Introduction
Migraine is a complex neurological syndrome, with two main forms (migraine without aura, MO, and migraine with aura, MA). It is typically characterised by severe, neurogenic pain and neurological symptoms varying from mild tiredness to paralysis, lasting from days to weeks. Migraine has been a recognized disease since ancient Greece, where Hippocrates and Aretaeus wrote extensively about hemicrania, a condition of the nerves (Sacks, 1995), with the latter also describing aura and recognizing its connection to some but not all migraine. As detailed in the previous chapter, migraine has a roughly equal prevalence across the globe, and thus as far as can be determined, a similar presentation across both time and place. Despite its common nature and the extent to which it burdens the healthcare system, the importance of migraine as a disease entity was realized late, with the first specialist institution founded in 1970 (Sacks, 1995) and the first specific clinical criteria set in 1988 (International Headache Society, 1988). Considerable underreporting and lack of awareness of migraine has been widely reported (as reviewed by Buse et al. (Buse et al., 2009)) as well as under-treatment - a US study in 2007 found that 43% of migraine patients had never used migraine preventative medication (Lipton et al., 2007). A study on headache specialists (though positive selection may play a role) estimated the lifetime prevalence of migraine to be as high as 71.9% for men and 81.5% for women (Evans et al., 2003).
Prevalence, incidence and effect on public health
Migraine is roughly three times more common among women than in men. A clear majority of the difference between migraine incidence between the sexes occurs at the time of puberty, and is virtually removed after menopause (as seen in Figure 8 (Stewart et al., 1991)), suggesting a link between hormonal balance and migraine.
The overall prevalence of migraine and the incidence peak during working age makes migraine a somewhat unusual neurological disease. Estimates of the one-year prevalence range from 10% (Rasmussen et al., 1991) to 15% (O'Brien et al., 1994),
Figure 8. Sex-specific incidence rates of migraine with and without aura for A) females and B) males per 1000 person-years based on 10,131 survey respondents in Washington County, Maryland, USA. Adapted from Stewart et al., 1991.
with the largest study of 51,383 subjects reporting 12% (Hagen et al., 2000). Lifetime prevalence estimates between 13-18% in Europe (Stovner et al., 2006), it is by far the most common neurological condition in this age group. Lifetime prevalence of MA alone has been estimated to be 7% (Ulrich et al., 1999). According to WHO statistics, migraine ranks as the 19th most severe disease according to years lived with disability (YLD) in the global population, and the 9th among women (Leonardi and Mathers, 2003).
In terms of disability-adjusted life years (DALY), the WHO 2004 estimate (World Health Organization, 2008) of loss due to migraine is 177 years per 100,000 Finns (2004 average for EU member states: 176), making it the 4th most severe neuropsychiatric condition overall (after unipolar depressive disorders, alcohol use disorders and dementias including Alzheimer’s disease; V. Anttila, unpublished data based on WHO measures; see Figure 9 (Lokal_profil, 2009)). Among the 15-59 age group, migraine is the third most severe, with dementia understandably much rarer in this age group. A 1991 study in the US estimated the number of people suffering moderate to severe disability to be 11.3 million (8.7 million females, 2.6 million males), with 4.5 million people (3.4 million females, 1.1 million males) suffering from such attacks monthly (Stewart et al., 1992). The same study found that in the US migraine correlates strongly with economic status, with a 60% higher prevalence of migraine in the poorest income group when compared to the highest income groups.
The effects on quality of life are considerable (Solomon et al., 1993).
In Europe, a 2004 study estimated the total cost of migraine to be €27 billion in the EU, accounting for roughly a third of all costs due to neurological diseases – most in indirect costs (Andlin-Sobocki et al., 2005) (see Table 4). A US study in 2008 found the average direct cost of migraine to be $2,571 per patient (significantly higher than a matched migraine-free cohort) (Hawkins et al., 2008), with most of the costs arising from out-patient care and prescriptions; in-patient and emergency department care, though common in this group, accounted for only $1.25 billion (or ~10%) of direct costs as procedures or advanced interventions are rarely needed. An epidemiological study in 1999 calculated the average number of bed rest days due to migraine in the US to be 3.8 for men and 5.6 for women per year, for a total of 112 million bedridden days (Hu et al., 1999) – or approx. 1.8% of total workdays lost due to migraine.
