Migraine is the most frequent debilitating main headache all over the world. Typical signs of an attack include a unilateral throbbing headache and other symptoms such as nausea, multisensory hypersensitivity, and extreme fatigue.

What Migraine Headache?

Migraine is a genetically driven complicated illness characterized by bouts of moderate-to-severe headache, most of which are unilateral and are frequently accompanied by nausea and heightened sensitivity to light and sound. The term migraine comes from the Greek word "hemikrania," which was then translated into Latin as "hemigranea."

The French word for such a condition is "migraine." Migraine is a leading cause of disability and job loss. Migraine episodes are a complicated brain event that occurs on a recurring basis and can last from hours to days. The most frequent form of migraine is one that does not have an aura (75 %).

Migraine types

Migraine can be classified into subtypes, according to the headache classification committee of the International Headache Society: 

• Migraine without aura is a recurring headache attack lasting 4 to 72 hours that is generally unilateral in site, pulsing in nature, moderate to severe in severity, worsened by physical activity, and associated with nausea, light and sound sensitivity, and other symptoms (photophobia and phonophobia).
• Migraine with aura. Migraine with aura is characterized by recurring completely reversible attacks that last minutes and include one or more of the following unilateral symptoms: visual, sensory, speech and language, motor, brainstem, and retinal symptoms, which are generally followed by headache and migraine symptoms. 
• Chronic migraine. Chronic migraine is defined as a headache that occurs 15 or more days per month for more than three months and has migraine symptoms on at least eight days per month.
• Complications of migraine

1. Status migrainosus is characterized by a severe migraine attack that lasts more than 72 hours.
2. Persistent aura without infarction is an aura that persists for more than one week without evidence of infarction on neuroimaging.
3. Migrainous infarction is defined as one or more aura symptoms linked with brain ischemia on neuroimaging during a normal migraine episode.
4. Migraine aura-triggered seizure happens when a migraine episode with aura triggers a seizure.

• A probable migraine attack is defined as a symptomatic migraine attack that lacks one of the characteristics necessary to meet the criteria for one of the above and does not match the criteria for another form of headache.
• Episodic syndromes that may be associated with migraine

1. Recurrent gastrointestinal disturbances 
2. Benign paroxysmal vertigo has brief recurrent attacks of vertigo.
3. Benign paroxysmal torticollis is recurrent episodes of head tilt to one side.

Epidemiology 

Migraine is quite common, affecting 12% of the population and impacting up to 17% of women and 6% of men each year. North America has the greatest adjusted prevalence of migraine, followed by South America, Central America, Europe, Asia, and Africa. It is the world's second leading cause of disability.

Migraine is a condition that runs in families. It is typically the fourth or fifth most prevalent reason for emergency visits, accounting for 3% of all emergency visits on a yearly basis. Its prevalence rises after puberty but continues to rise until the age of 35 to 39 before declining later in life, particularly after menopause.

Migraine causes

Genetics and Inheritance

Migraine is strongly influenced by genetics. The incidence of migraines in unwell relatives is three times higher than in non-ill relatives, although no pattern of inheritance has been observed. The genetic basis of migraine is complex, and it is unknown which loci and genes are involved in the pathogenesis; it could be based on more than one genetic source at different genomic locations acting in tandem with environmental factors to bring susceptibility and disease characteristics in such individuals. The discovery of these genes in a migraine sufferer might lead to focused preventive therapy.

Familial Hemiplegic Migraine

Hemiplegic migraine can develop in families or on its own (one individual, as the first member of the family to have a hemiplegic migraine).

• Melas

Melas is a syndrome characterized by mitochondrial encephalomyopathy, lactic acidosis, and stroke-like symptoms. A multisystemic disease inherited from the mother that can cause recurring migraine headaches.

• Cadasil

Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy) angiopathy caused by mutations in the NOTCH3 gene (notch receptor 3) on chromosome 19 that can show migraine with aura (prodrome in 80% of carriers) in almost 50% of carriers.

• Hihratl

1. Hereditary infantile hemiparesis,
2. retinal arteriolar tortuosity, and
3. leukoencephalopathy

• Herns

1. Hereditary endotheliopathy 
2. retinopathy,
3. nephropathy, and
4. stroke

Triggers

Several variables, both withdrawn and exposed, contribute to the development of migraine headaches. According to a retrospective research, 76 percent of patients identified triggers. Some of them are likely contributors, whilst others are merely potential or untested.

