Migraine is a common, multifactorial, disabling, recurrent, hereditary neurovascular headache disorder affecting 15% of the population during the formative and most productive periods of their lives, between the ages of 22 and 55 years. It usually strikes sufferers a few times per year in childhood and then progresses to a few times per week in adulthood, particularly in females. Attacks often begin with warning signs (prodromes) and aura (transient focal neurological symptoms) whose origin is thought to involve the hypothalamus, brainstem, and cortex. Once a headache develops, it typically throbs, intensifies with an increase in intracranial pressure, and presents itself in association with nausea, vomiting, and abnormal sensitivity to light, noise, and smell. It can also be accompanied by abnormal skin sensitivity (allodynia) and muscle tenderness.
Chronic migraine is an important treatable cause of neurological disability. It is vital to make a diagnosis and ensure that any concomitant medical or psychological conditions are treated in parallel with interventions aimed at reducing the biological tendency to headaches. It is also important to set patients’ expectations as to what can be achieved. The tendency to migraine is genetic, and will rise and fall in people’s lives; migraine cannot be ‘cured’ in any sense. In refractory cases Botox injections should be considered as per NICE protocol and can prove extremely effective. New acute and preventive options are now available, including calcitonin gene-related peptide (CGRP) antagonists and antibodies, and drugs targeted at other serotonin receptor subtypes.
Collectively, the symptoms that accompany a migraine from the prodromal stage through the headache phase suggest that multiple neuronal systems function abnormally. As a consequence of the disease itself or its genetic underpinnings, the migraine brain is altered structurally and functionally. These molecular, anatomical and functional abnormalities provide a neuronal substrate for an extreme sensitivity to fluctuations in homeostasis, a decreased ability to adapt, and the recurrence of a headache.
Migraine is a recurrent headache disorder affecting 15% of the population during the formative and most productive periods of their lives, between the ages of 22 and 55 years. It frequently starts in childhood, particularly around puberty, and affects women more than men (3:1 female-to-male ratio). It tends to run in families and, as such, is considered a genetic disorder.
Advances in understanding the genetic predisposition to migraine, and the discovery of multiple susceptible gene variants (many of which encode proteins that participate in the regulation of glutamate neurotransmission and proper formation of synaptic plasticity) define the most compelling hypothesis for the generalized neuronal hyperexcitability and the anatomical alterations seen in the migraine brain. Regarding the headache pain itself, attempts to understand its unique qualities point to activation of the trigeminovascular pathway as a prerequisite for explaining why the pain is restricted to the head, often affecting the periorbital area and the eye, and intensifies when intracranial pressure increases.
In some cases, the headache begins with no warning signs and ends with sleep. In other cases, the headache may be preceded by a prodromal phase 9 prodromes are symptoms that precede a headache by several hours) that includes fatigue; euphoria; depression; irritability; food cravings; constipation; neck stiffness; increased yawning; and/or abnormal sensitivity to light, sound, and smell and an aura phase that includes a variety of focal cortically mediated neurological symptoms that appear just before and/or during the headache phase. Symptoms of migraine aura develop gradually, feature excitatory and inhibitory phases, and resolve completely. Positive (gain-of-function) and negative (loss-of-function) symptoms may present as scintillating lights and scotomas when affecting the visual cortex; paresthesia, and numbness of the face and hands when affecting the somatosensory cortex; tremor and unilateral muscle weakness when affecting the motor cortex or basal ganglia; and difficulty saying words (aphasia) when affecting the speech area.
In many cases, migraine attacks are likely to begin centrally, in brain areas capable of generating the classical neurological symptoms of prodromes and aura, whereas the headache phase begins with consequential activation of meningeal nociceptors at the origin of the trigeminovascular system. Only some clues about how the occurrence of aura can activate nociceptors in the meninges exist. A mechanistic search for a common denominator in migraine symptomatology and characteristics points heavily toward a genetic predisposition to generalized neuronal hyperexcitability (Ferrari et al., 2015). Mounting evidence for alterations in brain structure and function that are secondary to the repetitive state of headache can explain the progression of the disease.
In the context of migraine, prodromes are symptoms that precede the headache by several hours. Examination of symptoms that are most commonly described by patients point to the potential involvement of the hypothalamus (fatigue, depression, irritability, food cravings, and yawning), brainstem (muscle tenderness and neck stiffness), cortex (abnormal sensitivity to light, sound, and smell), and limbic system (depression and anhedonia) in the prodromal phase of a migraine attack.