Figure 9. Disease-adjusted life years lost due to migraine in 2002 per 100,000 inhabitants, according to WHO data. For reference, see text. No data was available for Morocco.
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Table 4. Costs due to brain disorders in Europe in 2004, organized by disease category. All costs in millions of euros, adjusted for purchasing power parity. From Andlin-Sobocki et al., 2005. Used with permission.
€ million in costs Healthcare Direct
non-medical Indirect Total
Neurosurgical diseases 4 099 269 3155 7523
Brain tumour 1 162 269 3155 4586
Trauma 2 937 2937
Neurological diseases 21 286 20259 42389 83934
Epilepsy 2 752 4240 8554 15546
Migraine and other headaches 1 495 25507 27002
Multiple sclerosis 2 194 3977 2598 8769
Parkinson’s disease 4 582 6140 10722
Stroke 10 263 5901 5730 21895
Neurological/mental disorders 12 840 42337 55176
Dementia 12 840 42337 55176
Mental disorders 97 221 9336 132985 239542
Addiction 16 655 3962 36657 57274
Affective disorders 28 639 77027 105666
Anxiety disorders 22 072 19301 41373
Psychotic disorders 29 855 5374 35229
All brain disorders 135 445 72200 178530 386175
Migraine attack
A migraine attack typically consists of four phases, any of which may be absent from an attack. These phases are the premonitory phase, the aura phase, the headache phase, and the postdromal phase (see Figure 10). The first (premonitory) and last (postdromal) phases are characterized by either positive or negative symptoms. The positive symptoms are roughly similar to an episode of hypomania, including hyperactivity, cravings and elevated and optimistic mood. More common are the
Figure 10. The typical procession of a migraine attack. Considerable variation exists – for example, the pain can immediately progress into the severe phase, or alternate between mild and severe pain.
Figure 11. Time series of fMRI imaging results showing a wave of cortical spreading depression, as it begins to spread from the occipital lobe of the brain of a patient having a migraine attack.
Different measurement points along the cortex reveal that the depolarization wave is spreading across the visual cortex. Adapted from Hadjikhani et al., 2001. Used with permission.
negative symptoms, similar to a depressive episode, including sadness, hopelessness, hypoactivity, excessive sleep and lack of motivation (International Headache Society, 2004).
The aura phase, present in MA patients and absent in MO patients, is detailed below.
The headache phase of a migraine attack typically lasts 4-72 hours. The pain has a number of typical features, which include a combination of some of the following: 1) a pulsating nature, that is, the intensity of the pain intensifies and de-intensifies with the heartbeat, 2) it is aggravated by physical activity, both suggesting a vascular link, 3) unilateral location, suggesting a central origin and the involvement of only one brain hemisphere, 4) to be of moderate or severe intensity, and 5) to be associated with nausea and/or vomiting and/or sensitivity to light or sounds, characterizing a general oversensitivity of the sensory system. Osmophobia (the fear of smells or in this case oversensitivity to smells) is, although not an official part of the criteria, considered a part of the clinical picture as well (International Headache Society, 2004).
Migraine aura and the cortical spreading depression
The migraine aura, presence of which differentiates the two main forms of common migraine, refers to gradually developing neurological symptoms (ranging from auditory hallucinations to full paralysis, and covering most neurological symptoms possible), lasting at least several minutes and less than one hour, although in reality the variation is greater and
aura may, in rare cases, last even for several weeks. The symptoms are fully reversible, though they may be followed by a post-ictal phase after the attack, and the symptoms are typically
only one-sided (International Headache
Society, 2004).
The aura is thought to be the outcome of a slowly spreading wave of depolarization in the brain, called cortical spreading depression (CSD), first detected in 1944 by Leao et al. (Leao, 1944). It is a wave of increased neuronal activity and cerebral blood flow, which moves at 2-3 mm / minute (Pietrobon, 2005). After the wave has passed, a recovery period
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occurs within the neurons and cerebral blood flow is reduced. In imaging studies (see Figure 11), the spread of the CSD correlates with symptoms on the affected cortical region – for example, as the wave spreads across the visual cortex, the patient can observe a corresponding pattern in the visual field (Hadjikhani et al., 2001).
