Migraine With Aura

Etiology

Current knowledge indicates that primary neuronal dysfunction leads to a sequence of intracranial and extracranial changes that cause migraines. Cortical spreading depression of Leão, a self-propagating wave of neuronal and glial depolarization that spreads across the cerebral cortex, underlies the etiology of both the headache and aura associated with migraine.[1] This cortical depression activates trigeminal afferents, causing an inflammatory molecular cascade of events in the meninges, generating the pain associated with migraine. 

Genetics and Inheritance

Migraine exhibits a strong genetic component. Relatives of patients with migraine have a 3 times higher risk of developing migraine than those without a familial history. However, the precise genetic mechanisms involved are complex and warrant comprehensive understanding. Diverse abnormalities related to membrane channels, receptor families, and enzyme systems are observed among affected families. Most likely, multiple genes at multiple genetic loci combine with environmental factors to determine an individual's susceptibility.[2][3] The equilibrium between excitation and inhibition at different levels of the nervous system plays a pivotal role in determining whether genetically predisposed individuals will develop migraine. 

Genes with a suspected link to migraine are the KCNK18 gene, which encodes for TRESK, a 2-pore domain potassium channel, and the CSNK1D gene, which encodes casein kinase I isoform delta. In the future, identifying these genes in individuals with migraines may enable the prediction of targeted prophylactic treatments tailored to their genetic profiles.

Triggers

Nearly 75% of patients report at least 1 trigger for their migraine.[4] Commonly reported migraine triggers include the following:

• High stress or anxiety
• Menstruation
• Fasting;
• Weather like storm fronts, strong winds, and altitude changes
• Too little or too much sleep 
• Food items like aged cheese
• Nitrates
• Obesity
• Neck pain
• Heat
• Sexual activity
• Alcohol
• Smoke
• Exercise
• Caffeine intake or withdrawal
• Exposure to bright lights, loud noise, or strong odors [5]

Although patients often report monosodium glutamate (MSG) as a general headache trigger, its role as a migraine trigger remains unverified. Similarly, smoking, odors, chocolate, and tyramine have not been conclusively proven as triggers for migraines or general headaches. 

Epidemiology

Migraine affects approximately 12% to 15% of the general population. Women encounter migraines more frequently than men, with 17% of females and 6% of males experiencing attacks each year.[6] Migraine ranks as the fourth or fifth leading cause of emergency room visits, accounting for 3% of all emergency visits annually.[7] 

Migraine prevalence starts to rise during puberty and continues to increase until the age of 35 to 39, with a decrease later in life, especially after menopause.[8] Additionally, migraine ranks second only to back pain in terms of disability when comparing years of life lived with disability.

Pathophysiology

The pathophysiology of migraine involves the cortical spreading depression of Leão and activation of the trigeminovascular system.[1]

Cortical Spreading Depression

The depolarization of neuronal and glial cells spreads across the cerebral cortex, leading to:

• Induction of the migraine aura
• Activation of trigeminal nerve afferents
• Modification of blood-brain barrier permeability through matrix metalloproteinase activation and upregulation

Activation of the trigeminal nerve's afferent neurons brings about inflammatory changes in the pain-sensitive meninges, contributing to the headache associated with migraine. Specifically, cortical spreading depression prompts the opening of pannexin-1 megachannels, activating caspase-1. This cascade causes the release of proinflammatory mediators, activation of nuclear factor kappa-B in astrocytes, and the transduction of the inflammatory signal to trigeminal nerve fibers around pial vessels.

Trigeminovascular System

The trigeminovascular system originates from the trigeminal ganglion and upper cervical dorsal roots. These sensory neurons project to innervate significant cerebral vessels, the dura mater, and pial vessels. The convergence of these projections at the trigeminal nucleus caudalis explains the distribution of migraine pain, impacting both the anterior and posterior regions of the head and the upper neck. Stimulation of the trigeminal ganglion by the proinflammatory mediators results in neurogenic inflammation upon releasing substance P, neurokinin A, and calcitonin-gene-related peptide (CGRP). Neurogenic inflammation is an essential contributor to the prolongation and intensification of the pain of migraine.[9]

