REVIEW URRENT C OPINION
Migraine and structural abnormalities in the brain Anders Hougaard, Faisal Mohammad Amin, and Messoud Ashina
Purpose of review The aim is to provide an overview of recent studies of structural brain abnormalities in migraine and to discuss the potential clinical significance of their findings. Recent findings Brain structure continues to be a topic of extensive research in migraine. Despite advances in neuroimaging techniques, it is not yet clear if migraine is associated with grey matter changes. Recent large populationbased studies sustain the notion of increased prevalence of white matter abnormalities in migraine, and possibly of silent infarct-like lesions. The clinical relevance of this association is not clear. Structural changes are not related to cognitive decline, but a link to an increased risk of stroke, especially in patients with aura, cannot be ruled out. Summary Migraine may be a risk factor for structural changes in the brain. It is not yet clear how factors such as migraine sub-type, attack frequency, and sex affects this association. Additional longitudinal studies are needed to address these issues. Brain structure changes in migraine could potentially serve as disease biomarkers or as a mean of identifying sub-groups of patients with specific therapeutic needs and prognoses. Keywords brain structure, cortical thickness, migraine, MRI, voxel-based morphometry, white matter hyperintensities
INTRODUCTION Migraine has traditionally been considered a disorder caused by dysfunction of the brain and trigeminovascular nociception, not involving structural brain abnormalities. The natural history of migraine is usually non-progressive and without development of persisting symptoms. Therefore, in current clinical practice, brain imaging of migraine patients has the sole purpose of excluding structural causes of secondary migraine, and migraine-associated pathology. The advent of MRI has made it possible to non-invasively obtain high-resolution anatomical images, optimized for visualizing different tissues and features of the human brain. This has fostered extensive research into the brain structure of migraine patients, now suggesting abnormalities of grey and white matter as key characteristics of this disorder. The purpose of this review is to summarize the current literature on this subject.
GREY MATTER Voxel-based morphometry (VBM) [1] is probably the most widely used method for whole-brain evaluation of local grey matter morphology based on magnetic resonance (MR) images. It is not well
understood what VBM changes reflect. Histological measures, such as neuronal density, do not correlate with VBM grey matter probability maps [2] and changes in cerebral blood flow produce ‘apparent’ grey matter volume changes in VBM analyses [3 ]. In a typical whole-brain VBM analysis, there are more than 10 00 000 comparisons of grey matter voxels carried out. Correcting the statistics for multiple comparisons is therefore essential to avoid falsepositives, and efficient statistical methods have been developed to address this issue [4]. Only two [5,6] out of eight VBM studies [5–12] comparing migraine patients to healthy controls have reported significant differences on a whole-brain level following correction for multiple comparison. These were &
Danish Headache Center and Department of Neurology, Glostrup Hospital, Faculty of Health and Medical Sciences, University of Copenhagen, Denmark Correspondence to Messoud Ashina, MD, PhD, DMSc, Danish Headache Center and Department of Neurology, Glostrup Hospital, Faculty of Health and Medical Sciences, University of Copenhagen, Ndr. Ringvej 67, Building 14, DK-2600 Glostrup, Denmark. Tel: +45 38 63 30 54; fax: +45 38 63 38 39; e-mail: [email protected] Curr Opin Neurol 2014, 27:309–314 DOI:10.1097/WCO.0000000000000086
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KEY POINTS The existence, and possible significance, of structural grey matter abnormalities of the brain in migraine patients is presently uncertain, and more research into this topic is warranted. Migraine has been linked to a moderately increased prevalence of white matter abnormalities and silent infarct-like lesions on brain imaging evaluation, but the clinical significance of these changes is unclear. Increased white matter abnormalities and infarct-like lesions in migraine patients could be confined to certain sub-groups of patients with distinct pathophysiological characteristics. Migraineurs with a normal neurologic examination do not require routine MR. Incidental findings of infarct-like lesions or pronounced white matter abnormalities should prompt screening for stroke risk factors in persons with or without migraine.