Typically, the migraine aura includes a combination of visual, sensory, and speech disturbances. These are divided into positive and negative symptoms, depending on whether the disturbance is adding sensory (non-existing) information or removing it.
Examples of positive symptoms include scintillating scotoma (visual cortex), where objects “gain” jagged edges, or the sensory symptom of “pins and needles”, a pain sensation without an external cause (sensory cortex). Negative symptoms can include partial blindness (visual cortex) or numbness (sensory cortex).
International Classification of Headache Disorders
The first version of the headache classification, ICHD-I (Headache Classification Committee of the International Headache Society, 1988), was published in 1988 by the International Headache Society (see Table 5). It was the first time a hierarchical classification of all headache-related disorders was published, and represented a major step in reproducibility for both research and clinical practice for disorders which are, after all, largely description-based. It is part of the WHO International Classification of Diseases (ICD-10). It was last updated in 2004 with the introduction of the 2nd edition (see Table 6), ICHD-II (International Headache Society, 2004).
Table 5. Diagnostic criteria for Migraine without Aura, 1988 (Headache Classification Committee of the International Headache Society, 1988) and 2004 (International Headache Society, 2004). Criteria have remained unchanged between the editions.
1.1 Migraine without aura
A. At least five attacks fulfilling criteria B–D
B. Headache attacks lasting 4–72 h (untreated or unsuccessfully treated) C. Headache has at least two of the following characteristics:
1. Unilateral location 2. Pulsating quality
3. Moderate or severe intensity (inhibits or prohibits daily activities) 4. Aggravation by walking stairs or similar routine physical activity D. During headache, at least one of the following:
1. Nausea and/or vomiting 2. Photophobia and phonophobia E. At least one of the following:
1. History, physical - and neurological examinations do not suggest secondary cause of headache
2. History, physical - and neurological examinations do suggest such disorder, but it is ruled out by appropriate investigations
3. Such disorder is present, but migraine attacks do not occur for the first time in close temporal relation to the disorder
Table 6. Diagnostic criteria for migraine with aura, according to the 1988 IHS classification (1.2 Migraine with Aura) (Headache Classification Committee of the International Headache Society, 1988) and the 2004 classification (1.2.1 Typical Aura with Migraine Headache) (International Headache Society, 2004).
1.2 Migraine with aura (1988)
A. At least two attacks fulfilling criterion B
B. At least three of the following four characteristics:
1. One or more fully reversible aura symptoms indicating focal cerebral cortical and/or brain stem dysfunction
2. At least one aura symptom develops gradually over >4 min, or >= 2 symptoms occur in succession
3. No aura symptom lasts >60 min. If more than one aura symptom is present, accepted duration is proportionally increased
4. Headache follows aura with a free interval of >60 min (it may also begin before or simultaneously with the aura)
C. At least one of the following:
1. History, physical - and neurological examinations do not suggest secondary cause of headache
2. History, physical - and neurological examinations do suggest such disorder, but it is ruled out by appropriate investigations
3. Such disorder is present, but migraine attacks do not occur for the first time in close temporal relation to the disorder
1.2.1 Typical aura with migraine headache (2004) A. At least two attacks fulfilling criteria B–D
B. Aura consisting of at least one of the following, but no motor weakness:
1. Fully reversible visual symptoms including positive features (e.g., flickering lights, spots, or lines) and/or negative features (i.e., loss of vision)
2. Fully reversible sensory symptoms including positive features (i.e., pins and needles) and/or negative features (i.e., numbness)
3. Fully reversible dysphasic speech disturbance C. At least two of the following:
1. Homonymous visual symptoms (note: additional loss or blurring of central vision may occur) and/or unilateral sensory symptoms
2. At least one aura symptom develops gradually over >=5 min, and/or different aura symptoms occur in succession over >= 5 min
3. Each symptom lasts >= 5 and <= 60 min
D. Headache fulfilling criteria B–D for 1.1 Migraine without aura begins during the aura or follows aura within 60 min
E. Not attributed to another disorder (note: history and physical - and neurological examinations do not suggest any of the disorders listed in groups 5–
12 [see Table 3], or history and/or physical and/or neurological examinations do suggest such disorder but it is ruled out by appropriate investigations, or such disorder is present but attacks do not occur for the first time in close temporal relation to the disorder)
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Figure 12. Illustration of the relevant anatomical structures involved in migraine pathophysiology, from Goadsby et al, 2002. Copyright © [2002] Massachusetts Medical Society. All rights reserved. (reprinted with a permission from New England Journal of Medicine).