Calcitonin Gene-Related Peptide

CGRP is a neuropeptide expressed in trigeminal ganglia nerves that serves as a potent vasodilator of cerebral and dural vessels and plays an essential role in the pathogenesis of migraine.[10][11] CGRP mediates pain transmission from the intracranial vessels to the central nervous system and is involved in the vasodilatory component of neurogenic inflammation.[12]

Serotonin

Serotonin, released from the brainstem serotonergic nuclei, may play a role in migraine, although the precise nature of this role is subject to debate.[13] Proposed mechanisms for serotonin's involvement in migraine include:

• Direct action upon the cranial vasculature
• The role in central pain control pathways 
• Cerebral cortical projections of brainstem serotonergic nuclei [14][15]  

It is speculated that serotonin levels are low between migraine attacks, potentially contributing to a deficiency in the serotonin pain inhibitory system. This deficiency may aid in the activation of the trigeminovascular nociceptive pathways, thereby contributing to migraine episodes. 

Sensitization

Sensitization occurs as the neurons become increasingly sensitive to nociceptive and non-nociceptive stimulation. This phenomenon occurs in the primary afferent neurons, the second-order neurons in the trigeminal nucleus caudalis, and higher-order neurons in the central nervous system. Sensitization helps explain the throbbing quality of the pain and exacerbation of pain with activities like coughing, bending, sudden head movements, hyperalgesia, and allodynia.

Genetic Basis

The genetic basis of migraines is complex. While mutations in a single gene may cause some migraine disorders, others result from polymorphisms in multiple genes.[16] Family studies suggest that mutations in 3 distinct ion channel genes—CACNA1A, SCN1A, and ATP1A2— could contribute to genetic predispositions for migraine disorders. Additionally, hemiplegic migraine, a migraine with motor weakness, is believed to be dominantly inherited.[17]

Right-to-Left Cardiac Shunt

Right-to-left cardiac shunts, notably patent foramen ovale, have been associated with migraine. Atrial septal defects and pulmonary arteriovenous malformations seen in hereditary hemorrhagic telangiectasia may also have a connection, albeit to a lesser degree.

Conflicting evidence exists regarding the link between right-to-left shunts and migraine. Some researchers suggest that a genetic predisposition increasing the risk of a PFO may also elevate migraine risk. Another hypothesis suggests that vasoactive substances in venous circulation could trigger migraines, gaining access to cranial circulation when a right-to-left shunt is present. Finally, it is proposed that a right-to-left shunt may serve as a pathway for paradoxical embolism and subsequent cerebral ischemia, potentially triggering migraines.

History and Physical

Migraine is a recurrent disorder characterized by attacks lasting from hours to days. A typical migraine has 4 phases: the prodromal phase, aura, headache, and the postdromal phase. 

Prodromal Phase

The prodromal phase precedes the onset of headache by 24 to 48 hours in approximately 77% of patients with migraine. Hallmark symptoms of migraine prodrome include yawning, irritability, euphoria, neck stiffness, and cravings for specific foods. 

Aura 

Nearly 25% of patients with migraine experience aura, which can precede the headache or coincide with it. Auras develop gradually and consist of positive and negative symptoms, typically lasting no more than 60 minutes. Aura symptoms are entirely reversible.[2] Positive symptoms arise from active discharge from central nervous system neurons, while negative symptoms result from absence or loss of function. 

Aura symptoms are primarily visual but can be auditory, motor, or somatosensory. Positive symptoms are:

• Bright lights, lines, and shapes
• Tinnitus or music
• Paresthesias
• Jerky or repetitive movements [18]

Examples of negative symptoms are:

• Loss of vision
• Hearing loss
• Sensory loss
• Inability to move parts of the body [18]

Patients with a migraine equivalent or acephalic migraine develop an aura without a subsequent headache. This variant of migraine presents a unique challenge in diagnosis and management, requiring careful evaluation to differentiate it from other neurological conditions.

Visual auras classically begin as a small area of vision loss or the appearance of bright lines or shapes in the visual field, known as a scintillating scotoma. This visual disturbance then expands to involve a quadrant or hemifield of vision. Upon resolution, the central vision is restored first.

Sensory auras may occur independently but typically follow visual auras within minutes. A typical sensory aura manifests as tingling localized to a limb or one side of the face. Following the paresthesias, localized numbness may persist for up to 60 minutes. Some patients may experience sensory auras within the mouth, including the involvement of half of the tongue. The presence of positive visual or sensory symptoms followed by negative symptoms is characteristic of migraine and aids in distinguishing migraine from ischemic events.