• Stress in 80% of cases
• Hormonal changes in 65% during menstruation, ovulation, and pregnancy 
• Skipped meals 57%
• Weather changes in 53% 
• Excessive or insufficient sleep in 50% 
• Odors in 40% (perfumes, colognes, petroleum distillates)
• Neck pain in 38%
• Exposure to lights in 38% 
• Alcohol ingestion in 38% 
• Smoking in 36% 
• Late sleeping 
• Heat 
• Food 
• Sexual activity in 5%

Migraine food triggers

• Sourdough bread, bagels, doughnuts, and coffee cake are examples of yeast-based baked foods.
• Chocolate.
• Dairy products with a culture (like yogurt and kefir)
• Citrus fruits, dried fruits, bananas, raspberries, red plums, papayas, passion fruit, figs, dates, and avocados are all examples of fruits or juices.

Pathophysiology

There was formerly a vascular hypothesis of migraine that described how the headache was caused by vasodilation and the aura by vasoconstriction, however this idea is no longer valid. Currently, it is proposed that numerous primary neuronal abnormalities result in a succession of intracranial and extracranial alterations that produce migraines.

It is thought that the cortical spreading depression of Leo, a propagating wave of neuronal and glial depolarization that begins a cascade, causes the aura, activates trigeminal afferents, and changes the hematoencephalic barrier permeability by activating brain matrix metalloproteinases.

Cortical depression may occur in regions where depolarization is not consciously experienced, such as the cerebellum, in migraine without aura. Trigeminal afferents are activated by neuronal pannexin-1 megachannel opening and subsequent Caspase-1 activation, which is followed by the release of proinflammatory mediators, activation of NF-kB (nuclear factor kappa-B), and spread of this inflammatory signal to trigeminal nerve fibers around pia mater vessels.

This sets off a chain of cortical, meningeal, and brainstem processes that induce inflammation in the pain-sensitive meninges, resulting in headaches via central and peripheral pathways. As a result, this route can explain both the cerebral depression (which causes the aura) and the subsequent prolonged activation of trigeminal nociception (which leads to headache).

The ophthalmic division of the trigeminal nerve innervates the anterior tissues the most, which might explain discomfort in the anterior region of the head. There is a convergence of fibers from the upper cervical roots that originate the trigeminal nerve neurons, as well as the trigeminal ganglion and the trigeminal nerve, at the trigeminal nucleus caudalis, which can explain the anterior to posterior distribution of pain, from where the fibers ascend to the thalamus and the sensory cortex.

Neurogenic inflammation, characterized by vasodilation, edema, and plasma protein extravasation, is caused by nociceptor activation, namely of the trigeminal system. It is linked to the production of vasoactive neuropeptides substance P, calcitonin gene-related peptide, and neurokinin a, all of which are released by trigeminal ganglion activation. 

These neuropeptides have been discovered in high concentrations in the spinal fluid of chronic migraine sufferers. Sensitization is the process through which neurons become more sensitive to stimulation as a result of neurogenic inflammation. This may explain certain clinical signs of pain as well as the transition from episodic to chronic migraine.

Serotonin, which is produced by the brainstem serotonergic nuclei, may have a role in migraine; however, the precise function of its processes is unknown. Most likely, serotonin levels are low between attacks because it may create a deficit in the serotonin pain inhibition mechanism, allowing the trigeminal system to be activated.

It might operate directly on cranial arteries, in central pain control pathways, or via cortical projections of brainstem serotonergic nuclei.

The peptide derived from the calcitonin gene is prevalent in trigeminal ganglion neurons. It is secreted within the trigeminal ganglion and released from peripheral nerve and central nerve terminals.

When it is released from the peripheral terminals, it causes an increase in nitric oxide production and, later, trigeminal nerve sensitization. It is a potent vasodilator of cerebral and dura mater vessels and therefore a component of neurogenic inflammation; it also modulates trigeminal pain transmission from vessels to the central nervous system.

Migraine Botox

Botox is only authorized by the FDA for persistent migraines, which occur 15 or more days per month. Botox is injected around the pain fibers that cause headaches. Botox penetrates the nerve terminals around the injection site and inhibits the release of molecules involved in pain transmission. This inhibits pain networks in the brain from activating.