Migraine pathophysiology: neuronal versus vascular theory
Relatively little is known of the pathophysiology of migraine and discussion has been dominated by two theories: the neuronal and the vascular theories of migraine. The former is currently favored (Dodick and Silberstein, 2006). The consensus is that some triggering event, with or without genetic or environmental predisposing factors, sets up a state of cortical neuronal hyperexcitability (Pietrobon and Striessnig, 2003).
This puts the brain in a state that allows the propagation of a strong polarizing wavefront. Various mechanisms have been implicated to explain why the brain is susceptible to such waveforms, like excess glutamate in the brain, but no consensus on the matter exists yet. In contrast, the propagation of brain waves is more strictly controlled in the normal state brain (Lopes da Silva, 1991). CSD and its progression across different regions of the cortex are considered to be responsible for the various aura symptoms. The intense neuronal activity associated with the passing wave and the reduced blood flow following it are thought to trigger the pain sensation of migraine. The likely mechanism for the pain is thought to be a combination of neurogenic sterile inflammation and central sensitization (i.e. incorrect pain handling).
This central sensitization is believed to arise from brainstem dysfunction causing impaired nociception, especially in the region of periaqueductal grey (PAG), various
brainstem nuclei and the trigeminal ganglion (see Figure 12). A generalized decreased inhibition in this region is thought to underlie both the pain perception, the sensitivity to sensory stimuli (Pietrobon et al., 2003), and the response to stress (Domingues et al., 2009), which is one of the key triggers of migraine. Other observations supporting the role of a neuronal mechanism in migraine include a recent imaging study that pointed to the role of hypothalamic activation in migraine (Denuelle et al., 2007) and several studies that have pointed to abnormal response to stimuli and signal processing in migraineurs between attacks. Abnormal habituation is seen to characterize the response to both visual and auditory signals in MA patients (Afra et al., 2000) and both MA and MO patients (Wang et al., 1996), suggesting a migraine brain potentiates certain types of abnormal repeated stimuli. Abnormal habituation suggests an ongoing interictal habituation dysfunction among migraineurs. A number of studies have linked such habituation defects to glutamate in Aplysia (Ezzeddine and Glanzman, 2003) and mice (Bespalov et al., 2007). In rats, blockage of metabotropic glutamate receptors were found to influence short-term habituation to olfactory stimuli (Best et al., 2005, (Yadon and Wilson, 2005). In summary, the neuronal theory of migraine postulates that this neurogenic activity is sufficient to cause migraine, and that the vascular aspects of migraine are caused by CSD or other neuronal phenomena (Dodick et al., 2006).
The vascular theory of migraine is based largely on the observation that a number of vasodilatory substances can induce migraine in humans (Schytz et al., 2009) and that migraine medications, like ergotamine (Tunis and Wolff, 1953) and triptans (Humphrey and Goadsby, 1994), produced strong vasoconstriction. Vascular smooth muscle dysfunction is also often suggested to play a role in migraine pathophysiology (Tietjen, 2009). The vascular theory is also supported by a number of findings in monogenic syndromes, as discussed in chapter 5. However, current understanding heavily favors the neuronal hypothesis, which accounts for the vascular effects as incidental or unrelated (Goadsby, 2009). For instance, a recent imaging study showed the lack of cerebral vasodilation during migraine attacks (Schoonman et al., 2008).
