Migraine Headache – Causes, Symptoms. Treatment

Migraine Headache/Migraine is a genetically influenced complex disorder characterized by episodes of moderate-to-severe headache, most often unilateral and generally associated with nausea and light and sound sensitivity. This activity reviews the evaluation and treatment of migraines and highlights the role of the interprofessional team in evaluating and treating patients with this condition.

Migraine is a genetically influenced complex disorder characterized by episodes of moderate-to-severe headache, most often unilateral and generally associated with nausea and increased sensitivity to light and sound. The word migraine is derived from the Greek word “hemicrania” that later was converted into Latin as “emigrants.” The French translation of such a term is “migraine.”[rx] Migraine is a common cause of disability and loss of work. Migraine attacks are a complex brain event that unfolds over hours to days, in a recurrent matter. The most common type of migraine is without aura (75% of cases).

Types of Migraine Headache

Migraine can be classified in subtypes, according to the headache classification committee of the International Headache Society:[rx]

• Migraine without aura is a recurrent headache attack of 4 to 72 hours; typically unilateral in location, pulsating in quality, moderate to severe in intensity, aggravated by physical activity, and associated with nausea and light and sound sensitivity (photophobia and phonophobia).
• Migraine with aura has recurrent fully reversible attacks, lasting minutes, of typically one or more of these unilateral symptoms: visual, sensory, speech and language, motor, brainstem, and retinal, usually followed by headache and migraine symptoms.
• Chronic migraine is a headache that occurs on 15 or more days in a month for more than three months and has migraine features on at least eight or more days in a month.
• Complications of migraine

  • Status migrainosus is a debilitating migraine attack that lasts more than 72 hours.
  • Persistent aura without infarction is an aura that persists for more than one week without evidence of infarction on neuroimaging.
  • Migrainous infarction is one or more aura symptoms associated with brain ischemia on neuroimaging during a typical migraine attack
  • Migraine aura-triggered seizure occurs during an attack of migraine with aura, and a seizure is triggered

• Probable migraine is an asymptomatic migraine attack that lacks one of the features required to fulfill criteria for one of the above and does not meet the criteria for another type of headache.
• Episodic syndromes that may be associated with migraine

  • Recurrent gastrointestinal disturbances are recurrent attacks of abdominal pain and discomfort, nausea and vomiting, that may be associated with migraines.
  • Benign paroxysmal vertigo has brief recurrent attacks of vertigo.
  • Benign paroxysmal torticollis is recurrent episodes of head tilt to one side.

Causes of Migraine Headache

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 there has not been any pattern of inheritance identified.[rx][rx] 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.[rx] The identification of these genes in an individual with migraines could predict the targeted prophylactic treatment.

Familial Hemiplegic Migraine

• Hemiplegic migraine can occur in families or sporadically (one individual, as the first member of the family to have a hemiplegic migraine).[rx] Channelopathies cause the primary three types:
• Type 1 is caused by mutations in the CACNA1A gene (calcium voltage-gated channel alpha 1A subunit) on chromosome 19p13.[rx]
• Type 2 is caused by mutations in the ATP1A2 gene (ATPase, Na+/K+ transporting alpha 2 subunit) on chromosome 1q23.[rx]
• Type 3 is caused by mutations in the SCN1A gene (sodium voltage-gated channel Type 1 alpha subunit).
• Mutations in the PRRT2 (Proline-Rich transmembrane 2) gene is recognized as a possible cause.[rx] PRRT2 gene encodes a protein that interacts with the SNAP25 (synaptosomal nerve-associated protein 25), which may pose a role in voltage-gated calcium channel regulation.[rx]
• Mutations in the SLC4A4 (solute carrier family 4 member 4) gene have also been associated with familial forms of migraine.[rx]

MELAS – Melas is a syndrome of mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes a multisystemic disorder by maternal inheritance that can present recurrent migraine headaches.[rx]

