Do you know…migraines affect more than 10% of the world population?

In this post we discuss a topic that everyone will have heard of. Let’s talk about migraines, a disorder that hides a huge physiological and molecular background, and having an impact alarmingly high around the globe. We are going to enter the etiology of the disease, in all molecular and supramolecular processes that trigger it and we are going to finally talk about the traditional therapies, the most novel therapies and, of course, prophylaxis or prevention of migraines.This post is not intended to be a review, but a somewhat more scientific than is generally known about migraines, explained so that everyone can understand and enjoy its content expansion.

Migraine is a common and incapacitating neurovascular disorder, primarily genetic in origin and is characterized by very severe headaches, dysfunction of autonomous nervous system and, in some patients, the appearance of an aura that encompasses visual, sensory and/or speech symptoms temporarily.The headache is usually throbbing and appears on one side of the head, it is unilateral. According to the World Health Organization (WHO), migraine has an average prevalence of 10-15% of the global population. Furthermore, the risk for this disorder is up to three times higher for women due to certain hormonal influences that we are going yo explain later. In turn, WHO has classified chronic migraine as one of the most disabling disorders beside with quadriplegia, psychosis and dementia.

Although migraine attacks can start at any age, the incidence is concentrated mainly in adolescence.The average frequency is 1.5 attacks per month and the average duration of attacks is about 24 hours but it can reach 2-3 days if no appropriate treatment is available.In migraine without aura, also called common migraine, attacks are associated with nausea, vomiting and excessive sensitivity to light (photophobia), sound or movement.About 65% of patients have common migraine, 20% migraine with aura and 15% both.Some subjects gradually evolve from episodic migraine to chronic, which affects 1-2% of the general population and is characterized by 15 days or more of headache per month.It is important to note that patients with episodic migraine may have aura or may not as well as chronic migraine patients, although it is true that the incidence of aura is higher in the latter. Therefore, chronic is not synonymous to aura, but more than 15 days per month with headache.The following image shows the representation of unilateral headache that is experienced during a migraine, including visual and auditory area.

Migraines have an important psychological, social and economic impact.About 75% of patients are functionally impaired during an attack and more than half of them require assistance from third parties.The annual economic impact of migraine is estimated at 27 billion euros in lost work days around Europe.

The management of migraines includes an adequate pain relief and the reduction or complete elimination of the attacks. Nowadays, it has several acute and prophylactic treatment of migraines, but a small proportion of patients are untreatable and no treatment / drug has emerged in recent years to try to solve this problem.

Migraine is a complex condition whose pathophysiology is not completely understood.The most widely accepted theory for initiation and perpetuation of migraine is a combination of vascular and neural mechanisms.This theory suggests that the headache depends on the activation of trigeminovascular pain pathway and in patients with migraine with aura a wave of neuronal hyperactivity followed by occipital cortical depression (back of the brain), called cortical spreading depression CSD, represents this famous aura.

Like most solid organs, the brain is insensitive to pain. The sensitive intracranial structures, including nociceptors (pain receptors) are on the walls of arteries, veins, venous sinus and meninges (connective tissue membranes covering the brain). Peripheral vessels and meninges have sympathetic and parasympathetic sensory innervation.The trigeminovascular system consists of large intracranial blood vessels innervated by the ophthalmic division of the trigeminal nerve. This nerve is also known as the fifth cranial nerve, it has sensory and motor branches, and it is the largest of all cranial nerve. Within these nociceptors sensory branches of the face and inside the skull are enclosed, including the meninges. In the next picture you can see an example of trigeminovascular system innervation of the meningeal vessels, as well as the rise of the sensory pathways to the brain

As mentioned above, about 20% of patients with migraine have a neurological phenomenon called aura.This event has been linked with cortical spreading depression or CSD, which refers to a wave of neuronal hyperactivity followed by a depression or decreasing of the activity of neurons long lasting.It triggers generally in the occipital part of the cortex and from there it is slowly propagated at a speed of 2-5 mm/min forward to adjacent tissues.In the following animation you can see a representation of the spread of the wave.

This wave is initiated by massive increases in extracellular potassium and excitatory neurotransmitter glutamate, which can trigger depolarization or activation of nociceptive neural endings of the trigeminovascular system.Potassium stimulates nerve endings itself, while glutamate exerts its effect by its function as a neurotransmitter.The increase of potassium and glutamate is explained in part by mutations in certain ion channels (below).Activation of these nociceptive terminals causes neuronal depolarization and subsequent release of vasoactive neuropeptides such as: CGRP (from calcitonin gene related peptide),substance P and neurokinin A, all with both vasodilatory and neuronal excitation capacity. CGRP can increase the sensitivity of perivascular nociceptors and vasodilate cranial vessels by stimulate the release of nitric oxide, a potent vasodilator. Substance P is a mediator that, on the one hand increases the sensitivity of nerve endings of pain indirectly by stimulating blood mast cells to produce histamine (inflammatory mediator) and on the other hand vasodilates intrancraneales vessels. All these phenomena create a feedback loop that progressively increases pain. Another neural messenger that plays a key role in the pathophysiology of migraines is the polypeptide PACAP (from pituitary adenilate cyclase-activating polypeptide), expressed in trigeminal neurons, whose induction, shown in experimental studies in humans, causes an increase in extracerebral vessels vasodilation.