Clinical and preclinical studies suggest that migraine aura is caused by cortical spreading depression (CSD), a slowly propagating wave of depolarization/excitation followed by hyperpolarization/inhibition in cortical neurons and glia. While specific processes that initiate CSD in humans are not known, mechanisms that invoke inflammatory molecules as a result of emotional or physiological stress, such as lack of sleep, may play a role.
The trigeminovascular pathway conveys nociceptive information from the meninges to the brain. The pathway originates in trigeminal ganglion neurons whose peripheral axons reach the pia, dura, and large cerebral arteries (Uddman et al., 1985), and whose central axons reach the nociceptive dorsal horn laminae of the SpV. The ascending axonal projections of trigeminovascular SpV neurons may be critical for the initiation of nausea, vomiting, yawning, lacrimation, urination, loss of appetite, fatigue, anxiety, irritability, and depression by the headache itself.
Chronic migraine is the term that the International Classification of Headache Disorders (ICHD) uses to describe patients with frequent headaches, believed to be biologically migrainous. The meaning of the term ‘chronic migraine’ has evolved over the last two decades, as it has steadily replaced earlier terminology such as ‘chronic daily headache’ and ‘transformed migraine’. As per the International Headache Society, chronic migraine is defined as a headache occurring on 15 or more days per month for more than three months, which, on at least 8 days per month, has the features of a migraine headache. Chronic migraine occurs in approximately 1% of the population. Studies estimate that about 2.5% of people with episodic migraine will transition to chronic migraine each year.
When assessing a patient with chronic headaches (that is, by definition, headaches on at least 15 days per month), it is important from the outset to ascertain how the headaches originally developed. There are two typical patterns. In one set of cases, patients with a pre-existing primary headache disorder (usually, but not exclusively migraine) have ever-increasing attacks until they reach a stage where they do not recover headache freedom in between, a pattern originally called ‘transformed migraine’. In the other set of cases, patients start to have a headache one day, and it simply never goes away. This is a syndrome that goes under the name ‘new daily persistent headache’ (NDPH) [Goadsby and Boes, 2002], and is an important pattern to recognize because it is within this set of headaches that many of the serious causes lie, including those conditions which may present with a thunderclap headache. After investigation, however, many cases of new daily persistent headache do not have an underlying cause and are essentially chronic versions of the more familiar episodic headache disorders.
Patients may be surprised that you want to know about events that happened in the past (sometimes some years previously) and what their headaches used to be like, but because chronic headaches often become steadily more featureless over time, establishing the original phenotype can be crucial in making an accurate diagnosis, without which treatment is unlikely to be successful.
The name ‘migraine’ originally comes from the Greek word hemicrania, meaning ‘half of the head’, representing one of the most striking features of the condition: that in many cases pain only affects one half of the head. Equally commonly, however, pain is felt bilaterally, at the front or the back of the head, more rarely in the face, and rarer still in the body (‘migrainous corpalgia’). The pain is generally throbbing in nature and typically made worse by any form of movement or even modest exertion. The majority of migraine attacks are severe or at least moderately so.
The pain of migraine is typically accompanied by other features such as nausea, dizziness, extreme sensitivity to lights, noises, and smells, lack of appetite, disturbances of bowel function, and so on. The typical constellation of symptoms experienced by migraine sufferers is reflected in the ICHD criteria for the diagnosis of migraine. It should be remembered that these criteria were originally designed for the purpose of ensuring coherent patient populations for research in headache disorders and that not everyone’s migraine has the same textbook features.
Between 10% and 20% of migraineurs experience premonitory symptoms up to 48 h before their migraines.These may include fatigue or abnormal bursts of energy, neck stiffness, yawning and frequent urination. Particular areas of the brain have now been identified that are active during the premonitory phase. A higher proportion experience a postdrome during which they may experience a grumbling headache, a bruised feeling in the head, fatigue, and nausea, and a continuing sensitivity to lights, noises, smells and movement.
Only about 20% of migraine sufferers experience aura , usually (but not invariably) before the headache starts. Most aura is visual, consisting of a combination of positive visual phenomena (floaters, flashes of light, moving or expanding zig-zag patterns, and so on) and negative phenomena (loss of vision causing blind spots). Many sufferers also experience sensory aura, consisting of tingling and numbness, often spreading over the hand, arm, face, lips and tongue on one side of the body. Weakness, dysphasia, and other aura symptoms are rare.
(1) At least five attacks fulfilling criteria (2)–(4)
(2) Headache attacks lasting 4–72 h (untreated or unsuccessfully treated)
(3) Headache has at least two of the following four characteristics:
(a) unilateral location
(b) pulsating quality
(c) moderate or severe pain intensity
(d) aggravation by or causing avoidance of routine physical activity
(4) During headache at least one of the following:
(a) nausea and/or vomiting
(b) photophobia and phonophobia
(5) Not better accounted for by another ICHD-3 diagnosis.
