I[delta].14 In addition, 38 genomic loci associated with migraine have been validated by population studies.15 Of these loci, there were genes enriched that are expressed in vascular and gastrointestinal tissue, and during wound healing and cell-cell interaction, supporting the complexity of the pathogenesis of migraine.

In addition to increased knowledge of migraine pathophysiology, improved characterization of each phase of migraine has been advanced through imaging research.16 The premonitory phase can begin as early as 3 days before the onset of headache and is characterized by modulation of nociceptive signaling in cortical and subcortical regions of the brain, such as the hypothalamus and brainstem nuclei.

Studies have documented changes in quantitative sensory testing before headache onset consistent with increased pain sensitivity and afferent activation.17,18 During the headache phase, the trigeminovascular system is activated, and may be accompanied by a cortical spreading, depression-like event causing aura symptoms.

For the one-third of patients who suffer from migraine with aura, it has been shown that aura symptoms are associated with neuronal and glial cell depolarization and hyperpolarization that occurs in affected regions of the brain.

Although increased brainstem perfusion has been shown, there is no evidence of blood-brain barrier disruption during migraine with aura.19 Functional changes in brain connectivity have been identified, particularly in connectivity between the cortex, thalamus, hypothalamus, brainstem, amygdala, and cerebellum, which is consistent with alterations in overlapping sensory and pain-processing circuits.20-25

Medication Overuse Headache

Patients who have been using multiple medications for acute migraine and who report worsening migraine symptoms may experience medication overuse headaches. The ICHD-3 criterion for medication overuse headache includes patients with worsening symptoms who use ergotamines, triptans, combination analgesics, or opioids for at least 10 days per month for 3 months or longer. If the patient is only using simple analgesics, such as nonsteroidal anti-inflammatory drugs and acetaminophen, it must be for at least 15 days per month for at least 3 months. The ICHD-3 definition of medication overuse is controversial, as progression from episodic to chronic migraines has been shown to occur in as short as 5 days per month for barbiturates and 8 days per month for opioids.26

Treatment of Migraine

In both children and adults, effective management of migraine requires a multimodal approach often starting with lifestyle factors, such as identifying triggers, monitoring dietary and sleep habits, and working with patients and families to encourage at least the recommended level of physical activity (150 minutes of moderate-to-vigorous activity weekly).

For adults, caffeine intake, reducing tobacco and other nicotine products, and alcohol use may also be important factors. The plan and implementation of care should include monitoring headache frequency, associated symptoms, potential triggers, pharmacologic and nonpharmacologic treatments (including over-the-counter medications, herbal and dietary supplements).

In addition to daily behaviors, psychosocial, biobehavioral, and mind-body therapies have been shown to be effective treatment options for migraine, particularly when combined with pharmacologic therapies, including27:

* Relaxation training;

* Electromyography biofeedback;

* Thermal biofeedback combined with relaxation training; and

* Cognitive-behavioral therapy.

More recent reviews of nonpharmacologic treatments include nutraceuticals (food and dietary supplements), acupuncture, noninvasive neuromodulation (including transcutaneous cranial nerve stimulation, noninvasive vagus nerve stimulation, single-pulse transcranial magnetic stimulation, transcranial direct current stimulation, percutaneous mastoid stimulation, and brachial nerve stimulation), invasive stimulation, sphenopalatine ganglion stimulation, and high cervical spinal cord stimulation.28

Nutraceuticals, especially riboflavin and magnesium, have a strong evidence base for use in prophylaxis, and can be used in patients with comorbidities or individuals who cannot tolerate drug side effects.29 Although the field of noninvasive neuromodulation is expanding at a rapid pace, the technologies and expertise are not widely available except in specialized centers. In addition, there is a need for more clinical trials investigating the efficacy in comparison to standard treatments, costs, and effects on patients' function and quality of life. Invasive (implantable) neuromodulation devices are reserved for the most serious or refractory patients, and a thorough review of the pros and cons, risks, and potential complications should be shared and discussed with the patient and family before considering these options.28

Acute Migraine Treatment

For patients who continue to have recurrent episodes of migraine, triptans, nonsteroidal anti-inflammatory drugs, and antiemetics have been used as standard treatment for many years.30,31 Although evidence is limited on whether migraine with (vs without) aura responds differently to treatment, they are often treated with the same agents.32 In addition to standard agents, magnesium, furosemide, and single-pulse transcranial magnetic stimulation have evidence for effectiveness in acute treatment of migraine.33

