I. What every physician needs to know

Migraine is derived from the Greek word ‘hemi-kranion’, which literally means half skull. It is classically described as a unilateral headache even though unilateral symptoms are experienced in 59% of the patients. Migraine affects approximately 28 million Americans and 1 in 4 women will experience migraine in her lifetime.

Migraine can generate a high degree of disability. According to the American Migraine Prevalence and Prevention (AAMP) study, only 7% of patients are reported as being able to function normally during a severe headache. The Migraine Disability Assessment (MIDAS) grade assessment showed that over a third of patients experience some degree of disability.


The exact mechanism of how a migraine is triggered is still not fully understood. Improvement in modern technology such as positron emission tomography (PET), functional magnetic resonance imaging (MRI) studies, genetic engineering and identification of genetic predisposition, understanding of neurotransmitters, and role of presence of serotonin secreting neurons concentrated in the brainstem raphe and its projections have provided better understanding in managing these patients.

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Research to date suggests that the initiation of a migraine attack is a primary neuronal phenomenon with activation of trigeminal nerve afferents controlling pain signals with subsequent hemodynamic consequences. Defects in mitochondrial oxidative phosphorylation associated with alteration in neuronal voltage gated channelopathies may lead to hyper-excitability and spontaneous depolarization of neurons containing 5-hydroxytriptamine (5-HT) and Calcitonin gene related peptide (CGRP). Release of 5-hydroxytriptamine (5-HT) also known as serotonin constricts large arteries and dilates arterioles and capillaries. The 5-hydroxytriptamine (5-HT)-containing neurons in the brainstem interconnected with trigeminal tracts in several subcortical centers including the ventroposterior medial nucleus of the thalamus, the reticular formation of the brain stem, and the limbic system, may explain genesis of pain and associated response. Furthermore, the disparate symptoms of nausea, osmophobia (sensitivity to smell), photophobia, and phonophobia may point to an abnormality of processing sensory input during an attack leading to normal stimuli causing pain.

Genetics may play a role in the predisposition of some patients to have migraines. Prevalence of a family history of migraine was recognized as early as the 17th century. There is no clear inheritance pattern except for the rare autosomal dominant type of familial hemiplegic migraine (FHM). FHM is associated with mutations in three genes:

  • CACNA1A located in chromosome 19p13 encodes P/Q type calcium channels

  • ATP1A2 in chromosome 1q21-23 encodes Na-K ATP ace channels

  • SCN1A with mutation in the sodium channel


According to the International Headache Society 2013 guidelines, migraine can be classified as the following:

1.1 Migraine without aura

1.2 Migraine with aura

1.2.1 Migraine with typical aura Typical aura with headache Typical aura without headache

1.2.2 Migraine with brainstem aura

1.2.3 Hemiplegic migraine Familial hemiplegic migraine (FHM) Familial hemiplegic migraine type 1 (FHM1) Familial hemiplegic migraine type 2 (FHM2) Familial hemiplegic migraine type 3 (FHM3) Familial hemiplegic migraine, other loci Sporadic hemiplegic migraine

1.2.4 Retinal migraine

1.3 Chronic migraine

1.4 Complications of migraine

1.4.1 Status migrainosus

1.4.2 Persistent aura without infarction

1.4.3 Migrainous infarction

1.4.4 Migraine aura-triggered seizure

1.5 Probable migraine

1.5.1 Probable migraine without aura

1.5.2 Probable migraine with aura

1.6 Episodic syndromes that may be associated with migraine

1.6.1 Recurrent gastrointestinal disturbance Cyclical vomiting syndrome Abdominal migraine

1.6.2 Benign paroxysmal vertigo

1.6.3 Benign paroxysmal torticollis

II. Diagnostic Confirmation: Are you sure your patient has migraine?

A. History Part I: Pattern Recognition

Migraine occurs in an episodic fashion and classically follows the stages of prodrome, aura, headache, and postdrome.

Prodrome occurs 24 to 48 hours before the onset of headache and may be experienced as mood swings, alteration in bowel habits, craving for sweets, and increased yawning.

