Did you know that ... migraines affect more than 10% of the world population?

In this post we discuss a topic that everyone would have heard before. Let's talk about migraines, a disorder that involves a huge physiological and molecular background, and it has an alarmingly high impact worldwide. We are going to talk about the etiology of the disease, the molecular and supramolecular processes that trigger it and we will end talking about 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 explanation that what is generally known about migraines, explained so that everyone can understand and enjoy its content.

What are migraines?

Migraine is a common and incapacitating neurovascular disorder, primarily genetic in origin and 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, i.e. 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 will explain later. In turn, WHO has classified chronic migraine as one of the most disabling disorders along 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. As in the case of epileptic seizures, one of the more consolidates triggers of migraines is stress. It is important to note that aura can appear in patients with either episodic or chronic migraines, although the incidence of aura is higher in the latter. Therefore, chronic is not synonymous to aura, but to more than 15 days per month of headache. The following image shows the representation of unilateral headache that is experienced during a migraine, including visual and auditory area.

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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 work days lost around Europe.

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

How are migraines originated?

Migraine is a complex condition whose pathophysiology is not completely understood. The most widely accepted theory for the 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 aura, this aura is represented by a wave of neuronal hyperactivity followed by occipital cortical depression (back of the brain), called cortical spreading depression or CSD.

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 branch of the trigeminal nerve. This nerve, also known as the fifth cranial nerve, has sensory and motor branches, and it is the largest of all cranial nerves. Among these sensory branches we find the facial and scalp nociceptors, including the meninges. In the next picture we can see an example of trigeminovascular system innervation of the meningeal vessels, as well as the ascension of the sensory pathways to the brain.

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As mentioned above, about 20% of patients with migraine have a neurological phenomenon called aura. This event has been linked to cortical spreading depression (CSD), which refers to a wave of neuronal hyperactivity followed by a long lasting decrease in neuronal activity. Generally, it is triggeredin the occipital part of the cortex and from there it is slowly propagated at a speed of 2-5 mm/min towards adjacent tissues. In the following animation we can see a representation of the wave spreading through the brain.

Creative Commons Attribution: PJ Lynch, Jaffe CC.

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

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The wave of neuronal hyperactivity and vasodilation results in a wave of hiperemia (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 with 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 experiment in one eye during a migraine attack. Increased blood volume stimulates the retina, causing the appearance of phosphenes or bright spots, while the subsequent decrease in blood volume stops this process. This process is constantly repeated. Despite what it may seem,CSD does not cause tissue damage in healthy brains. 

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Certain genetic susceptibility or familial predisposition is involved in the etiology of the disease. We mentioned earlier that increase in 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 leading to the development of the pathophysiology of migraines, but we will not dwell on many details. As an example, we will 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 encoding for ion channels.

• CACNA1A: encodes the α1A subunit of neuronal calcium channel P/Q type. Mutations in this gene result in gain of function of calcium channel Ca 2.1 and the subsequent release of dependent neurotransmitters, including glutamate, from cortical neurons, facilitating the induction and propagation of the CSD and the activation of the trigeminovascular system.
• ATP1A2: Encodes the α2 subunit of ATPase Na+/ K+, expressed in glial cells and involved in extracelular 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, reducing the CDS threshold.
• SCN1A: encodes the α1 subunit of the voltaje-dependent sodium channel Nav1.1. This channel is critical for the generation and propagation of action potentials. A mutation in this gene may lead to increased excitability of dendrites and neuronal firing.

Therefore, roughly speakin in patients with common migraine without aura, the 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 positively regulate each other. These events are produced mainly by genetic factors.

One reason for the fact that the risk of migraines is 3 times higher in women than in men is the existence of genetic polymorphisms in the estrogen receptor ESR1, which increase its 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. Exacerbated activation of this receptor stimulates the release of nitric oxide via CGRP and, in turn, the production of more CGRPs by the action of glutamate.

How can we treat migraines?

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, 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. These include, aspirin, acetaminophen, ibuprofen, naproxen or diclofenac.

Agonists of the 5-HT1B/1D receptor: Also called triptans they should only we considered 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 exert their action at three levels: 

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

CGRP receptor antagonists: Currently, monoclonal antibodies against CGRP or its receptor have showed very promising results in animal models. Nowadays, certain clinical trials are performing investigations in human patients with monoclonal antibodies and the preliminary data is very encouraging. However, there are still no definitive conclusions on such studies.

The prophylaptic options recommended are:

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

For all the above, migraines are 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 still many loose ends at the mechanistic level in the pathophysiology of migraines, as well as many links between discoveries and isolated observations, but gradually we will finally understand the complex neural and vascular network.

Finally we include a very interesting and informative video created by Novartis that advertize one of its flagship drugs, Excedrin, very popular to treat migraine attacks. It is composed of a mixture of aspirin, acetaminophen and caffeine. In this video, titled “What does a migraine feel like?”, they use a helmet and virtual glasses specially developed to simulate the symptoms of a migraine attack on healthy people. Surely you will be surprised. We hope you like it.

For any questions or suggestions do not hesitate to contact us.

Acknowledgement: Thanks to José Manuel González-Navajas and Beatriz Lozano-Ruiz from CIBERehd Alicante for their great support and help in the translation.

REFERENCES:

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