CADASIL – Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy) angiopathy by autosomal dominant inheritance, caused by mutations in the NOTCH3 gene (notch receptor 3) on chromosome 19, that can present migraine with aura (prodrome in 80%) in nearly 50% of carriers.[rx]

RVCL – Retinal vasculopathy with cerebral leukodystrophy is angiopathy by C-terminal frame-shift mutations in TREX1 (three prime repair exonuclease 1) presents almost 60% of the cases.[rx]

HIHRATL – Hereditary infantile hemiparesis, retinal arteriolar tortuosity, and leukoencephalopathy

HERNS – Hereditary epitheliopathy with retinopathy, nephropathy, and stroke

Triggers

Withdrawn or exposed to several factors contribute to the development of migraine headaches.[rx] A retrospective study found that 76% of the patients reported triggers.[rx] Some of them are probable factors that contribute, while others are only possible or unproven factors.

• Stress in 80% (probable factor)
• Hormonal changes in 65% during menstruation, ovulation, and pregnancy (probable factor)
• Skipped meals 57% (probable factor)
• Weather changes in 53% (probable factor)
• Excessive or insufficient sleep in 50% (possible factor)
• Odors in 40% (perfumes, colognes, petroleum distillates)
• Neck pain in 38%
• Exposure to lights in 38% (probable factor)
• Alcohol ingestion in 38% (wine as a probable factor)
• Smoking in 36% (unproven factor)
• Late sleeping in 32%
• Heat in 30%
• Food in 27% (aspartame as a possible factor, and tyramine and chocolate as unproven factors)
• Exercise in 22%
• Sexual activity in 5%

Pathophysiology

At first, there was a vascular theory of migraine, which explained that the headache was produced by vasodilation and aura by vasoconstriction, but this theory is not viable anymore.[rx] Nowadays, the suggestions pose that multiple primary neuronal impairments lead to a series of intracranial and extracranial changes that cause migraines.[rx]

The cortical spreading depression of Leão, a propagating wave of neuronal and glial depolarization that initiates a cascade, is hypothesized to cause the aura, activate trigeminal afferents, and alter the hematoencephalic barrier permeability by activating brain matrix metalloproteinases.[rx] In migraine without aura, the suggestions are that cortical depression may occur in areas where depolarization is not consciously perceived, such as the cerebellum.[rx] There is activation of trigeminal afferents by neuronal pannexin-1 mega channel opening and subsequent activation of Caspase-1, followed by the release of proinflammatory mediators, activation of NF-kB (nuclear factor kappa-B), and spreading of this inflammatory signal to trigeminal nerve fibers around vessels of the pia mater.[rx] This causes a series of cortical, meningeal, and brainstem events, provoking inflammation in the pain-sensitive meninges that concludes in headache through central and peripheral mechanisms.[rx][rx] This pathway can, therefore, explain the cortical depression (which establishes the aura) and the latter prolonged activation of trigeminal nociception (which leads to headache).

The anterior structures are most innervated by the ophthalmic division of the trigeminal nerve, which could explain the pain in the anterior region of the head. There is a convergence of fibers from the upper cervical roots which originate the trigeminal nerve neurons along with the trigeminal ganglion and the trigeminal nerve at the trigeminal nucleus caudalis which can explain the anterior to the posterior distribution of pain, from where the fibers ascend to the thalamus and the sensory cortex.[rx]

Neurogenic inflammation, which is based on vasodilation, edema, and plasma protein extravasation, results from nociceptor activation; in this case, the trigeminal system. It is associated with the release of substance P, calcitonin gene-related peptide, and neurokinin a; all vasoactive neuropeptides liberated by trigeminal ganglion stimulation.[rx] Elevated levels of these neuropeptides have been found in the spinal fluid of chronic migraine patients.[rx][rx] Neurogenic inflammation can lead to sensitization, which is the process in which neurons tend to become more responsive to stimulation. This can explain some clinical symptoms of the pain and the conversion from episodic migraine to a chronic one.[rx]

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. 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.[rx][rx]

Calcitonin gene-related peptide is abundant in trigeminal ganglion neurons. It is released from the peripheral nerve and central nerve terminals as well as secreted within the trigeminal ganglion. When released from the peripheral terminals, it initiates an increased synthesis of nitric oxide and latter sensitization of trigeminal nerves.[rx][rx] It is a strong vasodilator of cerebral and dura mater vessels, therefore a component of neurogenic inflammation, and it also mediates trigeminal pain transmission from vessels to the central nervous system.