A recent investigation was conducted to evaluate the efficacy and safety of low-dose ketamine for acute migraine treatment in the emergency department.34 In this small randomized, double-blinded, placebo-controlled trial, subjects were randomized to receive 0.2 mg/kg of IV ketamine or an equivalent volume of normal saline. Among the 34 subjects enrolled to the ketamine (n = 16) versus placebo (n = 18) group, there was no statistically significant difference in the numeric rating scale score after 30 minutes. The median numeric rating scale score reduction at 30 minutes was 1.0 for the ketamine group and 2.0 for the placebo group. Although there were no adverse events reported in the study, the use of ketamine 0.2 mg/kg IV did not produce a greater reduction in pain compared with placebo. Future studies are needed to evaluate other dosing regimens and/or routes of administration.

Regarding the treatment of more rare types of migraine, triptans traditionally have been contraindicated in hemiplegic migraine and migraine with brainstem aura. However, this is being reconsidered, with new evidence suggesting that these agents may be safe to use for even in these less common types of migraine.35 Sphenopalatine ganglion nerve block is another option for patients with acute migraine that has demonstrated good results with few side effects.38

Migraine Prevention Therapy

Beyond identifying and avoiding migraine triggers, patients who have continued recurrence of migraines each month may benefit from prevention therapy with [beta]-blockers, tricyclic antidepressants, anticonvulsants (topiramate or divalproex sodium), or, for chronic migraine, onabotulinum toxin A.36,37 More recently, candesartan was evaluated in a randomized placebo-controlled study and found to be effective for preventive therapy among 72 participants with migraine, and had excellent tolerability.38

For episodic and chronic migraine, erenumab (formerly known as AMG334) was approved by the FDA in 2018. Erenumab is a new human monoclonal antibody that binds to calcitonin gene-related peptide (CGRP) ligand and blocks its binding to the receptor.

The effectiveness of erenumab for prevention of episodic migraine was evaluated in a randomized, double-blind placebo-controlled phase 3 study.39,40 In the trial (http://ClinicalTrials.gov NCT 02483585), 577 adults with episodic migraine were randomized to placebo or 70 mg of erenumab, with the primary end point being change in monthly migraine days. Secondary end points were 50% or more reduction in monthly migraine days, change in acute migraine-specific treatment days, and 5-point or more reduction in the Physical Impairment and Impact on Everyday Activities domain of the Migraine Physical Function Impact Diary. The end points were used to assess change from baseline to the end of the study at 3 months.

The participants randomized to erenumab treatment experienced -2.9 days' change in monthly migraine days compared with -1.8 days for placebo {least-squares mean [95% confidence interval (CI)] treatment different of -1.0 [-1.6 to -0.5] (P < 0.001)}. A 50% or more reduction in monthly migraine days was achieved by 39.5% in the erenumab group versus 29.5% in the placebo group (odds ratio: 1.59; 95% CI, 1.12-2.27; P = 0.010). Migraine-specific medication treatment days were reduced by -1.2 in the erenumab group compared with 0.6 days in the placebo group, a treatment difference of -0.6 (-1.0 to -0.2) (P = 0.002). Physical Impairment and Impact on Everyday Activities scores were not statistically significant between the groups. The safety and adverse event profiles of erenumab were similar to placebo, with the most frequent adverse events being injection-site pain, upper respiratory tract infection, and nasopharyngitis.40

Also approved in 2018 for preventative treatment of migraine in adults was fremanezumab-vfrm, a CGRP antagonist that inhibits activation of central trigeminovascular neurons with input from the intracranial dura but not the facial skin or cornea.41 At present, the site of action along the trigeminal pathway remains uncertain. Fremanezumab-vfrm was evaluated in 2 phase III, placebo-controlled trials as a stand-alone preventive treatment or for use in combination with other oral preventive treatments.42,43 Among 875 adults [http://ClinicalTrials.gov NCT 02629861], participants were randomized 1:1:1 to receive subcutaneous monthly fremanezumab (n = 290, 225 mg at baseline and week 4, and week 8); a quarterly dose regimen of fremanezumab (n = 291, 675 mg of fremanezumab at baseline, placebo at weeks 4 and 8); or placebo (n = 294; at baseline, week 4, and week 8). Compared with placebo, monthly dosing resulted in -1.5 days' mean migraines per month (95% CI, -2.01 to -0.93 days, P < 0.001) and quarterly dosing resulted in -1.3 days' mean migraines per month (95% CI, -1.79 to -0.72 days; P < 0.001). The most common adverse events that led to discontinuation were injection-site erythema or induration, diarrhea, anxiety, and depression.