Decisions on investigation of patients with chronic migraine are driven by two highly prevalent cultural myths: that headaches are commonly due to brain tumours; and that in modern medicine, diagnoses can only be made on the basis of an abnormal scan or blood test result. With regard to the former, evidence shows that when a diagnosis of migraine can be made on clinical grounds, the chances of the patient having a brain tumour are 0.045% [Kernick et al. 2008a]; no investigation is indicated, therefore, not least because there is a 1–2% chance of picking up an incidental intracranial abnormality which may cause anxiety, or even have an adverse influence on life insurance applications. Imaging should be reserved for situations when clinical assessment suggests that the probability of an underlying tumour has exceeded 1%; examples include the finding of papilloedema on fundoscopy, headache with fixed abnormal neurological signs, headaches associated with new-onset seizures or significant alterations in consciousness, memory or coordination, or headaches in patients with a history of cancer elsewhere in the body. In such cases, MRI is the modality of choice. Other investigations such as blood tests or cerebrospinal fluid analysis are only indicated in cases of diagnostic uncertainty.
There are three broad approaches to treating chronic migraine:
While many patients find that lifestyle adjustments such as regularizing meals and sleep can reduce the frequency of their attacks, some form of medication or other treatment is almost invariably necessary in patients with chronic migraine.
When patients have chronic severe headaches, it can be difficult to recognize specific triggers. Paradoxically it is often the case that as chronic headaches start to improve with treatment, triggers become more obvious. The regularity of regimen with regard to meals, hydration, sleep, and stress is always helpful in reducing the tendency to migraines; recognizing that this is helpful is straightforward, but actually making the requisite changes in a modern busy life may be more difficult.
Many patients with chronic migraine will have other problems that exacerbate their tendency to headaches: these include depression, anxiety, other pain syndromes such as fibromyalgia, localized pain in head and neck structures, and conditions that create ‘metabolic’ strain such as sleep apnoea or postural orthostatic tachycardia syndrome. Proper management of these is necessary to maximize the effect of any other migraine treatments. It is particularly important to recognize and manage medication overuse (including caffeine overuse) as failure to do so will render most attempts at preventive treatment ineffective.
Patients with chronic migraine often find it difficult to know when to take acute treatments. Both patients and physicians may be concerned about the possibility of medication overuse, and in the early stages of management, it may be preferable to avoid acute painkillers altogether. Once a stage is reached where there are clear ‘good days and bad days’, or a situation when there is a background headache with clearly defined exacerbations, then acute treatment can be reintroduced. The usual principles apply: attacks should be treated early, when the pain is still mild; effective doses should be used, treatments being titrated steadily up to the maximum tolerated dose before being abandoned as ineffective; associated symptoms such as nausea should also be treated; and an appropriate route of delivery should be chosen (various medications can be given by nasal spray or via a suppository). If simple analgesics are not effective, then triptans should be used and opiates avoided if possible. Strict limits should be set on the frequency with which acute treatments are used to avoid worsening the situation through medication overuse.
Medication overuse headache is an important entity which needs to be recognised and treated appropriately. People who use acute pain-relief medicine more than two or three times a week or more than 10 days out of the month can set off a cycle called ‘medication-overuse headaches’ (MOH). As each dose of medicine wears off, the pain comes back, leading patients to take even more. This overuse causes the medicine to stop helping the pain and actually start causing headaches. MOH can occur with both over-the-counter and prescription pain-relief medicines. They can also occur whether patients take them for headache or for another type of pain.
Preventive treatment is usually considered when headache frequency or severity increases to a point when it is significantly interfering with work, school or social life. For patients with chronic migraine this is invariably the case, and some form of preventive medication or other intervention is almost universally indicated. Evidence from the American Migraine Prevalance and Prevention study shows, however, that as many as 40% of those patients who might benefit from preventive treatment are never offered it.
Numerous medications have been shown to be effective in the preventive treatment of migraine. Not all of these are licensed for this purpose in the United Kingdom. The choice of treatment can be influenced to varying degrees by the pattern of headaches, patient comorbidity, tolerability, teratogenicity, potential side effects, ease of use and patient choice. Preventive treatments should be commenced at a low dose to minimize the possibility of developing side effects. The dose should be steadily and regularly increased until the medication works, intolerable side effects occur or a maximum dose is reached, at which point it can be concluded that the medication does not work for that individual patient. Adherence should be closely monitored, as levels are known to be low. At this point, another preventive treatment can be tried. If a preventive treatment works well, it should be continued for a few months before weaning the dose down. In many cases, this process can be achieved without headache frequency suddenly worsening again.
