Concepts and Mechanisms of Migraine Chronification

Authors

  • Marcelo E. Bigal MD, PhD,

    1. From the Departments of Neurology, Albert Einstein College of Medicine and The Montefiore Headache Center, Bronx, NY, USA (Bigal); Departments of Neurology and Epidemiology and Population Health, Albert Einstein College of Medicine, and The Montefiore Headache Center, Bronx, NY, USA (Lipton).
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  • Richard B. Lipton MD

    1. From the Departments of Neurology, Albert Einstein College of Medicine and The Montefiore Headache Center, Bronx, NY, USA (Bigal); Departments of Neurology and Epidemiology and Population Health, Albert Einstein College of Medicine, and The Montefiore Headache Center, Bronx, NY, USA (Lipton).
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  • Conflict of Interest: None

Marcelo E. Bigal, Department of Neurology, Albert Einstein College of Medicine, 1165 Morris Park Avenue, Bronx, NY, USA.

Abstract

Migraine is a chronic recurrent disorder with episodic manifestations that is progressive in some individuals. Migraine progresses clinically, physiologically, and anatomically. Progression may be a consequence of the mechanisms that generate the migraine attacks (eg, cortical spreading depression) or it may be a function of the activations generated by the attacks (eg, lesions in the periaqueductal gray area), a hypothesis supported by the increase in lesions with attack frequency. Progression may also be partially explained by common genetic or environmental risk factors. Finally, migraine with aura is associated with an elevated Framingham score and with risk factors for cardiovascular disease. Research on this issue is in its infancy and cautions are necessary before extrapolating this information into clinical practice.

INTRODUCTION

Traditionally seen as an episodic disease, our understanding of migraine has evolved over the past decades.1 Interictally, migraineurs have an enduring predisposition to attacks,2 abnormalities in cortical processing,3,4 and impaired health-related quality of life.5 These findings all support the idea that migraine is not just an episodic disorder but a chronic disorder with episodic manifestations.6 Furthermore, some migraine sufferers have a clinically progressive disorder characterized by attacks of increasing frequency, at times leading to headaches more days than not. This state is often referred to as transformed or chronic migraine (TM or CM), a subtype of the chronic daily headaches (CDH).7 Finally, recent evidence suggests that migraine, particularly migraine with aura, is a risk factor for anatomical brain lesions.8 Therefore, migraine is now seen as a chronic disorder with episodic manifestations, progressive in some individuals.9-11

Accordingly, some people with migraine experience long-term changes that may be conceptualized as complications of migraine and measured at clinical, function, and anatomic levels of analysis. Typically, progression refers to increases in attack frequency over time leading to CM, which characterizes clinical progression. A less discussed form of migraine progression may be defined in terms of physiological progression, where migraine leads to changes in the central nervous system which manifest themselves through alterations in nociceptive thresholds (allodynia) and alterations in pain pathways (eg, central sensitization). Finally, an even less discussed form of progression takes the form of definitive lesions (anatomical progression), and includes stroke, white matter lesions, and other enduring features (Fig. 1).

Figure 1.—.

Overall concept of migraine natural history. PAG = periaqueductal gray.

In this paper, we conceptualize migraine as a progressive disease and propose mechanisms to justify the current findings. We first clinically describe migraine progression. We then define the nonmutually exclusive forms of progression. We close by speculating on the mechanisms that may lead to migraine progression.

