The Migraine
Migraine is a neurological disorder characterised by recurrent headaches, usually unilateral, throbbing in nature and often accompanied by photophobia, phonophobia and nausea. The headache may be preceded by premonitory symptoms followed by an aura with visual and acoustic disturbances. The headache is nearly always aggravated by sound, light and head movement (jolt accentuation) and is usually followed by a postdrome comprising fatigue, drowsiness and prolonged sleep. There is a strong hereditary tendency towards migraine, and hormones also appear to play a significant role.
The migraine may come in many different forms, including migraine with aura, migraine without aura, or simply the aura itself. For the purposes of this paper, the term migraine will encompass all four elements of the condition, namely the prodrome, aura, migraine headache, and postdrome.
Pathophysiology
For much of the 20th century migraine was thought to be the result of a disturbance of the cranial vessels. The aura was explained by vasoconstriction of cranial vessels causing localised hypoxia, and the characteristic throbbing headache was explained by vasodilatation of the same vessels (Goadsby, 2012).
More recent research has suggested that migraine is a result of a primary neuronal dysfunction in which the trigeminovascular system is activated (Vasudevan and Bozoghlanian, 2011, and Goadsby, 2012). The activation of the trigeminal system is thought to be a result of a phenomenon known as the “cortical spreading depression”, a self-propagating wave of neural depolarisation that spreads across the cerebral cortex (Leao, 1944). The cortical spreading depression causes an inflammatory reaction and blood vessel dilatation in the meninges which by a complex cascade of molecular events results in both the aura and the headache (Cutrer and Bajwa, 2018). Migraine has also been associated with changes in levels of neurotransmitters and neuropeptides including serotonin, calcitonin gene-related peptide (CGRP) and others (Cutrer and Bajwa, 2018). As the meninges are very pain sensitive structures that are innervated by branches of the trigeminal nerve (mostly the ophthalmic branch) it follows that even small disturbances in metabolic function resulting in meningeal inflammation can lead to headaches and migraine (Cutrer and Bajwa, 2018). It appears that the vasodilatation that has been observed in migraine sufferers over the centuries is an effect of the pathophysiology rather than the cause, even though mechanical attempts to limit the extracranial circulation such as compression and bandaging had some effect in reducing the severity of the headache (Cutrer and Bajwa, 2018).
One of the most ancient remedies for migraine and other headaches is found in the Ebers Papyrus, an ancient Egyptian text that recommends attaching a baby clay crocodile to the skull with strips of linen inscribed with the names of the Gods. It is presumed and hoped that the hapless sufferer gained some symptomatic relief from the compression of the extra-cranial arteries, something that could probably have been accomplished with a sympathetic finger (Lance, 2018).
The 21st century has seen the advent of new technologies including positron emission tomography (PET)+ that allows for functional brain imaging. PET scanning of patients in various stages of migraine have shown alterations in blood flow to different areas of the brain including the visual and auditory cortices, hence the commonly described visual and auditory disturbances and hallucinations in the aura phase (Cutrer and Bajwa, 2018).
Sensitisation and spontaneous activity of neurons in the trigeminal system are now thought to be responsible for the severity and characteristics of the pain that is typically felt in the headache stage of a migrainous attack. The characteristic features of the headache stage of migraine such as the throbbing nature of the pain, hyperalgesia, allodynia (pain produced by light touch and other non-noxious stimuli), jolt accentuation and even increased pain with eye movements is now largely attributed to the phenomenon of neuronal sensitisation in the trigeminal systems and its connections.
Causes
Migraine is now known to be associated with neuronal changes in the trigeminal nerve complex and connected afferents, possibly even including the brainstem (Vasudevan and Bozoghlanian, 2011). However, while there are a number of known triggers that may lead to migraines in susceptible individuals, the underlying causes remain unknown. Whilst the prevailing view of current researchers favours the cortical spreading depression as a causal initiating factor, it is unknown what causes the cortical spreading depression. What is known, however, is that genetics, hormonal and environmental factors all play a significant role (Cutrer and Bajwa, 2018).
Family history, genetics and hormonal changes all have strong links to migraine (Charles, 2009). Changes in oestrogen levels that occur during the menstrual cycle, with pregnancy, oral contraceptive use and menopause may also increase or decrease the tendency to migraine in susceptible females (MacGregor, 2004). It has been found that falling concentrations of oestrogen or ‘oestrogen withdrawal’ can cause an onset of what is called a ‘premenstrual migraine without aura’. Clinical trials have shown that women who suffer from menstrual cycle related migraines often experienced prolonged migraines during periods of decreased oestrogen levels compared with those with rising concentrations (MacGregor, 2004). In contrast, in some women it is the high plasma concentrations of oestrogen that are a causal factor for migraine attacks with aura (MacGregor, 2004).