Migraine symptoms

Migraine attacks occur through four phases: 

• Prodrome: premonitory symptoms linked to hypothalamic stimulation (dopamine)

1. Up to 24 to 48 hours before the beginning of the headache, around 77 percent of patients experience prodromic symptoms. Females are more likely to be affected than males (81 to 64 percent ).
2. Yawning (34 percent), mood change, lethargy, neck symptoms, light sensitivity, restlessness, difficulty concentrating vision, feeling chilly, hunger, sound sensitivity, perspiration, excess energy, thirst, and edema are the most common symptoms.

• Aura: alterations in brain function, blood circulation, and neurovascular integration. It happens in around 25% of the cases.

1. It can precede the headache, or present simultaneously.
2. They are usually gradual, last less than 60 minutes, are mostly visual, and feature both pleasant and negative sensations.

• Positive symptoms are generated by the active discharge of neurons in the central nervous system (bright lines or shapes, tinnitus, noises, paresthesias, allodynia, or rhythmic movements).

1. The most common positive visual symptom is the scintillating scotoma (an area of absent vision with a shimmering or glittering zigzag border).

• Negative symptoms imply a loss or lack of function (reduction or loss of vision, hearing, sensation, or motion).

1. They have to be fully reversible.
2. Visual auras are the most frequent ones.
3. The most common negative visual symptom is the visual field defects.
4. Sensory auras are also common. They can follow visual symptoms or occur without them.

• Headache

1. Unilateral, with a pulsatile or throbbing characteristic and rising severity within the first several hours.
2. Nausea, vomiting, photophobia, phonophobia, rhinorrhea, lachrymation, allodynia, and osmophobia can all be associated with varying degrees of intensity.
3. It might happen in a matter of hours or days.
4. Patients may have to seek respite in dark locations since the pain generally goes away while they sleep.

• Postdrome: persistent blood changes with symptoms after headache termination.

1. This phase consists of a movement-vulnerable pain in the same location as the previous headache.
2. Common symptoms include: exhaustion, dizziness, difficulty concentrating, and euphoria.

Migraine diagnosis

Migraine is diagnosed based on the patient's history, physical examination, and fulfillment of the diagnostic criteria. Migraine is a clinical condition. A thorough history and physical examination are required to make a diagnosis.

Following are certain criteria specified by the International Classification of Headache Disorders, 3rd edition (ICHD-3), which can help in diagnosing migraine with aura: 

• A. At least 2 attacks that fulfill criteria B and C
• B. One or more of the following aura symptoms that are reversible:

Visual, retinal, sensory, brainstem, motor, speech, or language

• C. At least 3 of the 6 characteristics below:

1. At least 1 aura symptom that spreads gradually over greater than 5 minutes
2. 2 or more symptoms in succession
3. At least 1 unilateral aura symptom
4. At least 1 positive aura symptom
5. Each aura symptom lasting 5 to 60 minutes
6. Aura accompanied by or followed by headache within 60 minutes

• D. No other ICHD-3 diagnosis accounting for the symptoms

There is no test to diagnose migraines. Most patients do not require neuroimaging. Neuroimaging may be recommended in the following circumstances:

• Sudden severe headache
• New neurological symptom or sign on examination
• Headache not responding to treatment
• New-onset headache greater than 50 years of age
• Change in frequency, pattern, or severity of headaches
• New-onset headache in patients with HIV infection or cancer
• Associated symptoms or signs suggestive of meningitis or stroke

Management

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

Acute or Abortive treatment

The goal of acute therapy is to halt the progression of a headache. It must be treated as soon as possible and with a high single dosage. In migraine patients with stomach stasis, oral medications may be ineffective. As a result, parenteral medicine may be the only option for certain individuals, particularly those suffering from nausea or vomiting. Therapy is divided into several categories:

• NSAIDs (nonsteroidal anti-inflammatory drugs): ibuprofen, naproxen, diclofenac, aspirin, or acetaminophen. For 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.

1. Triptans should be limited to less than ten days of use within a month to avoid medication overuse.
2. There are recommendations against using it in individuals with ischemic stroke, ischemic heart disease, poorly managed hypertension, angina, pregnancy, hemiplegic or basilar migraine due to the activation of the 5-HT(1B) and 5-HT(1D) receptors on coronary arteries and brain vessels.
3. Because of the danger of serotonin syndrome, it is advised that patients take selective serotonin reuptake inhibitors or selective serotonin-noradrenaline reuptake inhibitors and have their medication monitored.