Language and motor auras are less frequently observed. Patients affected by these auras may experience transient word-finding difficulties, dysphasia, or unilateral limb or facial weakness. The occurrence of unilateral facial or limb weakness in the presence of a migraine is termed hemiplegic migraine. 

Some patients may develop cutaneous allodynia, where normally non-painful stimuli such as brushing hair, touching the scalp, shaving, or wearing contact lenses may trigger symptoms associated with migraine. Cutaneous allodynia is believed to result from the sensitization of neurons in the trigeminal pathway, contributing to the pain experienced during migraine attacks.

Headache

The headache phase of migraine typically manifests unilaterally but can be bilateral. The pain is usually described as throbbing or pulsatile and intensifies gradually over several hours. Nausea, vomiting, photophobia, phonophobia, osmophobia, and cutaneous allodynia are all potential features of the headache phase. Patients often seek relief in a dark, quiet environment; if left untreated, symptoms can persist for hours to days. The headache associated with migraine may resolve during sleep.  

Postdrome

Postdrome commences once the spontaneous throbbing subsides. During this phase, patients can experience transient headaches triggered by sudden head movements. Individuals are often left feeling exhausted, though some report elation or euphoria.

Neurological examination typically yields no concerning findings in most patients with migraine. Some individuals may exhibit cranial and cervical muscle tenderness, conjunctival injection, hypertension or hypotension, and bradycardia or tachycardia. The presence of amaurosis, temporal artery tenderness in older patients, meningismus, fever, lethargy, jaw claudication, seizure, and mental status changes should prompt consideration of underlying pathology beyond migraine. 

Migraine variants that present with focal neurological deficits include:

• Hemiplegic migraine: Unilateral paralysis or weakness

• Retinal migraine: Visual disturbance, papilledema, and retinal hemorrhages affecting 1 eye

• Migraine with brainstem aura: Vertigo, dizziness, confusion, dysarthria, tingling of the extremities, and incoordination.

Ophthalmoplegic migraine, now reclassified as neuritis by the International Headache Society, presents symptoms such as third nerve palsy, ocular muscle paralysis, and ptosis, which may involve or spare the pupillary response. The underlying etiology is likely a transient idiopathic inflammatory neuritis.

Evaluation

Migraine diagnosis relies on a clinical assessment, necessitating a comprehensive history and physical examination. Key historical data include:

• Patient's demographic information
• Onset of headache
• Location of pain
• Presence of radiating pain
• Intensity of the pain
• Qualitative characteristics of pain
• Duration of pain
• Time of day when pain occurs
• Evolution of symptoms over time
• Frequency of symptoms
• Potential triggers
• Coexisting symptoms
• Relationship between headache and sleep
• Factors exacerbating headache severity
• Measures alleviating headache
• Efficacy and frequency of medication use for symptom relief

The diagnostic criteria established by the International Classification of Headache Disorders, 3rd edition (ICHD-3) include migraine without aura and migraine with aura. These criteria serve as standardized guidelines to aid clinicians in accurately diagnosing migraine.

Migraine Without Aura

At least 5 attacks with the following criteria:

• Headaches that last 4 to 72 hours, either treated or untreated
• Headaches with ≥2 of the 4 following characteristics:
  • Unilateral location
  • Pulsating or throbbing quality
  • Moderate or severe pain 
  • Aggravation by routine physical activity
• The presence of ≥1 of the following:
  • Nausea
  • Vomiting
  • Phonophobia
  • Photophobia
• No other ICHD-3 diagnosis better explains the patient's symptoms

Migraine With Aura

At least 2 attacks that meet the following criteria:

• ≥1 fully reversible aura symptoms:
  • Visual
  • Sensory
  • Speech
  • Language
  • Motor
  • Brainstem
  • Retinal [18]
• ≥3 of the following 6 characteristics:
  • 1 aura symptom that spreads gradually over ≥5 min
  • ≥2 aura symptoms occurring in succession
  • Individual aura symptoms lasting 5 to 60 minutes
  • ≥1 unilateral aura symptom
  • ≥1 positive aura symptom
  • Headache appears within 60 minutes of aura symptoms [18]
• No other ICHD-3 diagnosis better explains the patient's symptoms [18]

No specific diagnostic test is available for migraine. The patient's clinical history and physical examination determine the necessity for testing. Consider ordering a C-reactive protein or erythrocyte sedimentation rate in older patients with scalp tenderness.