CONCEPTUALIZING MIGRAINE PROGRESSION

Migraine progression is supported by both clinical observation and epidemiologic research.12-14 In a longitudinal epidemiologic study, the Frequent Headache Epidemiology Study, over the course of 1 year, 3% of individuals in the general population with infrequent episodic headache (2 to 104 headache days per year) progressed to CDH; an additional 6% progressed to high frequency episodic headaches, characterized by 105-179 headache days/year.14 In a larger follow-up study of 11,000 migraineurs from the population (the American Migraine Prevalence and Progression-AMPP study), 3.2% developed CDH over the course of 1 year (Lipton and Bigal, data in preparation). Rates of progression in clinic-based studies are higher.15

These and other observations support a transition model for migraine, where migraine progression does not occur abruptly (Fig. 2). According to this model, individuals with low frequency episodic migraine sometimes progress to an intermediate state of high frequency episodic migraine (HFEM), with a transition rate λ1. HFEM remits with a rate λ2 and transitions to CM with a rate λ3. CM remits with a rate λ4. All transition rates can be modeled as a function of demographic, environmental, and genetic risk factors. This model addresses the observation that transitions from one form of migraine to another are frequent and bidirectional14 (Lipton et al, unpublished data). It also provides a framework for understanding the influence of risk factors at various stages of illness and lends itself to the development and testing of stage specific intervention strategies.

Figure 2.—.

Conceptual framework of migraine clinical progression. λ are described in the text.

Although some factors associated with λ1 (determining an increase in episodic migraine frequency) may be different than the factors associated with λ3 (determining CM), to the best of our knowledge, the currently identified risk factors for CM also increase episodic migraine frequency (eg, obesity, caffeine overuse, medication overuse).13,16-18 This justifies our staged model of migraine progression and also has clinical implications. Using this framework, when clinicians treat HFEM, the goals are to increase clinical remission (enhancing λ2) and prevent clinical progression by minimizing λ3. In the treatment of CM the initial goal is to maximize λ4.

THE CLINICAL PROGRESSION OF MIGRAINE

Migraine progression usually happens over months or years, and as headache increases in frequency, associated symptoms become less severe and frequent. The process of transformation frequently ends in a pattern of daily or nearly daily headache that may resemble chronic tension-type headache, with some attacks of full-migraine superimposed.7,12,13 In the clinical setting, migraine progression is most often related to acute medication overuse,15,19,20 but in the population, more than half of the cases are associated with other risk factors.14 Describing the risk factors for migraine progression is beyond the scope of this paper and authors are referred to Scher and Lipton, in another section of this supplement.

The distinguishing feature of CM is that it does not develop de novo in a previously headache-free subject (if CDH develops de novo, the diagnosis is new daily persistent headache). Subjects may not recall the escalation in headache frequency. However, without a past history of episodic migraine or escalation in headache frequency, there is no migraine progression.

The Phenotype of CM Changes with Age and Disease Duration.— Over the past years, there has been a lot of controversy about the best way to classify the result of migraine clinical progression. Initially, the Second Edition of the International Classification of Headache Disorders (ICHD-2) required the presence of 15 or more days of migraine per month.21 Based on research that demonstrated the unfeasibility of use of such criteria,22,23 the ICHD-2 was revised to 15 days of headache per month and 8 days of migraine or use of specific migraine medications.24

The difficulty in classifying CM is largely caused by the fact that phenotype of the disease changes over time. In a study of 402 subjects with CDH evolving from migraine, we showed that the proportion of migraine attacks decreased with age (with a proportional increase of tension-type headache attacks), from 71% below the age of 30 years to 22% aged 60 or above.25 Migraines were also more common in those with shorter interval from the onset of migraine to the onset of TM (<5 years, P = .003), and in those with a more recent onset of TM (<6 years, P < .0001). These findings suggest that initially, CM is characterized by migraine in most days. Subsequently, the frequency of migraine attacks diminishes, and most attacks will lack migraine features (Fig. 3). The findings of this study support what is seen in clinical practice and has been taught by headache specialists for many years.

Figure 3.—.

Proportion with subjects with chronic migraine and ≤15 and with 15 or more days of migraine per month as a function of time elapsed between the onset of episodic headache and the onset of transformed migraine.