Regardless of the underlying theory, a number of observations point to a potentially pivotal role of enhanced brain glutamate levels behind the hyperexcitability of a migrainous brain, as well as in the triggering of migraine attacks (Goadsby et al., 2006). The main findings supporting a key role for glutamate in migraine pathophysiology include: (i) glutamate receptor antagonists may have acute anti-migraine activity (Andreou and Goadsby, 2009); (ii) the great majority of preventive migraine agents, despite belonging to widely different pharmacological classes, share the ability to block CSD in experimental animal models (Ayata et al., 2006) and may modify the glutamate-mediated trigeminal pain pathway (Shields and Goadsby, 2005, (Storer and Goadsby, 1999); (iii) the increased cortical release of glutamate fully explains the dramatically increased susceptibility to CSD seen in transgenic mouse models of FHM1 (Tottene et al., 2009, (van den Maagdenberg et al., 2010); (iv) noxious dural stimulation, as an experimental animal model for acute migraine, increases glutamate release from trigeminal ganglion neurons (Goadsby and Classey, 2000); (v) plasma (Ferrari et al., 1990) and cerebrospinal fluid (Martinez et al., 1993) levels of glutamate are increased in migraineurs with and without aura in between attacks, further rising during attacks; (vi) a recent magnetic resonance spectroscopy study suggested that migraineurs have different glutamate-to-glutamine ratios when compared to controls, suggesting malfunction of excitatory amino acid transporters in
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deep brain structures of migraineurs (Prescot et al., 2009); (vii) in a patient with a severe phenotype of migraine-like headaches and additional neurological episodic features, a missense mutation in the EAAT1 glutamate transporter gene was associated with severely reduced glial uptake of glutamate (Jen et al., 2005); and (viii) glutamate-mediated thalamocortical transmission is crucial for head pain (Storer et al., 1999). A recent study suggested that in trigeminal neurons, glutamate release (as well as the release of calcitonin-gene related peptide, another neurotransmitter intricately linked with migraine) is controlled by calcium channels (Xiao et al., 2008), providing a possible link between glutamate and the known familial hemiplegic migraine genes (see Chapter 5).
Arecommonformsofmigrainedistinctorpartofthesamespectrum?
One of the key open questions in migraine research is whether the two main types of common migraine are separate entities or simply slightly weaker/stronger versions of the same condition. The main arguments in favor of the “distinct disorders”
hypothesis are that: the affected-sibling risk ratios are considerably different: 1.9 for MO, 3.8 for MA (Russell and Olesen, 1995); a majority of patients never suffer from attacks with aura; the existence of a form of migraine where aura is present without headache (equivalent migraine); and that these forms are traditionally clearly dichotomized in diagnostic criteria ( (International Headache Society, 1988)). The
“distinct disorders” hypothesis is also supported by several population-based surveys (Russell et al., 1995, Russell et al., 1996, Russell et al., 2002) and it should be noted that a majority of the comorbidity studies in migraine (see below) have found positive correlations specifically with MA and not migraine in general. One example of this is a recent study which showed that the risk of developing epilepsy was considerably increased in MA patients, but not in MO patients (Ludvigsson et al., 2006).
Furthermore, the study by Kruit et al., 2004 showed that the increased risk for brain lesions was only found among MA patients.
Counterarguments in favor of the “variations on a spectrum” hypothesis also exist (e.g. Kallela et al., 2001b) and are supported by genetic studies and a latent class analysis of migraine (Ligthart et al., 2006, Nyholt et al., 2004). Arguments in favor of this view include that most MA patients suffer from both types of attacks with varying frequencies and that patients suffering attacks where solely aura is present being a rarity, as well as that affected-sibling risk ratios are higher across the diseases - that is, the likelihood for a second sibling to develop MA when the first sibling has MO is greater than the general risk (Ulrich et al., 1999), and vice versa. Indeed, most MA patients suffer from attacks with and without aura, and thus fall on a frequency (or
Counterarguments in favor of the “variations on a spectrum” hypothesis also exist (e.g. Kallela et al., 2001b) and are supported by genetic studies and a latent class analysis of migraine (Ligthart et al., 2006, Nyholt et al., 2004). Arguments in favor of this view include that most MA patients suffer from both types of attacks with varying frequencies and that patients suffering attacks where solely aura is present being a rarity, as well as that affected-sibling risk ratios are higher across the diseases - that is, the likelihood for a second sibling to develop MA when the first sibling has MO is greater than the general risk (Ulrich et al., 1999), and vice versa. Indeed, most MA patients suffer from attacks with and without aura, and thus fall on a frequency (or