• Metoclopramide, chlorpromazine, and prochlorperazine are antiemetics that can be used. They are typically used in conjunction with NSAIDs or triptans to reduce nausea and vomiting, particularly in the emergency room. To avoid dystonic responses, diphenhydramine can be added (mostly with metoclopramide).
• Calcitonin-gene-related peptide antagonists: Rimegepant and ubrogepant are being evaluated for individuals who have not responded to standard therapy or who have coronary artery disease.
• Ergots: ergotamine and dihydroergotamine, recommended for acute attacks as a parenteral administration, and effective as bridge therapy for medication overuse headache and status migrainosus. Ergotamine hasn't shown much efficacy yet, and it can have serious adverse effects.
• Dexamethasone does not provide immediate relief but can reduce the recurrence of early headaches. 
• Transcutaneous supraorbital nerve stimulation can reduce intensity. 
• Transcranial magnetic stimulation has been shown to be an effective second-line therapy with no significant adverse effects. It can also be provided as a treatment option for persistent migraines. It is not recommended for people who have epilepsy.
• Electric neurostimulation could be considered as a first-line treatment in some patients. 
• Peripheral nerve blocking (occipital plexus and sphenopalatine ganglion). 

Prophylactic or Preventive Treatment

Preventive therapy attempts to minimize attack frequency, enhance response to the severity and length of acute episodes, and reduce impairment. Migraine triggers must be documented by each individual in order to be reduced 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
• 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

Migraine Prevention 

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 

• Lifestyle change requires the patient's commitment; nevertheless, social support is critical to improving mental health and assisting the patient's engagement.
• Regular exercise
• Yoga
• Relaxation training
• Cognitive-behavioral therapy
• Biofeedback
• Reduction of triggers
• Detoxification
• Butterbur
• Melatonin

Differential Diagnosis

The following should be considered in a patient with migraine:

• Tension-type headache
• Cluster headache
• Cerebral aneurysms
• Chronic paroxysmal hemicrania
• Dissection syndromes
• Encephalitis
• Subarachnoid/intracranial hemorrhage
• Meningitis
• Temporal/giant cell arteritis

Tension headaches are generally bilateral and last from 30 minutes to 7 days. The patient feels pressure or tightness yet continues to move around. There are no accompanying symptoms.

Cluster headaches are unilateral and began abruptly around the eye or temple. Within minutes, the intensity increases to severe constant deep agony. It might last anything from 15 minutes to 3 hours. Lacrimation and redness of the eye, rhinorrhea, pallor, sweating, Horner syndrome, agitation, and focal neurologic symptoms are all associated symptoms. It is readily triggered by alcohol.

Prognosis

Migraine is a chronic disease that might return to episodic migraine in between 26 and 70% of individuals. Prolonged remissions are typical; nevertheless, some individuals have a tendency to leave and return to chronic conditions. With age, the severity and frequency of episodes might lessen. Episodes rise with adolescence but continue to rise until the age of 35 to 39, then fall later in life, especially after menopause.

Complications of migraine

• Seizures
• Brain infarction
• Work disability
• Loss of work

Conclusion

Migraine is the largest cause of disability in the globe. Migraines affect around 15% of the population in the United States. Most migraine sufferers believe that others who do not suffer from them frequently underestimate their illness. 

Migraine is the most frequent headache diagnosis for which patients seek treatment, affecting about 30 million individuals in the United States. Migraine is a chronic, frequently hereditary disease characterized by hypersensitivity of the brain and a reduced threshold for trigeminal-vascular activation. Autonomic, gastrointestinal, and neurologic symptoms define intermittent debilitating episodes.

Migraine reduces a patient's quality of life significantly, as evaluated by physical, mental, and social health-related measures. An accurate assessment of a patient's impairment will assist doctors in providing suitable modalities of therapy. Migraine, on the other hand, continues to be underdiagnosed and undertreated. Migraines have an impact on people's quality of life as well as their capacity to engage in job, family, and social activities.

Nonpharmacologic methods, as well as abortive and preventive medicines, may be used in a complete migraine therapy approach. It is important for effective outcomes to inform patients about realistic treatment expectations, possibly delayed efficacy of medicines, caffeine avoidance, and medication overuse.

Migraine management is a continuous process since headaches evolve over time and drug tachyphylaxis might occur, prompting therapy adjustments. Lasmiditan, ubrogepant, and rimegepant are currently emerging acute migraine therapies that may be added to current migraine management.