The Phenotype of CM is Not the Same in Adolescents and Adults.— Differences exist regarding the clinical presentation of CM in adolescents and adults as well. Most adults with CM have less than 15 days of full-blown migraine per month, and more days of headache resembling tension-type headache than of migraine. CM in adolescents is replete of migraine attacks, further supporting the concept that the phenotype of CM changes as a function of age and duration of disease.26 Second, most adults with CM are overusing acute medication (84%), while most adolescents (58.9%) are not, suggesting the importance of biological risk factors in those who develop CM early in life.27

THE PHYSIOLOGICAL PROGRESSION OF MIGRAINE

An imaging study has shown that iron deposition occurs in the periaqueductal gray (PAG) area in subjects with frequent headaches.28 The PAG area is related to descending analgesic network and is important in controlling pain and providing endogenous analgesia. It is closely related to the trigeminal nucleus caudalis. Welch et al compared individuals with episodic migraine, CDH, and controls, imaged with a 3.0-tesla magnetic resonance system. For each subject, mean values of the relaxation rates, R2 (1/T2), R2* (1/T2*), and R2′ (R2*– R2) were obtained for the PAG, red nucleus, and substantia nigra. There was a significant increase in mean R2′ and R2* values in both the migraine and CDH groups (P < .05) compared with the control group, but no significant difference in these values was demonstrated between the migraine and CDH groups, or between those with migraine with or without aura in the migraine group. Positive correlations were found for duration of illness with R2′ in the migraine and CDH groups. A decrease in mean R2′ and R2* values also was observed in the substantial nigra and red nuclei on the CDH group compared with migraineurs, and in migraineurs compared with controls (P < .05).

The authors suggested that iron homeostasis in the PAG was selectively, persistently, and progressively impaired in the migraine and CDH groups, possibly caused by repeated migraine attacks. These results support and emphasize the role of the PAG modulating migraine attacks, potentially by dysfunctional control of the trigeminovascular nociceptive system. Although the iron accumulation observed in this study could be considered anatomical rather than functional, we elected to discuss it herein because the relevant finding is indeed the functional impairment in the PAG that may happen as a consequence of repetitive migraine attacks. The iron accumulation would be just a biomarker of such impairment. Furthermore, the PAG damage may happen as a consequence of central sensitization (see below), which is manifested by cutaneous allodynia (CA), another marker of functional progression.

Burstein et al showed that around 75% of the migraine sufferers develop central sensitization (sensitization of the second order trigeminal neuron, which is clinically manifested by the development of CA) during the course of a migraine attack.29 In the population, CA correlates with migraine frequency, severity, and disability.30 CA is more prevalent in individuals with CM than with episodic migraine and in both CM and episodic migraine than in chronic tension type headache, suggesting that CA maps onto migraine biology (Fig. 4).31 Finally, CA appears to be associated with triptan refractoriness.32

Figure 4.—.

Relative frequency and severity of CA according to the headache subtype. CA = cutaneous allodynia; CM = chronic migraine; ETTH = episodic tension-type headache; M = migraine; O-CDH = other chronic daily headaches; PM = probable migraine. From Bigal et al.31

Central sensitization may play a role in the progression of the disease itself. It may be suggested that repeated central sensitization episodes are associated with permanent neuronal damage at the level of, or close to, the PAG, with poor modulation to pain, and treatment refractoriness, therefore predisposing to disease progression. Central sensitization is also a functional marker of progression, since it is more common in CM than in migraine (Fig. 3).

THE ANATOMICAL PROGRESSION OF MIGRAINE

Markers of Progression in the Brain.— White matter hyperintensities (WMHs) have traditionally been considered to be more common in migraineurs, although the variability of the prevalence (4% to 40%) is within the limits generally reported in the population.33 In a meta-analysis of published studies, WHMs were more common in migraineurs than controls (OR = 3.9, 95% CI = 2.2-6.7) and the risk was independent of age and vascular risk factors.34

More recently, Kruit et al used a cross-sectional design to study Dutch adults aged 30-60 years.8 They showed that male subjects with migraine with aura, and women with migraine with or without aura were at a higher risk of deep white matter lesions, compared with controls. The white matter lesions increased with attack frequency, possibly demonstrating progression of the disease. This study showed a dose–response effect, in that the number of lesions increased with migraine attacks frequency, even after adjusting for confounders.