Neuroimaging is unnecessary for stable patients who meet the diagnostic criteria for migraine. However, if neuroimaging is warranted, magnetic resonance imaging (MRI) is the preferred imaging study. Computed tomography (CT) scans are reserved for emergencies. Indications for neuroimaging include:

• Sudden onset of severe headache
• New neurological signs or symptoms on examination
• Headache not responding to treatment
• Headache duration >72 h
• New-onset headaches in patients older than 50
• A significant change in the frequency, pattern, or severity of headaches
• Severe headache pain described as "the worst headache of my life" or a headache that awakens the patient from sleep
• New-onset headache in a patient who is immunocompromised
• Associated symptoms or signs suggestive of meningitis or stroke 
• Posterior location of a headache, which is especially important in children [19]

Indications for lumbar puncture are:

• A severe first or the worst headache of a patient's life
• Severe, rapid-onset, recurrent headache
• Progressive headache
• Unresponsive, chronic, intractable headache

Neuroimaging is conducted before considering a lumbar puncture to assess for the presence of a mass lesion or elevated intracranial pressure. This precaution helps ensure the safety and appropriate management of the patient.

Treatment / Management

Alongside avoiding migraine triggers, maintaining a daily headache diary can aid in tracking progression and therapy response. Lifestyle adjustments to control migraine headaches include following routine meal schedules, exercising regularly, and practicing good sleep hygiene. Biofeedback, stress reduction techniques, and cognitive behavioral therapy are helpful adjunctive treatments. 

Migraine treatment involves abortive and prophylactic therapy. Abortive treatment (see Table 1. Acute Therapy for Migraine) aims to stop the progression of a current headache, while prophylactic therapy (see Table 2. Preventive Therapy for Migraine) seeks to reduce the frequency or severity of headaches, thereby improving patients' quality of life. Patients should also implement strategies to avoid migraine triggers. 

Abortive Therapy

Place patients in a dark and quiet environment to alleviate discomfort. To abort a migraine, expedient treatment with a single large medication dose is crucial. Treatment yields optimal results when administered promptly, ideally within 15 minutes of symptom onset, particularly mild symptoms. Some patients may require parenteral therapy due to migraine-induced gastric stasis.[20][21][22] Therapy generally follows a stratified approach.(A1)

Nonsteroidal anti-inflammatory medications

Nonsteroidal anti-inflammatory (NSAID) medications are effective in treating mild to moderate attacks without accompanying nausea or vomiting. If one NSAID proves ineffective, an alternative class of medication is typically required. Commonly used NSAIDs include:

• Ibuprofen 400 mg to 600 mg
• Naproxen 275 mg to 825 mg
• Diclofenac 65 mg
• Aspirin 900mg to 1000 mg 
• Acetaminophen 1000 mg [23] 

Triptans

Triptans are 5-hydroxytryptamine₁ ( 5-HT₁) agonists and are recommended as first-line therapy for patients experiencing allodynia and those with moderate to severe pain. Triptans, with or without naproxen, are suitable for treating moderate to severe attacks. Combining NSAIDs with a triptan has shown greater efficacy than using either drug class alone.

Initial therapy may involve prescribing a single tablet containing sumatriptan succinate 85 mg and naproxen sodium 500 mg.[24] If necessary, triptan doses may be repeated once after 2 hours. However, patients should avoid using a different triptan within the same 24-hour period, although they may use a different formulation of the same triptan for repeat dosing.(A1)

• Sumatriptan:
  • 6 to 12 mg subcutaneous injection over 24 hours or,
  • 20 to 40 mg nasal spray over 24 hours or,
  • 22 to 44 mg of nasal powder over 24 hours or,
  • or 50 to 200 mg orally over 24 hours

• Zolmitriptan:
  • 10 mg per 24 hours dosed as 2.5 to 5 mg as a single dose intranasally or 2.5 mg as a single dose orally

• Eletriptan, rizatriptan, almotriptan

Unlike NSAIDs, patients who do not respond favorably to one triptan may find relief with another, allowing for individualized therapy approaches. Limiting triptan use to 10 days per month or 3 days a week is recommended to prevent medication overuse headaches. Reduce the dose of rizatriptan to 5 mg for patients concurrently taking propranolol. Additionally, prescribing sumatriptan, zolmitriptan, and rizatriptan should be avoided in patients using monoamine oxidase inhibitors. 