Aura is experienced in 30% of patients up to 60 minutes prior to onset of headache and is commonly described as a shimmering arc of white or colored lights in lateral visual fields (scintillating scotoma) commonly followed by zone of vision loss (negative scotoma). Sensory symptoms such as paresthesia and numbness are also described. A slower rate of spread of sensory aura distinguishes migraine from seizures or transient ischemic attacks (TIA). Motor symptoms and aphasia are rare.

Migraine headaches are usually, but not always, unilateral, pounding or throbbing (pulsatile) in nature, and associated with photophobia, phonophobia, nausea, and/or vomiting. They are usually aggravated by physical activity and relieved by rest. Symptoms are improved by lying down in a dark and quiet room facing away from the light source. Other associated symptoms include osmophobia (sensitivity to smell), blurred vision, light-headedness, and diarrhea. Untreated headaches usually last longer than 4 hours but resolve within 72 hours.

In the postdrome phase the patient feels drained or exhausted, with mild elation or euphoria.

Cutaneous allodynia is the perception of pain and tenderness of the skin and scalp provoked by simple touch, combing, or shaving. The patient may have difficulty lying on the allodynic side. It occurs during the headache phase and triptans are less effective once allodynia has developed.

Migraine attacks are usually triggered by emotional stress, menstruation, visual stimuli, weather changes, fasting, odor, chocolate, wine, and sleep disturbance.

B. History Part 2: Prevalence

Migraine can begin at any age but most commonly begins during adolescence. Other serious intracranial pathology may mimic migraine and alternative diagnosis should be considered for new onset of migraine headache after the forties. Female to male ratio is approximately 3:1 with a slight Caucasian preponderance.

C. History Part 3: Competing diagnoses that can mimic migraine

Migraine variants

Basilar migraine presents with predominant brain stem symptoms such as dysarthria, vertigo, tinnitus, hyperacusia, diplopia, visual symptoms, ataxia, decreased level of consciousness, and bilateral paraesthesia. Symptoms usually resolve within 10-15 minutes and are followed by a typical migraine headache.

Retinal migraine, another rare form of migraine, presents with unilateral scotoma or blindness, which usually resolves within an hour, and is followed by headache. Permanent visual loss is reported in up to 43% of the patients with recurrent attacks.

Migraine aura without headache may present in elderly patients with a previous history of migraine and mimics a transient ischemic attack. It is a benign condition but can be diagnosed after ruling out other possible intracranial events such as TIA and seizures. This is a diagnosis of exclusion.

Ophthalmoplegic migraine usually presents as a prolonged headache followed by diplopia and signs of extranuclear ophthalmoplegia (usually third cranial nerve palsy).

Ophthalmoplegic migraine mimics the subarachnoid hemorrhage of berry aneurysm of a posterior communicating artery, especially for adult onset headache with no prior history.

Migraine infarction may occur in a patient with a new ischemic stroke and migraine-like symptoms. This mostly occurs in the posterior circulation and in young women.

Other causes of headache

Tension or muscle contraction headache alone or in combination with a vascular component is most often confused with common migraine. Careful physical examination is essential for every patient with severe headache, searching for any focal neurological deficit such as mild pronator drift, asymmetry of reflexes and mild hypoesthesia to suspect possible intracranial diseases.

Subarachnoid hemorrhage may present in patients with a sudden onset of a severe headache, lasting less than one hour (often seconds). It is often described as “the worst headache of my life”.

Benign intracranial hypertension (pseudotumor cerebri) can present with abrupt headache with nausea vomiting, dizziness blurred vision, and papilledema. The headache is often positional.

Malignant hypertension can present as a headache with severely elevated BP: systolic BP >210 or diastolic BP >120. The patient may also have altered mental status or encephalopathy.

Giant cell arteritis should be considered in elderly patients with unilateral headache with visual symptoms. It is usually associated with high erythrocyte sedimentation rate (ESR). Troost and Newton (1975) determined that the characteristic visual phenomena represent occipital epilepsy, and the non-alternating, unilateral character of the headache, as well as the history of a seizure, always distinguished these vascular malformations from migraine.

Carotid dissection can present with headache after minor trauma or sudden neck movement. The patient may have unilateral face pain and Horner’s syndrome on affected side.