Galcanezumab-gnlm is another CGRP antagonist approved in 2018 for preventive treatment of episodic and chronic migraine in adults. The recommended dosage of galcanezumab-gnlm is 240 mg subcutaneously once as a loading dose, followed by monthly doses of 120 mg. The approval of galcanezumab-gnlm was based on 2 phase 3 clinical trials in patients with episodic migraine [EVOLVE-1 (http://ClinicalTrials.gov NCT 02614183)44 and EVOLVE-2 (http://ClinicalTrials.gov NCT 02614196)45] and 1 phase 3 clinical trial in patients with chronic migraine [REGAIN (http://ClinicalTrials.gov NCT 02614261)46]. Both EVOLVE-1 and EVOLVE-2 were 6-month, double-blind, placebo-controlled clinical trials that enrolled adult patients with episodic migraine.

In EVOLVE-1,44 the baseline migraine headache day was 9.2 in patients randomized to galcanezumab-gnlm and 9.1 in patients randomized to placebo. The mean change from baseline days in the galcanezumab-gnlm 120-mg group (n = 210) was -4.7 days compared with -2.8 days (n = 425) in the placebo group (P < 0.001).

In the EVOLVE-2 trial,45 the baseline migraine headache day was 9.1 in the galcanezumab-gnlm group and 9.2 in the placebo group. The mean change from baseline was -4.3 days (n = 226) in the galcanezumab-gnlm 120-mg group compared with -2.3 days (n = 450) for placebo (P < 0.001). In the REGAIN trial, the baseline migraine headache day was 19.4 among participants randomized to the galcanezumab-gnlm group compared with 19.6 days in the placebo group.46 The mean change from baseline after 3 months of treatment was -4.8 days (n = 273) for the galcanezumab-gnlm 120-mg group compared with -2.7 days (n = 538) in the placebo group (P < 0.001). Injection-site erythema was the most common adverse event.

Eptinezumab (formerly known as ALD403) is currently in late-stage clinical development, and if approved, will be the first-to-market infusion therapy for prevention of migraine. It is being evaluated through the clinical trials, PROMISE 1 and PROMISE 2, as a quarterly infusion.47

Although these newly approved options for preventive treatment of migraine hold great promise for reducing pain and disability in migraine sufferers, the long-term effects of these medications have yet to be examined. All of the clinical trials conducted so far have only evaluated outcomes of 3 to 6 months, and long-term monitoring will be required to determine whether adverse events develop over time, the impact on disability and quality of life, safety profile in pediatric and adolescent populations, and the cost-benefit ratio to individuals and the health care system.

Conclusion

Migraines are common pain conditions that affect millions of people each year and have a wide range of characteristics that define the subtypes (aura vs without aura and episodic vs chronic). The pathogenesis of migraines was once thought to be primarily driven by vascular dysregulation. However, various psychosocial, genetic, hormonal, and biochemical factors contribute to the occurrence, severity, and frequency of migraines.

The history and physical examination of patients who present with migraine should focus on identification of red-flag conditions to detect pathologies that could result in permanent neurologic insult, and those with local or systemic infection or disease. Standard treatment of migraine should involve a multimodal approach that begins with symptom tracking, identification and avoidance of triggers, and adoption of healthy behaviors. Options for treatment of migraine with nutraceuticals or noninvasive neuromodulation should be discussed with patients and families. Practitioners should also discuss with patients and families the standard therapeutics used for acute (abortive) and preventative treatment. The approval of 3 CGRP agonists in 2018 represents a set of new options for adult patients with episodic and chronic migraine, although investigators must still study and report on long-term safety and effectiveness of these preventive treatments.

References