Triptans activate the 5-HT_1B  and 5-HT_1D  receptors in coronary arteries and cerebral vessels. Contraindications to triptans include:

• Hypersensitivity
• Ischemic heart disease 
• Coronary artery vasospasm
• Prinzmetal angina
• Angina pectoris
• Myocardial Infarction
• History of cerebrovascular syndromes
• History of hemiplegic or basilar migraine
• Peripheral vascular disease 
• Uncontrolled hypertension
• Use within 24 hours of ergotamine derivatives
• Use within 24 hours of another 5-HT₁ agonist
• Concurrent administration or within 2 weeks of discontinuing an MAO type A inhibitors
• Wolff-Parkinson-White syndrome or arrhythmias associated with other cardiac accessory conduction pathway disorders
• Severe hepatic impairment
• Pregnancy

Combining triptans with selective serotonin reuptake inhibitors (SSRIs) or selective serotonin-noradrenaline reuptake inhibitors (SNRIs) poses a risk of serotonin syndrome. Monitoring patients on this combination for signs of serotonin syndrome is essential. Additionally, triptan medications have the potential to lower the seizure threshold.

Ditans

Lasmiditan, a 5-hydroxytryptamine_1F receptor agonist, is available in doses of 50 mg or 100 mg. The dosage may be increased to 100 or 200 mg, but patients should not exceed 1 dose in 24 hours. A significant adverse effect of lasmiditan is dizziness. Patients should refrain from engaging in potentially hazardous activities or driving a motor vehicle for at least 8 hours after each dose. Additional adverse effects include nausea, fatigue, and paresthesia.[25] Ditans do not induce vasoconstriction, making them a suitable option for patients with cardiovascular risks.(A1)

Antiemetics

Antiemetics such as metoclopramide, chlorpromazine, and prochlorperazine are commonly utilized as adjunctive therapy alongside NSAIDs or triptans to alleviate nausea and vomiting, especially in the emergency department. Diphenhydramine may be administered to prevent dystonic reactions primarily associated with metoclopramide use.

Calcitonin gene-related peptide antagonists

Small molecule antagonists, or gepants, are oral agents proven effective for acute migraine treatment. Though more commonly used as a prophylactic therapy, some formulations are effective for abortive use. Rimegepant, administered as a single 75 mg dose, and ubrogepant are among the available options. CGRP antagonists are helpful for patients who do not respond to conventional therapy or those with coronary artery disease.[26] Rimegepant has approval for both acute and preventative treatment.[27] Zavegepant offers an intranasal option.

Rimegepant use should be avoided in patients with recent cardiovascular or cerebrovascular ischemic events. Nausea, dysgeusia, and drowsiness are the primary adverse effects associated with CGRP antagonists. Dose adjustments may be necessary for patients with renal and hepatic impairment, while use should be avoided entirely in patients with severe renal or hepatic impairment. The concurrent use of a CGRP antagonist with a triptan or ergotamine within 2 to 4 hours has not been established.

Ergots

Ergots bind to 5-HT_1B/1D receptors and act as vasoconstrictors by inhibiting dural plasma extravasation following trigeminal ganglion stimulation in rats and may centrally block the trigeminovascular pathway. The oral bioavailability of ergotamine is very poor. Ergots are effective via intravenous (IV), intramuscular (IM), subcutaneous, and intranasal routes. Dihydroergotamine has demonstrated efficacy in treating acute migraine attacks and serving as a bridge therapy for medication overuse headaches and status migrainosus. Nevertheless, further research is required to establish the full effectiveness of ergotamine.

Ergotamine is contraindicated in patients with severe hepatic or renal impairment, hypertension, ischemic heart disease, as well as pregnancy or breastfeeding. Additionally, it should not be used within 24 hours of triptans or ergot-like agents.