Specific trials in patients with chronic migraine are sparse, and in many cases the evidence for the use of standard preventive medications has to be extrapolated from studies in patients with highfrequency episodic migraine. Whilst NICE has recently recommended topiramate as the first-line preventive (on the basis that this medication has the most extensive high-quality clinical trial evidence on which to base the decision), most headache specialists continue to start with other older medications, probably of equivalent efficacy and certainly better tolerated, such as tricyclics (amitriptyline, nortriptiline or dosulepin), β blockers (propranolol, atenolol, nadolol or metoprolol). If these do not work then anticonvulsants such as topiramate or sodium valproate can be considered. The calcium channel blocker flunarizine may be helpful and anecdotally is said to be the drug of choice for patients with prolonged aura, hemiplegic attack or prominent vertigo. There is also increasing evidence that angiotensin blockers such as candesartan are useful and well tolerated in migraine prevention.
If first- or second-line preventives fail, the patient should be referred to a specialist headache clinic for reevaluation, and consideration of interventions such as greater occipital nerve blocks (case series suggest this may be useful in reducing headache frequency and severity for a limited period in over 50% of patients [Afridi et al. 2006], though a recent double-blind randomized controlled trial casts doubt on this [Dilli et al. 2014]) or Botox injections for chronic migraines (having been shown to reduce headache days by 50% over 6 months in such patients) [Aurora et al. 2011]. Botox injections in chronic refractory migraines are NICE recommended and can be very effective if appropriate protocols are followed and if patients are managed effectively for medication overuse headache prior to Botox treatment.
n 2018, the US Food and Drug Administration approved for migraine prevention 3 new monoclonal antibodies that target CGRP or its receptor: erenumab, fremanezumab, and galcanezumab. CGRP antagonists represent the first class of medications to target specifically the pathophysiologic processes implicated in migraine. Thus far, clinical trial data indicate that these 3 agents have comparable efficacy, are well tolerated, and are not associated with safety issues.
CGRP is a neuropeptide widely distributed in the nervous system, where it is thought to play a role in several processes, including vasodilation of cerebral and dural vessels, release of inflammatory mediators and transmission of nociceptive signals to the central nervous system.
The underlying pathophysiology of migraine is largely unknown, but calcitonin gene-related peptide (CGRP) most likely plays an important role. The first time CGRP was hypothesized to be involved in migraine was in 1985. This hypothesis was later supported by the finding of CGRP release during acute migraine attacks and the subsequent demonstration of normalization of CGRP levels in migraine patients after efficacious sumatriptan treatment.
Several lines of evidence support the role of CGRP in migraine:
Oral anti-CGRP medications called ‘gepants’ were initially developed and tested in the early 2000s but the discovery of liver toxicity with its use caused many drug companies to stop pursuing this class of drugs. With many drug companies halting the development of gepants, the use of monoclonal antibodies (mAbs) to target CGRP molecules and its receptors were developed. Monoclonal antibodies are proteins that use the immune system to target specific molecules inside your body. Currently, there are four anti-CGRP mAbs that have been developed, galcanezumab, eptinezumab, erenumab, and fremanezumab.
The first calcitonin-gene receptor peptide (CGRP) drug for treating migraines has been approved by the FDA this year with the introduction of Aimovig by Amgen and Novartis. Erenumab binds to the CGRP receptor and blocks the CGRP receptor function. The administration is monthly subcutaneous injections. The recommended dose of erenumab is 70 mg once monthly. Some patients may benefit from a higher dose of 140 mg once monthly, which is administered as two consecutive subcutaneous injections of 70 mg each.
The FDA’s approval for Aimovig was based on results obtained from a Phase IIIb clinical study known as LIBERTY. It was a multi-centre, double-blind, placebo-controlled study that enrolled 246 patients with episodic migraine who had between two and four unsuccessful treatments. The patients were randomised to receive either 140mg Aimovig or placebo for 12-weeks. The primary endpoint of the study was the percentage of patients with at least a 50% reduction of monthly migraine days from baseline over the last four weeks of the study. The most common adverse reactions found in patients treated with Aimovig were injection site reactions and constipation.
Patients treated with Aimovig showed significant reductions in the number of migraine days each month during the extensive clinical programme that involved the participation of 2,600 patients. The safety and tolerability profile of the drug was found to be similar to placebo.
Aimovig is now licensed for use in the UK. It has been approved for prophylaxis of migraine in adults who have 4 or more migraine days per month. It is not yet available on the formulary in most NHS hospitals but Dr. Krishna is able to prescribe it privately. Please contact us if you need further information.