bubble_chart Overview

Migraine is a type of periodic disorder with a familial predisposition. It manifests as episodic, unilateral, throbbing headaches accompanied by nausea, vomiting, and photophobia, recurring after intervals of remission. The headache is alleviated in a quiet, dark environment or after sleep. Neurological or psychiatric dysfunction may occur before or during the headache episode.

bubble_chart Etiology

The cause of the disease is unclear, with about 50% of patients having a family history. Female patients with migraine tend to experience attacks before menstruation, and the frequency decreases after pregnancy, suggesting that the onset may be related to endocrine changes or water retention. Factors such as mental stress, excessive fatigue, sudden climate changes, bright light stimulation, prolonged sun exposure, hypoglycemia, the use of vasodilators or reserpine, and the consumption of high-tyramine foods or alcoholic beverages can all trigger migraine attacks.

The mechanisms by which these triggers induce migraine attacks can generally be explained by the vascular and neurogenic theories. Wolff et al. used the vascular theory to explain the clinical manifestations of migraine. In typical migraines, intracranial artery constriction occurs first, leading to reduced local cerebral blood flow, which causes aura symptoms such as visual changes, paresthesia, or mild hemiplegia. This is followed by the dilation of intracranial and extracranial arteries, resulting in headache.

Observations conducted by various institutions using different methods on migraine patients during attacks have failed to identify a consistent relationship between intracranial vascular changes and headaches. During a migraine attack in a craniotomy patient, Goltman observed intracranial vasodilation. Thie et al., in a cerebral angiogram of a typical migraine attack stage, found that the diameters of all stirred pulses were relatively small, while Olson et al. observed no changes in cerebral angiograms of 11 typical migraine attacks. Lauritzen et al. used ¹³³

Xe-SPECT to observe 12 cases of common migraine attacks and found no abnormalities in rCBF. In 11 cases of typical migraine attacks, 8 showed a 17% average reduction in rCBF in the hemisphere corresponding to the aura symptoms compared to the contralateral region, persisting for 4–6 hours during the headache phase. No brain regions with increased rCBF were observed. Examinations during the interictal period revealed no abnormalities in either type of migraine, except for one case with a small hypoperfusion area in the insula. Andersen et al. used ¹³³Xe-SPECT to observe rCBF after the onset of migraine attacks: 3 cases showed no abnormalities, 2 had only localized hypoperfusion, and 7 typical migraines exhibited a 19% reduction in rCBF in the posterior hemisphere corresponding to the aura symptoms when headaches appeared. When the headache was mild or the pulsating headache disappeared, hyperperfusion occurred, with rCBF increasing by an average of 19% compared to the contralateral side, and in 2 cases, the hyperperfusion lasted for 24 hours. Olsen et al. induced typical migraines by injecting ¹³³Xe into the cervical stirred pulse and, using a 254-probe gamma camera, found that posterior CBF could decrease by up to 20 ml/(100g·min), with localized hypoperfusion persisting for several hours after the aura symptoms disappeared. Olesen et al. measured rCBF throughout the entire course of typical migraine attacks and observed pre-existing hypoperfusion in the occipital region before the attack, with rCBF decreasing by an average of 25–30% and gradually extending forward to the frontal region, lasting for the entire 4–6 hours of the headache phase. Kobari et al. used ¹³³Xe-enhanced CT to measure local cerebral blood flow (1CBF): all 10 cases in the remission stage were normal. In 6 cases of common migraine and 6 cases of typical migraine, within 30 minutes to 8 hours after the onset of the attack, when the aura symptoms had disappeared but headaches were present, bilateral 1CBF generally increased, exceeding the remission stage by 25–35%, most notably in the frontal and temporal cortices and thalamus, with no significant difference in the occipital region. There was no distinction between the two types of migraine. Qin Zhen et al. used transcranial Doppler (TCD) to examine 10 common migraine patients and found that during the headache remission stage, most patients exhibited abnormally increased blood flow velocity in bilateral or individual cranial base stirred pulses. In 5 migraine attacks across 3 cases, all showed abnormally increased cerebral blood flow velocity and broad-spectrum noise. Thie et al. observed similar findings in TCD examinations of one typical migraine and one migraine equivalent attack. Qin Zhen et al. performed ^99mTc-SPECT examinations on 2 common migraine cases and found hypoperfusion in the posterior parietal cortex and temporal lobe, respectively.