Although the white matter lesions are described herein as anatomical changes, we still do not know the nature of these lesions (ischemic, metabolic), and whether they are permanent or not. Current studies are exploring some of these issues (Ferrari, personal communication).

The association between migraine, especially with aura and stroke has been suggested for many years. In a population study in the Netherlands, migraine with aura was a risk factor for subclinical ischemic lesions in the posterior fossa and in the brainstem (table 1).8 In a second study, the same group found that migraineurs with infratentorial ischemia were more likely to have supratentorial white matter lesions as well. They suggested that hemodynamic changes may give rise to both deep white matter lesions and posterior fossa strokes.35

Markers of Progression Outside the Brain.— Two very large population studies also supported that migraine is a risk for cardivovascular illness overall, not just stroke. If migraine predisposes to cardiovascular events, these events should also be seen as markers of anatomical migraine progression.

In the Women's Health Study, a cohort study that followed nearly 28,000 women for an average of more than 10 years, migraine with aura increased the risk of angina, nonfatal ischemic stroke, myocardial infarction, as well as death related to cardiovascular events.36 The study followed presumably healthy women, aged 45 or older, to test the benefits of low dose of aspirin and vitamin E in the prevention of cardiovascular disease (CVD) and cancer. Migraine with aura was associated with about a 2-fold increased risk of major CVD, ischemic stroke and ischemic cardiovascular death and a 1.7-fold increased risk of myocardial infarction and coronary revascularization. These associations remained significant after adjusting for many cardiovascular risk factors and did not occur in the most common type of migraine, migraine without aura.

In the Physicians Health Study, Kurth et al followed men over the age of 45 and found that migraine was a risk factor for heart disease. Reasons for a weak association with stroke are uncertain.37

Accordingly, evidence supports the concept that at least migraine with aura is associated with deep brain lesions, ischemic stroke, and ischemic heart disease. Although it is difficult to exclude the possibility that in some individuals transient ischemic attacks (TIAs) are misclassified as aura, this seems unlikely.

POTENTIAL MECHANISMS OF MIGRAINE PROGRESSION

Although the source of pain in primary CDH is unknown and may be dependent on the subtype, recent work suggests that the following mechanism, alone or in combination, contribute to the process38: (1) abnormal excitation of peripheral nociceptive afferent fibers in the meninges; (2) enhanced responsiveness of trigeminal nucleus caudalis neurons; (3) decreased pain modulation from higher centers such as the PAG matter; (4) spontaneous central pain generated by activation of the “on cells” in the medulla; (5) abnormal serotonin modulation; (6) central sensitization.

Herein we discuss the forms of migraine progression under 3 perspectives: (1) cortical spreading depression (CSD) as a potential source of brain lesions; (2) brainstem activation as a potential source for subcortical lesions; (3) lessons from the epidemiological studies and the role of comorbidities.

CSD – MATRIX METALLOPROTEINASE (MMP)-9 AND MIGRAINE

Cortical spreading depression, a self-propagating wave of neuronal and glial depolarization, has been implicated in the genesis of aura.39 Cascading depolarization marching across the cortical mantle initiates a series of cellular and molecular events, resulting in transient loss of membrane ionic gradients, as well as massive surges of extracellular potassium, neurotransmitters, and intracellular calcium. CSD may mediate its effects in part by altering the permeability of the blood–brain barrier (BBB) via activation of MMPs, a family of neutral metalloproteases.40 MMP activation causes opening of the BBB, immune cell invasion of neural tissue, and direct cellular damage in nervous system diseases.