Dexamethasone

For patients experiencing severe or prolonged migraines, administering 4 mg of intravenous dexamethasone in combination with an abortive medication can be beneficial. This combination therapy helps reduce the risk of early headache recurrence. However, it does not immediately relieve headaches.[28][29] Oral corticosteroids are not effective for treating acute migraines.(B3)

Peripheral nerve blocking 

Nerve blocks targeting the occipital nerve, sphenopalatine ganglion, and trigeminal nerve occipital plexus offer an additional treatment option for migraines.[30][31] Contraindications include known allergies to local anesthetics, open skull defects, and overlying skin infections. Pregnancy is considered a relative contraindication for this procedure.(B3)

Migraine Treatment in the Emergency Setting

The management of patients presenting to an emergency room with severe migraine headaches associated with nausea and vomiting involves:

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

Adding dexamethasone to the treatment regimen for patients receiving the above therapies is recommended to reduce the risk of early headache recurrence. This adjunctive therapy can help improve the overall efficacy of migraine management in the emergency room setting.

Opioids and Barbiturates

The use of opiates and barbiturates for acute migraine treatment should be reserved as a last resort. Opiates are generally less effective than migraine-specific medications, and there is no evidence supporting the efficacy of barbiturates, such as butalbital-containing substances, in acute migraine treatment. Moreover, opioids and barbiturates are associated with an increased risk of chronic migraine and medication overuse headaches.

Prophylactic Therapy

Indications for prophylactic therapy

• Migraine frequency >2 per month
• Duration of individual attacks >24 hours
• Headaches causing major disruptions in the patient's lifestyle, with significant disability lasting ≥3 days
• Failure or overuse of abortive therapy
• Symptomatic medications are contraindicated or ineffective
• Use of abortive medications >2 times per week
• Hemiplegic migraine or rare headache attacks that produce a profound risk of permanent neurologic injury [32] 
(A1)

Prophylactic medications begin at low doses and are gradually titrated until the patient achieves the desired therapeutic benefit. The choice of preventative medication can take into account any comorbid conditions. Administration of any prophylactic medication will generally result in a 50% reduction in headache frequency. 

Beta-blockers

It is advisable to avoid initiating beta-blockers as initial therapy in patients older than 60 and those who smoke. When prescribed for hypertension, beta-blockers may be associated with a higher incidence of stroke and other adverse cardiovascular outcomes. Exercise caution when using beta-blockers in patients with asthma, erectile dysfunction, bradycardia, and peripheral vascular disease. Commonly utilized agents include:

• Propranolol in 2 divided doses starting at 40 mg/d; dose range is 40 to 240 mg/d
• Metoprolol in 2 divided doses starting at 50 mg/d; dose range is 50 to 200 mg/d 
• Nadolol starts at 20 mg/d; the dose ranges from 20 to 240 mg once daily
• Atenolol starts at 25 mg/d; the dose ranges from 25 to 100 mg once daily

Angiotensin-converting enzyme inhibitors and angiotensin II receptor blockers 

Small studies indicate that angiotensin-converting enzyme inhibitors like lisinopril and angiotensin II receptor blockers like candesartan may reduce the incidence of migraine. However, due to the limited size of these studies, further investigation is required to determine the efficacy of these medications as prophylaxis for migraine.

Antidepressants

• Amitriptyline beginning at 10 mg at bedtime with the range being 20 mg to 100 mg/d
• Venlafaxine starting at 37.5 mg once a day with the dose ranging from 75 to 150 mg/d 

Common adverse effects associated with amitriptyline, a tricyclic antidepressant, include dry mouth, constipation, tachycardia, palpitations, orthostatic hypotension, weight gain, blurred vision, and urinary retention. Confusion is a concern in older adults. Tricyclic antidepressants can be fatal in cases of overdose and should be avoided in patients at increased risk of suicide. Additionally, antidepressants increase the risk of suicidality in children and young adults, necessitating careful monitoring for the emergence of exacerbation of suicidal thoughts or behaviors in patients undergoing antidepressant treatment. 

Anticonvulsants 

• Valproate at doses between 500 to 1500 mg
• Topiramate beginning at 25mg/d and increasing by 25 to 50 mg/wk to a maximum dose of 100 mg twice a day

Paresthesia is the most common adverse effect of topiramate. Doses greater than 100 mg/d may alter the effects of oral contraceptive medications.

Calcium Channel Blockers

Despite their use, conflicting evidence exists regarding the efficacy of calcium channel blockers (CCBs) like verapamil or flunarizine.[33] Tolerance may develop with CCBs. 