Therefore, during a migraine attack, a significant proportion of patients may exhibit reduced or increased cerebral blood flow, or an initial reduction followed by an increase, abnormally accelerated cerebral blood flow velocity, and dilation or narrowing of cerebral blood vessels. However, these changes do not consistently correlate with the type of headache, aura, or headache onset. Some changes are more pronounced in the posterior head region, while others are more prominent in the anterior head region. The abnormal findings reported by the same author are not observed in all patients of the same category, and some patients exhibit localized hypoperfusion areas or accelerated cerebral blood flow velocity even during headache-free intervals. In summary, the relationship between migraine and cerebrovascular dysfunction remains to be further elucidated.

During a migraine attack, a series of generation and transformation changes also occur. In the aura phase, plasma serotonin (5-HT) levels may transiently increase; during headache onset, the urinary metabolite of 5-HT, 5-hydroxyindoleacetic acid (5-HIAA), may significantly rise. This suggests that plasma 5-HT is rapidly degraded and excreted in urine. 5-HT has a biphasic effect on smooth muscle: a decrease in plasma 5-HT causes contraction of small stirred pulses and dilation of larger stirred pulses. The contraction of small stirred pulses leads to cerebral ischemia, resulting in aura or other neurological symptoms, while the dilation of large stirred pulses causes headache. Some 5-HT fistula disease leaks into the extracellular fluid surrounding blood vessels, where it, along with neuropeptides such as histamine, bradykinin, and vasorelaxin, lowers the pain threshold of the vessel wall and induces "sterile inflammation" in stirred pulses. Vascular dilation combined with "sterile inflammation" produces the clinical symptoms of migraine. 5-HT is primarily stored in platelets. When platelet aggregation increases or 5-HT release factors are present, the platelet 5-HT content suddenly drops, coinciding with clinical onset. Certain drugs (e.g., reserpine) can release and deplete 5-HT, triggering headache attacks in migraine patients; 5-HT blockers (e.g., dihydroergotamine, pizotifen) are used to prevent migraine attacks. The decreased activity of monoamine oxidase (MAO) during the headache stage of attack may be related to the substantial consumption of MAO during 5-HT degradation.

Many experiments have confirmed that platelets in migraine patients are more prone to aggregation than those in healthy individuals. After aggregation, platelets release substances such as 5-HT, ADP, histamine, adrenaline, noradrenaline, arachidonic acid (AA), and thromboxane A₂ (TXA₂), which further promote platelet aggregation. This interaction generates large amounts of black catechu phenolamines, AA, and TXA₂, which have potent vasoconstrictive effects and reduce cerebral blood flow. Prostaglandin E₁ can induce headaches in individuals without migraines. Estrogen increases prostaglandin synthesis, and some women taking high-estrogen contraceptives may experience migraine attacks.

However, why do widespread systemic vascular regulatory dysfunction and numerous generation and transformation changes only cause head pain? Why are most headache attacks unilateral? And why do they sometimes alternate sides?

The neurogenic theory posits that the origin of migraine lies in the central nervous system, with endocrine changes and vasomotor disturbances being secondary phenomena—that is, the vascular findings in migraine are secondary to a "release" from the neural center. The various complex symptoms of migraine are the result of dysfunction in the cerebral cortex, possibly due to a lowered excitation threshold in the hypothalamus/diencephalon, leading to headache attacks.

Neurons containing norepinephrine and 5-HT innervate certain cranial blood vessels, with their cell bodies located in the locus coeruleus and raphe nuclei of the brainstem. Mental stress, anxiety, fatigue, or other factors can lead to increased excitation of brainstem neurons and enhanced neurotransmitter release, causing alterations in cranial vascular motility, cerebral ischemia, and "sterile inflammation" of blood vessels. This stimulates nociceptors in the trigeminal nerve endings within the vessels, transmitting pain signals to the brain. Additionally, trigeminal nerve endings can release vasoactive substances (vasodilatory and disease-related peptides, such as substance P) into larger intracranial and extracranial blood vessels.

bubble_chart Clinical Manifestations

According to the International Headache Classification and Diagnostic Criteria established by the International Headache Society in 1988, combined with clinical practice in China, the following is summarized as follows.

(1) Migraine without aura (common migraine) is the most common. Episodic grade II to grade III throbbing headache, accompanied by nausea, vomiting, or photophobia. Physical activity exacerbates the headache. At the onset, it is only a mild to grade II dull pain or discomfort, which develops into severe throbbing or pulsating pain within minutes to hours. About two-thirds are unilateral headaches, but they can also be bilateral, sometimes radiating to the upper neck and shoulders. The headache lasts 4 to 72 hours and often resolves after sleep. There are clear normal intervals between episodes. If 90% of the attacks are closely related to the menstrual cycle, it is called menstrual migraine. A diagnosis can only be made after at least five such episodes and the exclusion of various intracranial and extracranial organic diseases.