D. Physical Examination Findings

Normal physical examination is the rule; however, careful physical examination is essential for every patient with severe headache, searching for any focal neurological deficit such as mild pronator drift, asymmetry of reflexes and mild hypoesthesia to suspect possible intracranial diseases.

E. What diagnostic tests should be performed?

Diagnosis of migraine is based on the clinical criteria listed above.

1. What laboratory studies (if any) should be ordered to help establish the diagnosis? How should the results be interpreted?

Routine basic metabolic panel is helpful in the presence of severe nausea and vomiting. Erythrocyte sedimentation rate (ESR) is indicated if giant cell arteritis is suspected.

2. What imaging studies (if any) should be ordered to help establish the diagnosis? How should the results be interpreted?

Neuroimaging is not routinely performed. Indications for imaging include new onset of severe headache after 50 years of age; presence of altered mental state such as drowsiness, confusion, loss of consciousness, memory impairment; and presence of focal neurological deficits, asymmetry papillary response, neck stiffness, and papilledema.

F. Over-utilized or “wasted” diagnostic tests associated with this diagnosis

There is no routine laboratory or neuroimaging study for the management of acute migraine.

III. Default Management

The goals of care are:

  • Reduce the attack frequency, severity and disability

  • Reduced reliance on medication; improve quality of life

  • Avoid medication escalation

  • Educate patient to enhance personal control of migraine

  • Reduce headache related distress and psychological symptoms

A. Immediate management

Educate the patient about prodrome, warning symptoms and early use of abortive therapy. This can shorten the duration of migraine and avoid overuse of acute medication more than 10 days per month and may prevent the development of chronic daily headache.

Non-steroidal anti-inflammatory drugs (NSAIDs) are the first line therapy for mild to moderate attacks because of proven efficacy at low cost. Aspirin, indomethacin, ibuprofen, naproxen, and diclofenac are popular choices. Always consider switching the drug if symptom control is not optimal. All NSAIDs should be avoided in patients with active gastritis, history of gastrointestinal bleeds, peptic ulcer disease, renal insufficiency, and thrombocytopenia.

Migraine-specific agents such as triptans, dihydroergotamine (DHE) and ergotamine are indicated for severe headache and for those who respond poorly to NSAIDs.

Triptans are selective 5-hydroxytriptamine (5-HT 1B/1D) receptor agonists which may act directly on serotonin enriched dorsal raphe and periaqaductal gray matter of the midbrain and cause vasoconstriction, peripheral neuronal inhibition and inhibit both trigeminal afferent and second order neurons of the trigeminocervical complex.

There are numerous triptans that can be given by oral, nasal and subcutaneous formulation. For full list of commercially available triptans please see Table I.

Table 1.

Commercially available triptans.

Triptans are effective and relatively safe for the acute treatment of migraine in patients who have no contraindications otherwise. Triptans should be avoided in patients with FHM, basilar migraine, ischemic stroke, ischemic heart disease, Prinzmetal angina, uncontrolled hypertension, and pregnancy.

The most common side effects are dizziness, fatigue, nausea, and somnolence. Intranasal and SQ routes are preferred for patients with nausea and vomiting. Triptans are less effective in patients with cutaneous allodynia.

For patients with severe symptoms who are unable to take triptans, DHE 45 injection (dihydroergotamine)is an alpha-adrenergic blocker and potent vasoconstrictor that can be given parenterally and by the intranasal route. Efficacy is superior if it is given in combination with an antiemetic (metoclopramide). However, DHE are contraindicated in the setting of coronary artery disease.

Antiemetics such as metoclopramide, chlorpromazine and prochlorperazine can be given as monotherapy in mild to moderate symptoms but can be more effective if combined with other treatments such as NSAIDs and triptans.

Steroids have been shown to be an effective adjunctive therapy for acute migraine. A single dose of parenteral dexamethasone in combination with other abortive therapy is associated with a 26% relative reduction (number needed to treat: 9) within 72 hours. However, repeated and routine use should be avoided since potential side effects may outweigh the benefits.

B. Physical Examination Tips to Guide Management

Presence of cutaneous allodynia is the point against using triptans to abort the headache.