In animal models, CSD rapidly activated and upregulated MMPs, possibly via constitutive expression of MMPs in the blood vessels. MMP-9 activation occurs within 15 to 30 minutes of CSD propagation. During CSD, oxygen-free radicals, nitric oxide, and proteases – factors that have been implicated in MMP activation – are dramatically increased.40 The CSD-related MMP activation may underlie changes in vascular permeability in the central nervous system and thus contribute to the generation of migraine symptoms. The disruption in the steady state of the brain, leading to perfusion changes, may also explain why migraine with aura is consistently found as a risk factor for stroke and deep brain lesions.

LESIONS IN THE PAG AREA

The PAG area is important in controlling pain and providing endogenous analgesia. It is closely related to the trigeminal nucleus caudalis. As exposed above, Welch et al compared individuals with migraine, CDH, and controls and found iron deposition in the PAG area in migraineurs and CDH sufferers vs controls. The authors suggested that iron homeostasis in the PAG was selectively, persistently, and progressively impaired in the migraine and CDH groups, possibly because of repeated migraine attacks.30 It may be suggested that repeated central sensitization episodes are associated with permanent neuronal damage at the level of, or close to, the PAG, with poor modulation to pain, preventive treatment refractoriness and disease progression.

LESSONS FROM THE EPIDEMIOLOGICAL STUDIES

As discussed above, CSD and dysmodulation of the PAG may explain clinical progression and deep brain lesions, but could not explain the association between migraine and CVD, an issue that has raised much debate.

Although unlikely, spurious association should be bared in mind when assessing studies that addressed the potential for migraine complications (Fig. 5). The studies of Kurth, with its prospectively determined outcomes, protects against a number of sources of bias.36,37 Furthermore, the authors measured and adjusted for many, though certainly not all, risk factors for CVD. For example, patent foramen ovale (PFO) may be comorbid with migraine with aura (MA).41 Although it is unlikely that PFO explains the risk for coronary disease, it may have contributed to the association between migraine and stroke.

Figure 5.—.

Potential mechanisms that explain the relationship between migraine and cardiovascular disease. CM = chronic migraine; CVD = cardiovascular disease.

In most studies, the association of CVD is either limited to or much stronger in migraine with aura. In theory, the stress of migraine attacks could unmask coronary artery disease acutely, or contribute to the development of vasculopathy over multiple headache attacks. If that were true, we would expect an association also with migraine without aura. This hypothesis is, therefore, inconsistent with the data. Similarly, an environmental exposure, which accounted for the association would have to have differential effects in migraine with and without aura. For example, medications which constrict coronary arteries, such as the triptans and compounds containing ergotamine, could increase the risk of CVD in treated migraine sufferers. Since migraine with and without aura are similarly treated, this hypothesis seems unlikely.42,43

Two studies of Scher et al44,45 add to our knowledge in this regard. In comparison with controls, MA was associated with a significantly increased risk for hyperlipidemia, hypertension, and elevated Framingham scores. Furthermore, a polymorphism in the methyltetrahydofolate reductase gene (T677T) is associated with moderately elevated levels of homocysteine which, in turn, is associated with risk of CVD. The same polymorphism is over-expressed in migraine with but not migraine without aura.

CONCLUSION

Migraine should be seen as a chronic recurrent disease that is progressive in individuals with high biological predisposition or are exposed to risk factors. Progression happens clinically, but also functionally and anatomically. Progression may be a consequence of the underlying mechanisms that generate the migraine attacks itself (eg, CSD) or it may be a function of the activations generated by the attacks (eg, PAG lesions), a hypothesis supported by the increase in lesions with attack frequency. Progression may be partially explained by common genetic risks and exposures. Finally, migraine with aura is associated with an elevated Framingham score and with risk factors for cardiovascular disease. However, in most studies, adjustments for cardiovascular risk did not attenuate the association. Research on this issue is in its infancy and cautions are necessary before extrapolating this information into clinical practice.

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