(2) Migraine with aura (classic migraine) can be divided into two phases: aura and headache.

1. Aura phase: Visual symptoms are the most common, such as photophobia, flashes or sparks in the visual field, or complex visual hallucinations, followed by visual field defects, scotomas, hemianopia, or transient blindness. A few patients may experience hemilateral numbness, grade I hemiplegia, or speech impairment. The aura mostly lasts 5 to 20 minutes.

2. Headache phase: Often begins as the aura starts to subside. The pain usually starts in one supraorbital, retroorbital, or frontotemporal region, gradually intensifying and spreading to one side of the head, or even the entire head and neck. The headache is throbbing, pulsating, or drilling in nature, progressively worsening into continuous severe pain. It is often accompanied by nausea, vomiting, photophobia, and phonophobia. Some patients experience facial flushing, profuse sweating, and conjunctival congestion; others may have pale complexion, lethargy, and anorexia. An episode can last 1 to 3 days, with the headache usually significantly relieved after sleep, but fatigue may persist for several days afterward. The interictal period is entirely normal. The above classic migraine can be divided into several subtypes:

(1) Migraine with typical aura: Includes ocular migraine, hemiplegic migraine, aphasic migraine, etc. The diagnosis can only be established after at least two such typical episodes and the exclusion of organic diseases.

(2) Migraine with prolonged aura (complicated migraine): Symptoms are the same as (1). The aura persists during the headache attack, lasting more than 1 hour but less than 1 week. Neuroimaging does not reveal any intracranial structural lesions.

(3) Basilar-type migraine (formerly known as basilar artery migraine): Has clear aura symptoms originating from the brainstem or bilateral occipital lobes, such as blindness, visual symptoms affecting both temporal and nasal fields, dysarthria, vertigo, tinnitus, hearing loss, diplopia, ataxia, bilateral paresthesia, bilateral mild paralysis, or confusion. These symptoms usually disappear within minutes to an hour, followed by bilateral occipital throbbing headache. The interictal period is entirely normal.

(4) Migraine aura without headache (migraine equivalent): Presents with various aura symptoms seen in migraine attacks, but sometimes no headache follows. As patients age, the headache may completely disappear while episodic aura symptoms persist, but cases with only aura symptoms and no headache are rare. For those with their first episode after age 40, thorough examination is needed to exclude thromboembolic TIA.

(3) Ophthalmoplegic migraine: Extremely rare. Most cases occur before the age of 30. There is a history of fixed unilateral headache attacks, and after a particularly severe headache (orbital or retroorbital pain), ipsilateral ophthalmoplegia occurs, with ptosis being the most common. The paralysis lasts for days or weeks before resolving. In the initial episodes, the paralysis fully recovers, but after multiple attacks, partial ophthalmoplegia may remain. Neuroimaging does not exclude intracranial organic lesions.

(4) Benign paroxysmal vertigo of childhood (migraine equivalent) has a family history of migraine but the child themselves do not experience headaches. It manifests as multiple, brief episodes of vertigo, and may also present with paroxysmal imbalance, anxiety, accompanied by nystagmus or vomiting. Neurological examinations and EEG results are normal. The interictal period shows no abnormalities. Some children may develop migraine in adulthood.

(5) Status migrainosus Migraine attacks lasting more than 72 hours (with possible remission stages shorter than 4 hours in between) are referred to as status migrainosus.

bubble_chart Diagnosis

A history of recurrent headaches with normal intervals, normal physical examination, and a family history of migraine makes diagnosis straightforward. Those with focal neurological signs require exclusion of organic diseases. Ocular muscle paralysis may be caused by a pulsating tumor, and arteriovenous malformations can also accompany migraines. Cranial CT scans or cerebral angiography should be performed for a definitive diagnosis. Complex migraines are often caused by organic diseases and require neuroimaging studies. Occipital or temporal lobe tumors in the initial stage may present with visual field defects or other visual symptoms, but as the condition progresses, symptoms of increased intracranial pressure may eventually appear. In elderly individuals with temporal or occipital headaches, temporal arteritis must be ruled out. The superficial temporal or occipital arteries may become thickened like ropes, with significantly weakened or absent pulsations. A biopsy of the artery reveals characteristic multinucleated giant cell infiltration.

bubble_chart Treatment Measures

The goal of treatment is not only to relieve the symptoms of acute headache episodes but also to prevent or reduce the recurrence of headaches as much as possible. Various triggering factors should be avoided. Drug therapy, psychotherapy, acupuncture, and qigong are effective for some patients.