Diagnosis of

Migraine attacks occur through four phases:[rx]

• Prodrome: premonitory symptoms associated with hypothalamus activation (dopamine)[rx][rx]
  • Around 77% of patients suffer prodromic symptoms up to 24 to 48 hours before headache onset. It is more common in females than males (81% to 64%).
  • Frequent symptoms are yawning (34%), mood change, lethargy, neck symptoms, light sensitivity, restlessness, difficulties in focusing vision, feeling cold, craving, sound sensitivity, sweating, excess energy, thirst, edema
• Aura: changes in cortical function, blood circulation, and neurovascular integration. It occurs in about 25% of the cases.[rx][rx][rx][rx]
  • It can precede the headache, or it can present simultaneously.
  • They are typically gradual, with less than 60 minutes of duration, more often visual, and have positive and negative symptoms.
    • Positive symptoms are caused by active release from central nervous system neurons (bright lines or shapes, tinnitus, noises, paresthesias, allodynia, or rhythmic movements).
    • Negative symptoms point out a lack or loss of function (reduction or loss of vision, hearing, sensation, or motion).
  • They have to be fully reversible.
  • Visual auras are the most frequent ones.
    • The most common positive visual symptom is the scintillating scotoma (an area of absent vision with shimmering or glittering zigzag border).
    • The most common negative visual symptom is the visual field defects.
  • Sensory auras are also common. They can follow visual symptoms or occur without them.
    • It usually consists of tingling sensations on one side of the face or a limb. They are considered as paresthesias.
  • Language auras are not frequent. They consist of a transient dysphasia.
  • Motor auras are rare. They consist of complete or partial hemiplegia that can involve limbs and face.
• Headache: additional changes in blood circulation and function of the brainstem, thalamus, hypothalamus, and cortex.
  • Often unilateral, generally with a pulsatile or throbbing feature and increasing intensity within the first hours.
  • The intensity can correlate to nausea, vomiting, photophobia, phonophobia, rhinorrhea, lachrymation, allodynia, and osmophobia.
  • It can take place over hours to days.
  • Patients may have to seek relief in dark places, as the pain usually resolves in sleep.
• Postdrome: persistent blood changes with symptoms after headache termination.
  • This phase consists of a movement-vulnerable pain in the same location as the previous headache.
  • Common symptoms can be exhaustion, dizziness, difficulty concentrating, and euphoria.

Evaluation

The diagnosis of migraine is based on patient history, physical examination, and fulfillment of the diagnostic criteria. 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 the pain?
• How long does the pain last?
• In which moment 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?

The International Classification of Headache Disorders (ICHD-3) describes these diagnostic criteria.[rx]

B1. Migraine without aura:

• B1a. Headache attacks lasting 4 to 72 hours (untreated or unsuccessfully treated)
• B1b. Headache has at least two of the following characteristics:Unilateral location
• Pulsating quality
• Moderate or severe pain intensity
• Aggravation by or causing avoidance of routine physical activity (walking or climbing stairs)

B1c. During headache at least one of the following:

• Nausea and vomiting
• Photophobia and phonophobia

B2. Migraine with aura:

B2a. One or more of the following fully reversible aura symptoms:

• Visual
• Sensory
• Speech and language
• Motor
• Brainstem
• Retinal

B2b. At least two of the following characteristics:

• At least one aura symptom spreads gradually over ≥5 minutes
• Two or more aura symptoms occur in succession
• Each aura symptom lasts 5 to 60 minutes
• At least one aura symptom is unilateral
• At least one aura symptom is positive
• The aura is accompanied, or followed within 60 minutes, by a headache

C. On eight days or more per month for more than three months, fulfilling any of the following:

• Criteria B1b and B1c for migraine without aura
• Criteria B2a and B2b for migraine with aura
• It is believed by the patient to be migraine at onset and relieved by a triptan or ergot derivative

D. Not better accounted for by another ICHD-3 diagnosis

The ICHD-3 criteria for migraine without aura are

• At least five attacks fulfilling criteria B to D (see below)
• Headache attacks that last 4 to 72 hours, untreated or unsuccessfully treated
• Headache that has at least two of the following criteria:

  • Unilateral location
  • Pulsating quality
  • Moderate to severe pain intensity.
  • Aggravation by or causing avoidance of routine physical activity (as walking or climbing stairs)
• During headache at least one of the following:

  • Nausea, vomiting, or both
  • Photophobia and phonophobia
• Not better accounted for by another ICHD-3 diagnosis

 The ICHD-3 criteria for migraine with aura are

• At least two attacks fulfilling criteria B to D
• One or more of the following fully reversible aura symptoms:

  • Visual
  • Sensory
  • Speech and language
  • Motor
  • Brainstem
  • Retinal
• At least three of the following six characters:

  • At least one aura symptom spreads gradually over ≥5 minutes
  • Two or more symptoms occur in succession
  • Each aura symptom lasts 5 to 60 minutes
  • At least one aura symptom is unilateral
  • At least one aura symptom is positive
  • The aura is accompanied, or followed within 60 minutes, by a headache
• It is not better accounted for by another ICHD-3 diagnosis
• Hemiplegic migraine is diagnosed when the aura consists of motor weakness.
• Migraine with brainstem aura (previously known as basilar artery migraine or basilar migraine) is diagnosed if the aura symptoms emerge from the brainstem (bilateral hemianopic visual disturbance, diplopia, vertigo, ataxia, dysarthria, tinnitus, hyperacusis, bilateral paresthesia, or numbness)
• Retinal migraine is diagnosed when the aura involves a monocular visual field defect.

The ICHD-3 criteria for chronic migraine are

• Headache (tension-type-like or migraine-like) on 15 or more days per month for more than three months and fulfilling criteria B and C
• It is occurring in a patient who has had at least five attacks fulfilling the following criteria for migraine without aura (B1) or migraine with aura (B2)

Neuroimaging (computed tomographic scan, magnetic resonance imaging, magnetic resonance angiography, or magnetic resonance venography) is indicated in the following cases:[rx][rx]

• Acute severe headache, especially if it is the first or worst episode (to discard subarachnoid hemorrhage).
• Abnormal neurologic examination, especially if there are unexplained symptoms or signs (confusion, stiff neck, papilledema, epilepsy).
• Non-typical characteristics.
• Changes in the patient’s typical features or patterns
• Resistance to treatment.
• New episodes in older (>50 years of age) or immunosuppressed patients.
• Systemic or meningeal signs or symptoms (fever, weight loss, fatigue)

The commonly used acronym “SNOOP” can be used to aid in the determination of neuroimaging indications:

• “S” for systemic signs or symptoms, and secondary risk factors
• “N” for neurologic signs or symptoms
• “O” for onset
• “O” for older
• “P” for position-dependent intensity changes, prior pattern changes, papilledema, and precipitated by Valsalva maneuvers.

Cerebrospinal fluid analysis and electroencephalogram are not typically performed unless seizure activity of infectious etiology has to be excluded.

Treatment

Treatment options are based on the onset scenarios: acute or chronic.