• Verapamil starts at 120 mg/d and is divided into 3 doses ranging from 120 to 240 mg.  

Severe left ventricular dysfunction, hypotension, cardiogenic shock, and sick sinus syndrome are all contraindications to the use of CCBs.

Calcitonin gene-related peptide antagonists

CGRP antagonists are reasonable options for patients who are unresponsive to the above options. They are available in parenteral, large molecules monoclonal antibodies targeting the CGRP receptor and oral small-molecule antagonists.

• Eptinezumab dosed 100 to 300 mg IV infusion once every 3 months
• Fremanezumab dosed 225 mg subcutaneously once monthly or 675 mg once every 3 months
• Atogepant 10, 30, or 60 mg orally once daily
• Rimegepant 75 mg orally every other day for prevention and 75 mg once daily for acute treatment

Studies indicate that a trial of 3 to 6 months may be necessary to evaluate the full effect of some preventative medications. Avoid valproate in women of childbearing age and topiramate during pregnancy. 

Additional Treatment Options

Some other treatment agents are mentioned below. However, more trials are needed to authenticate their recommendation.

• Injection of botulinum neurotoxin A (BoNT-A)
  • Effective in chronic refractory migraines [34]
  • Not recommended for preventive treatment of episodic migraine [35]
• Coenzyme Q10 (CoQ10) [36]
• Riboflavin [37]
• Magnesium [38]
  • The usual dose is 400 to 600 mg daily for migraine prevention
  • Gastrointestinal discomfort and diarrhea are the most common side effects
• Feverfew
• Melatonin [39]
• Simvastatin plus vitamin D [40]
(A1)

Differential Diagnosis

The differential diagnoses for migraine include:

• Tension-type headache
• Cluster headache
• Transient ischemic attack (TIA)
• Syncope
• Vestibular disorders
• Headache due to other secondary causes like trauma and intracranial lesions
• Cervical artery dissection

A tension-type headache typically manifests bilaterally, with patients describing a sensation of pressure or tightness around the head that fluctuates over time. Unlike migraine headaches, individuals with tension-type headaches generally do not present with photophobia, nausea, or vomiting. The pain associated with tension-type headaches is severe and reaches a crescendo within minutes. Symptoms observed in cluster headaches include ipsilateral redness and lacrimation of the eye, rhinorrhea, nasal congestion, sweating, and responsiveness to oxygen therapy. 

The gradual onset, followed by complete resolution, aids in distinguishing migraine aura from ischemic events such as TIA. Additionally, patients experiencing a TIA are less likely to exhibit positive aura symptoms like visual scintillations or paresthesias, along with associated symptoms such as photophobia, phonophobia, nausea, and vomiting.

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

Though relatively benign, migraine can significantly affect patients' quality of life. Migraine is a chronic condition that tends to diminish in frequency and severity with age. Menstrual migraine tends to improve after menopause. Incorporating lifestyle changes, including meal schedules and good sleep hygiene, improves overall prognosis.

Complications

The complications of migraine include the following:

• Status migrainosus: Status migrainosus is a debilitating migraine attack lasting more than 72 hours. Some patients with status migrainosus require hospitalization due to the intensity of the pain.

• Migrainous infarction or stroke: Migrainous infarction, or stroke associated with migraine, presents a higher risk in patients with migraine accompanied by aura. This condition entails a migraine attack with aura symptoms lasting over an hour, coupled with infarction visible on neuroimaging. Risk factors commonly observed in patients under 45 include patent foramen ovale, female gender, and oral contraceptive use. Any history of migraine is associated with a higher incidence of significant cardiovascular disease. Patients experiencing migraine with aura have a 2.3-fold increased risk of cardiovascular death, while those with migraine without aura exhibit a risk equivalent to the general population. The reported incidence of stroke due to migraine (migrainous stroke) ranges from 0.8 to 3.4 per 100,000 individuals annually.

• Persistent aura without infarction: Aura lasting longer than 1 week after the headache has ended is considered persistent aura without infarction. Symptoms may resemble migrainous infarction, but neuroimaging does not show infarction.

• Migraine-aura triggered seizure: A seizure triggered by migraine with aura, generally occurring within 1 hour. 

• Psychiatric disorders: Some patients with migraine headaches are at an increased risk of developing psychiatric disorders such as major depressive disorder, bipolar disorder, or posttraumatic stress disorder.