**(1) Treatment of Acute Episodes** Rest in a quiet, dimly lit room. Mild cases can be treated with general analgesics and sedatives (such as aspirin, ibuprofen, etc.), which often provide relief. For headaches accompanied by nausea and vomiting, metoclopramide can be used.

Ergotamine is effective for some patients. It acts as an agonist for 5-HT receptors and also has direct vasoconstrictive effects. It primarily activates the 5-HT_1A receptor but also affects dopamine and adrenergic receptors, leading to significant side effects. The commonly used ergotamine-caffeine tablet (each containing 100mg caffeine and 1mg ergotamine) should be taken immediately at the onset of aura or dull pain, 1–2 tablets per dose. To avoid ergot poisoning, the single dose should not exceed 4 tablets, and the weekly total should not exceed 8 tablets. Alternatively, ergotamine tartrate 0.25–0.5mg can be administered subcutaneously or intramuscularly. Overdose of ergotamine may cause nausea, vomiting, abdominal pain, muscle pain, peripheral vasospasm, ischemia, and other side effects. It is contraindicated in patients with severe cardiovascular, hepatic, or renal diseases, as well as in pregnant women. It is also unsuitable for hemiplegic, ophthalmoplegic, and basilar-type migraines.

Sumatriptan is a 5-HT_1D receptor agonist with highly selective effects on cerebral blood vessels. Adults can take 100mg orally, with headache relief beginning within 30 minutes and optimal efficacy achieved after 4 hours. Subcutaneous injection of 6mg (adult dose) acts quickly, and symptoms can be retreated with another 6mg injection within 24 hours if they recur. Side effects are mild, including transient systemic warmth, dry mouth, head pressure, and joint pain. Occasionally, chest tightness, chest pain, or palpitations may occur.

For status migrainosus and severe migraines, chlorpromazine (1mg/kg) can be administered orally or intramuscularly, or ACTH 50 units can be given intravenously (in 500ml glucose solution). Alternatively, prednisone 10mg can be taken orally three times daily. For prolonged episodes, appropriate fluid replacement should be provided to correct typical edema and electrolyte imbalances.

**(2) Preventive Treatment** Patients experiencing headaches 2–3 times or more per month should consider long-term prophylactic drug therapy. These medications must be taken daily and require at least 2 weeks to take effect. If effective, treatment should continue for 6 months before gradually tapering off.

1. **Propranolol** A β-adrenergic receptor blocker, effective in about 50–70% of patients, reducing the frequency of attacks by more than half in one-third of cases. The usual dose is 10–40mg, three times daily. Side effects are minimal, and gradual dose escalation can reduce adverse reactions such as nausea, ataxia, and painful limb spasms.

2. **Pizotifen (Sandomigran)** A 5-HT antagonist with additional antihistamine, anticholinergic, and antibradykinin effects. The typical dose is 0.5mg once daily, gradually increasing to three times daily. After 4–6 months of continuous treatment, 80% of patients experience improvement or cessation of headaches. Side effects include drowsiness and fatigue, and it may increase appetite, leading to weight gain with long-term use.

3. **Methysergide** A 5-HT antagonist, primarily blocking the 5-HT₂ receptor. Treatment should start with a low dose (0.5–1mg/day), gradually increasing to 1–2mg twice daily over a week. Side effects include nausea, vomiting, vertigo, and drowsiness. Long-term use may cause retroperitoneal or pleuropulmonary fibrosis. Continuous use for 6 months must be followed by a 1-month break. It should only be considered for the most refractory cases.

4. Calcium channel blockers: Nimodipine and flunarizine (Sibelium) are commonly used. The usual dose of nimodipine is 20-40mg, three times daily. The drugs have minor side effects, which may include dizziness, headache, nausea, vomiting, insomnia, or skin allergies.

5. Sodium valproate 100～400mg, three times daily.

6. Amitriptyline is a tricyclic antidepressant that inhibits the reuptake of 5-HT. It is commonly used for depression and chronic pain management, and is effective for migraine accompanied by tension headache. The usual dose is 75～150mg/day.

7. Clonidine inhibits the vasomotor center and has hypotensive effects. It has a weak prophylactic effect on migraine but causes minimal side effects at low doses. The usual dose is 0.078mg～0.15mg, two to three times daily.