Women are three times more likely to suffer migraine than men, except in prepubertal ages where young boys are more susceptible than young girls (MacGregor, 2004). Whilst the association between migraine and sex hormones, and oestrogen in particular has been repeatedly demonstrated, the precise cause and pathophysiology of this association has not yet been clarified (MacGregor, 2004; Chai, Peterlin and Calhoun, 2014).
There are many environmental factors that may trigger migraines in susceptible individuals. Such triggers include various kinds of foods and food additives, alcohol, psychological stress, medications, changes in the weather (in particular a drop in barometric pressure) and extreme physical exertion (Friedman and De Ver Dye, 2009). Despite our knowledge of such triggers, the exact pathophysiology behind such triggers and how they lead to migraines with or without aura remains unknown.
Treatment
There are currently a variety of treatments available to migraine sufferers, and these treatments fall into three categories; avoiding known triggers, acute treatment and preventative anti-migraine therapy (Bartleson and Cutrer, 2005).
Avoidance of known triggers can be as simple as ensuring one is hydrated, not over exerting oneself in physical activity, and avoiding loud noises. In women who suffer migraines without aura during periods of falling oestrogen levels within the menstrual cycle, treatment with combined oral contraceptive pills or intravenous oestrogen supplements can be very effective (MacGregor, 2004).
In the event of an acute migraine attack, prompt action is necessary, and such action is known as ‘abortive treatment’ (Cutrer and Bajwa, 2018). A number of medications are available including a variety of tryptans and Dihydroergotamine (Bartleson and Cutrer, 2005). Tryptans belong to a class of drugs known as selective serotonin receptor agonists, or SSRA’s (Headaches.org, 2018). SSRA’s stimulate the neurotransmitter serotonin which leads to a constriction of the inflamed meningeal vessels, thereby reducing the headache. They also assist in relieving the nausea experienced by many patients suffering a migraine attack (Ahn and Basbaum, 2005). Studies have shown that tryptans are effective in relieving symptoms of headache and nausea in up to 75% of migraine sufferers (Bartleson and Cutrer, 2005).
Dihydroergotamine may also be used in the treatment of acute migraine attacks. It is a type of ergot alkaloid derived from the fungus Claviceps purpurea (Obermann and Naegel, 2010). Ergot alkaloids such as Dihydroergotamine may be useful in patients who do not respond well to SSRA’s. Their mechanism is similar to that of the SSRA’s in that they act as agonists on the 5-HT receptors to stimulate the release of serotonin which in turn leads to cranial vessel constriction (Charles, 2009). Dihydroergotamine has been found to be useful in the treatment of both migraines and cluster headaches, with both conditions involving both the nerves and blood vessels (Charles, 2009).
Patients who experience frequent migraines despite avoiding the known triggers may benefit from medications to prevent or limit the frequency and severity of migraine attacks (Bartleson and Cutrer, 2005).
Medications that have proven useful in preventing or limiting the frequency and severity of migraines include tricyclic agents, beta blockers, anticonvulsants and verapamil, and these medications may be used singly or in combination (Bartleson and Cutrer, 2005).
Tricyclic agents such as amitriptyline work by blocking the reuptake of 5-HT at central synapses (Mathew, 2011). Beta blockers such as propranolol and timolol have been utilised in the prevention of migraine headaches for decades, although it is unknown whether their efficacy is due to beta-blockade or 5-HT agonist action (Lance and Goadsby, 2000).
Our understanding of the pathophysiology, causes and treatment of migraine has increased greatly over the past 50 years. It is now known that migraine is not a vascular headache but rather one that involves stimulation of the trigeminal ganglia by a wave of cortical spreading depression, which in turn leads to meningeal inflammation and blood vessel dilatation resulting in a prolonged throbbing headache. Migraines both with and without aura have many known triggers including hormonal changes, and especially to changing oestrogen levels in susceptible females. However, the exact cause of migraine and its pathophysiology remains unknown. The primary form of treatment for migraine is mostly the selective serotonin receptor agonists which may abort or at least reduce the pain in an acute attack. Prophylactic medications, often used in combination can be useful in reducing the frequency and severity of migraines, however therapies to cure migraine and halt the physiological processes responsible do not currently exist, and further research is needed in this field.