• Acute or Abortive treatment: 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. For that reason, parenteral medication could be the rule for some patients, especially the ones with nausea or vomiting. Therapy consists of stratified options:[rx][rx][rx]

  • NSAIDs (nonsteroidal anti-inflammatory drugs): ibuprofen, naproxen, diclofenac, aspirin, or acetaminophen. Usually in mild to moderate attacks without nausea or vomiting.
  • Triptans (the first-line in patients with allodynia): sumatriptan, eletriptan, rizatriptan, almotriptan. With or without naproxen for moderate to severe attacks.

    • Triptans should be limited to less than ten days of use within a month to avoid medication overuse.
    • 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.
  • 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: rimegepant, ubrogepant. It could be considered in patients that don’t respond to conventional treatment or in those with coronary artery disease.[rx]
  • Ergots: ergotamine and dihydroergotamine, being this last one the only one 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.
  • Dexamethasone can reduce the recurrence of early headaches, but doesn’t provide immediate relief of headache.[rx][rx]
  • Transcutaneous supraorbital nerve stimulation can reduce intensity.[rx]
  • 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.[rx][rx][rx]
  • Nonpainful remote electric neurostimulation could be considered as a first-line treatment in some patients.[rx][rx]
  • Peripheral nerve blocking (occipital plexus and sphenopalatine ganglion).[rx][rx]
• Prophylactic or preventive treatment: preventive treatment aims to reduce attack frequency, and improve responsiveness to acute attacks severity and duration, and reduce disability.[rx][rx] Migraine triggers have to be documented by each individual to reduce them in the future.

  • Indications for preventive treatment are:

    • Frequent or long-lasting headaches
    • Attacks that cause significant disability and reduced quality of life
    • Contraindication or failure to acute therapies
    • Significant adverse effects of abortive therapies
    • Risk of medication overuse headache
    • Menstrual migraine (along with short-term premenstrual prophylaxis)
    • Hemiplegic migraine
    • Brainstem aura migraine
    • Persistent aura without infarction
    • Migrainous infarction
  • Preventive treatment agents are the following:

    • Beta-blockers: metoprolol and propranolol. Especially in hypertensive and non-smoker patients.
    • Antidepressants: amitriptyline and venlafaxine. Especially in patients with depression or anxiety disorders, and insomnia.
    • Anticonvulsants: valproate acid and topiramate. Especially in epileptic patients.
    • Calcium channel blockers: verapamil and flunarizine. Especially in women of childbearing age or patients with Raynaud’s phenomenon.
    • Calcitonin gene-related peptide antagonists: erenumab, fremanezumab, and galcanezumab.
• Alternative treatment:

  • Changes in lifestyle; must be a commitment from the patient; however, social support is of great importance to improve mental health to help the patient’s involvement.
  • Regular exercise
  • Yoga
  • Relaxation training
  • Cognitive-behavioral therapy
  • Biofeedback
  • Reduction of triggers
  • Detoxification
  • Butterbur
  • Melatonin

• https://www.ncbi.nlm.nih.gov/books/NBK560787/
• https://www.ncbi.nlm.nih.gov/books/NBK279373/
• https://www.ncbi.nlm.nih.gov/books/NBK377/
• https://www.ncbi.nlm.nih.gov/books/NBK544241/
• https://www.ncbi.nlm.nih.gov/books/NBK559083/
• https://www.ncbi.nlm.nih.gov/books/NBK562274/
• https://www.ncbi.nlm.nih.gov/books/NBK554611/
• https://www.ncbi.nlm.nih.gov/books/NBK557813/
• https://www.ncbi.nlm.nih.gov/books/NBK507862/
• https://www.ncbi.nlm.nih.gov/books/NBK544079/
• https://www.ncbi.nlm.nih.gov/books/NBK540991/
• https://www.ncbi.nlm.nih.gov/books/NBK557598/
• https://www.ncbi.nlm.nih.gov/books/NBK556134/
• https://www.ncbi.nlm.nih.gov/books/NBK507271/
• https://www.ncbi.nlm.nih.gov/books/NBK507725/
• https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4590146/