C. Laboratory Tests to Monitor Response to, and Adjustments in, Management.


D. Long-term management

The best treatment is prevention and avoidance of trigger factors such as stress, specific foods that contain tyramine such as aged cheese, smoked fish, artificial sweeteners, chocolate, citrus fruits, monosodium glutamate (MSG), nitrates in cured and processed meats (hot dogs and preserved cold cuts), nuts, peanut butter, and salty foods. Reduction of excessive caffeine intake, reducing alcohol intake and scheduling for adequate rest may be useful.

E. Common Pitfalls and Side-Effects of Management

Excessive and over prescribed use of over the counter pain relievers may lead to chronic daily headache also known as transformed migraine.

Use of opioid analgesics is effective in the quick relief of symptoms but should be reserved for severe and unresolved headache since there is a risk for drug dependency and tolerance.

IV. Management with Co-Morbidities

A. Renal Insufficiency

NSAIDs may produce nephrotoxicity, fluid and electrolytes abnormalities such as hyperkalemia, hyponatremia and fluid retention and worsen the underlying chronic kidney disease.

B. Liver Insufficiency

Acetaminophen should be used with caution in patients with known liver pathology.

C. Systolic and Diastolic Heart Failure

NSAIDs may increase afterload and worsen both systolic and diastolic heart failure.

D. Coronary Artery Disease or Peripheral Vascular Disease

Increased risk of cardiovascular events has been well recognized with prolonged used of both cyclooxygenase-1 and -2 (COX-1/COX-2) inhibitors.

E. Diabetes or other Endocrine issues

No change in standard management.

F. Malignancy

No change in standard management.

G. Immunosuppression (HIV, chronic steroids, etc.)

Migraine and human immunodeficiency virus (HIV) infection may coexist and a change in the pattern of headache is key to look for alternative diagnosis.

H. Primary Lung Disease (COPD, Asthma, ILD)

A worsening of headache in chronic obstructive pulmonary disease (COPD) patients may be attributed to hypercapnia and arterial blood gas (ABG) checks should always be carried out when doubtful.

I. Gastrointestinal or Nutrition Issues

NSAIDs are contraindicated in active gastritis and gastrointestinal bleeders.

J. Hematologic or Coagulation Issues

NSAIDs should be avoided in patients with pre-existing platelet dysfunction and severe thrombocytopenia (platelet count less than 50,000/mcl).

K. Dementia or Psychiatric Illness/Treatment

No change in standard management.

V. Transitions of Care

A. Sign-out considerations While Hospitalized

Order a neuroimaging and neurology consult if new symptoms of weakness and numbness develop.

B. Anticipated Length of Stay

Two to three days for uncomplicated cases.

C. When is the Patient Ready for Discharge?

Improved symptoms with absence of nausea and vomiting.

D. Arranging for Clinic Follow-up

Follow-up with primary care as well as neurology/headache clinic in 2-4 weeks.

1. When should clinic follow up be arranged and with whom?

Follow-up with primary care as well as neurology/headache clinic in 2-4 weeks.

2. What tests should be conducted prior to discharge to enable best clinic first visit?


3. What tests should be ordered as an outpatient prior to, or on the day of, the clinic visit?


E. Placement Considerations

Home with self-care.

F. Prognosis and Patient Counseling

Complete recovery is the rule.

VI. Patient Safety and Quality Measures

A. Core Indicator Standards and Documentation


B. Appropriate Prophylaxis and Other Measures to Prevent Readmission

Pharmacoprophylaxis is indicated in the following situations:

  • Recurrent headache interferes with patient’s routine

  • There is contraindication to or failure or overuse of acute therapy

  • An adverse event occurs with acute therapy

  • There is presence of uncommon conditions such as hemiplegic migraine, basilar migraine, migraine with prolonged aura, and migrainous infarction.

Several pharmacological therapies have been used over the decades and proven to be beneficial over placebos including antiepileptics, antidepressants, beta-blockers, calcium channel blockers, NSAIDs, serotonin antagonist, feverfew, magnesium, and vitamin B2. Sodium valproate, amitriptyline, propranolol, timolol, methysergide (serotonin agonist) and vitamin B2 have been well studied with proven efficacy and infrequent side effect profile.

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