The wave of neuronal hyperactivity and vasodilation results in a wave of hyperemia (increasing of blood volume in the brain).This phenomenon is followed by a wave of oligohemia (decreasing of total volume of blood) that runs through the cerebral cortex associated a wave of neuronal depression.The mechanisms leading to this depression in cortical activity are not entirely clear but a possible explanation is the decrease of occipital cortical metabolism by decreased blood volume.This would explain symptoms such as flashing lights that certain patients see in one eye within a migraine attack. Increased blood volume stimulates the retina, causing the appearance of phosphenes or bright spots, while consecutively decreasd blood volume stops this process and go on continuously. Despite what it may seem, CSD does not cause tissue damage in the healthy brains.

Certain genetic susceptibility or familial predisposition is involved in the etiology of the disease. We mentioned earlier that increased both extracelular potassium and glutamate may be due to mutations in certain ion channels.There are many genes whose mutation triggers changes in ion channels that lead to the development of the pathophysiology of migraines, but we will not dwell on many details. As an example, we’ll talk about Familiar Hemiplegic Migraine (FHM), an autosomal dominant migraine with an especially pronounced aura, in which mutations have been found in three causative genes, all involved in coding for ion channels.

• CACNA1A: encoding subunit ×ñ1A of neuronal calcium channel P/Q type. Mutations in this gene occur with gain function of calcium channel Ca 2.1 and subsequent release of dependent neurotransmitter of this channel, including glutamate, from cortical neurons, facilitating induction and propagation of the CSD and activation trigeminovascular system.
• ATP1A2: Encodes for the ×ñ2 subunit of ATPase Na+/ K+, expressed in glial cells and involved in extracellular K+ uptake and the production of a Na+ gradient that is used in glutamate recaptation. Mutations in this channel can lead to increased extracellular potassium and glutamate, and resulting in a reduction of the CSD threshold to occurs.
• SCN1A: encoding the ×ñ1 subunit of the voltaje-dependent sodium channel Nav1.1. This channel is critical in the generation and propagation of action potentials. A mutation in this gene may lead to increased excitability of dendrites and neuronal firing.

Therefore, we can say “roughly” that in patients with common migraine without aura headache is produced almost entirely by activation of trigeminovascular system and in patients with migraine with aura both phenomena occur, activation of the trigeminovascular system and cortical spreading depression (CSD), which mutual feedback. All of it produced mainly by genetic factors.

One reason for the fact that women have 3 times more risk of migraines than men is due to genetic polymorphisms in the estrogen receptor ESR1, which increase it activity. This receptor is a transcription factor that is expressed in several areas of the brain and regulates, among other functions, gene expression affecting the synthesis of CGRP, serotonin and glutamate. Excessive activation of this receptor stimulates the release of nitric oxide vasodilator via CGRP and, in turn, the production of more CGRPs by the action of glutamate.

Immediate treatment of an attack looks for a quick elimination of pain.In many patients the administration of analgesics is sufficient to control pain during an attack but, however, some individuals have a reduced response to pain medication so serotonin receptor 5-HT1B/1D agonists can be used. Another strategy to suppress migraine is blocking the release of neuropeptides or the activation of its receptors.

Analgesics: First treatment option.Among them,aspirin, acetaminophen, ibuprofen, naproxen or diclofenac.

Agonists of the 5-HT1B/1D receptor: Also called triptans should be considered only when there is an inadequate response to analgesics because they can produce certain side effects.Examples include eletriptan, sumatriptan, zolmitriptan, naratriptan or rizatriptan. They are very potent and effective, and act at three levels:

• Cranial vasoconstriction by inhibiting the release of vasodilators due to receptor activation serotonin 1B.
• Decreased peripheral pain transmission by inhibition of both peripheral neuronal transmission and trigeminocervical complex activation by activating serotonin 1D receptor.

CGRP receptor antagonists: Currently,monoclonal antibodies against CGRP or its receptor have proved to be very promising in animal models.Nowadays, certain clinical trials are ongoing investigations in human patients with monoclonal antibodies and previous results are very encouraging.However, there are still no definite conclusions on such studies.

Within prophylaxisÿoptions that are recommended:

• Beta blockers:Antagonists of adrenaline and noradrenaline at presynaptic level.They also inhibit the nitric oxide activity.
• Calcium antagonists: they block calcium channels, preventing the release of neurotransmitters such as glutamate.
• Antidepressants; such as amitriptyline, modulate pain. Prevent the recaptation of serotonin and norepinephrine, increasing its levels in the brain.
• Antiepileptics: such as topiramate, acting on processes that ultimately suppress the initiation and propagation of the CSD.

For all the above, migraine is a major public health problem that affects a large part of the population and which is being actively investigated with the aim of discovering more innovative and effective therapies, as well as to find a solution to intractable patients.There are many loose ends remaining mechanistic level in the pathophysiology of migraines, like many links between discoveries or isolated observations, but gradually we will finally understand the complex neural and vascular network which is such a mess.

Finally we leave a very interesting and informative video created by Novartis brandnames one of its star compounds, Excedrin, a very popular drug to treat migraine attacks composed of a mixture of aspirin, acetaminophen and caffeine. The video is titled “What does a migraine feel like?”and is based on putting healthy people a helmet and a virtual glasses specially developed to simulate symptoms during a migraine attack.Surely you will be surprised.We hope you like it.

References:

World Health Organization (WHO): http://www.who.int/es/

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