decreased grey matter in the anterior cingulate, frontal, temporal, and occipital cortex, and the cerebellum and brainstem [5,6]. Other VBM studies have reported grey matter decrease in a-priori designated areas of the brain, while correcting for multiple comparison of voxels in these areas specifically [5,8,11]. Notably, grey matter reduction of the cingulate cortex and insula, in migraine patients compared to controls, has been reported in two independent studies [11,13] using this approach. A recent longitudinal VBM study compared the grey matter of migraine patients before and after a 1-year period and found decreased grey matter volume in several cortical and sub-cortical brain areas, including the hippocampus, but not including the cingulate or insula [14 ]. Surface-based morphometry (SBM) is a more recent approach for automatically detecting white–grey matter boundaries, which allows detection of local differences in cortical thickness. When comparing whole-brain cortical thickness between groups, many comparisons are made, not of voxels as in VBM, but of thickness values at the vertices of the tessellated three-dimensional surface reconstruction. Six studies have applied SBM to compare migraine patients to healthy controls [15–18, 19 ,20]. One study reported an increase in grey matter thickness in the somatosensory cortex (SSC) in patients with migraine [16]. In addition, an increase in grey matter thickness in visual motion processing areas (V3A and MTþ) has been reported [15]. However, these findings could not be reproduced in a subsequent study of a large number of &
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patients [17]. One study reported a very small, but significant global increase of cortical thickness in migraine patients compared to controls (2.08 and 2.02 mm, respectively) [18]. Following correction for multiple comparisons, increased cortical thickness was observed specifically in the left temporooccipital incisure [18]. Maleki et al. [20] reported significantly thicker cortex in the precuneus and posterior insula in migraineurs compared to controls. In another study, demonstrating functional and structural differences between migraineurs with frequent and less frequent attacks, high-frequency migraineurs had a thinner cortex of the insula and cingulate and increased thickness of the somatosensory and temporal cortices compared to healthy controls, whereas low-frequency migraineurs had a thinner somatosensory and temporal cortex than controls [19 ]. Recently, studies of grey matter structure in migraine have focused on the basal ganglia. One study applied quantitative MR relaxometry to compare the structure of the thalamus between migraine patients with and without aura and healthy controls [21 ]. Relaxometry comprises mapping of magnetization transfer, and T1 and T2 relaxation. Magnetization transfer is considered a direct measurement of myelin, T1 relaxation is sensitive to tissue water, and T2 depends on iron content. The authors reported significant differences between patients with and without aura for all three measures, but found differences to controls only for T1 relaxation of the right thalamus. Another recent study, specifically investigating basal ganglia volume using automatic segmentation, reported volume reduction of the left caudate and right nucleus accumbens in migraineurs compared to controls [22]. In addition, increased hippocampal volume in low-frequency migraineurs, compared to both healthy controls and to high-frequency migraineurs, has been reported [23]. Collectively, the current literature does not leave a clear picture of grey matter structure in migraine. The reported abnormalities need confirmation from future studies, and more longitudinal studies are required to determine if potential changes develop or progress over time as a possible consequence of migraine. It is puzzling that VBM studies generally suggest decreased grey matter volume, whereas the opposite is the case for SBM studies. Concurrent VBM and SBM analyses in future studies could elucidate this issue. Structural images acquired for grey matter analysis could advantageously be accompanied by functional measurements, for example, of cerebral blood flow using arterial spin labelling, to circumvent possible confounding effects on the grey matter evaluation. &
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Migraine and structural abnormalities in the brain Hougaard et al.
WHITE MATTER Most MRI-based studies of white matter structure in migraine have focused on the prevalence of white matter hyperintensities (WMHs), which are small regions of high-signal intensity observed on T2-weighted MR images. In the general population, WMHs can be observed in 11–21% of adults aged around 64 and 94% at age 82 [24,25]. WMHs are more common in patients with cardiovascular risk factors [26], and they generally predict an increased risk of stroke, dementia and death [27]. The first study of the association between migraine and WMHs was published in 1988 by Soges et al. [28], who reported periventricular hyperintensities in 11 out of 24 (46%) migraine patients with and without aura. In the following decade, several clinic-based studies of WMHs in migraine were published; most [29–31], but not all [32,33], reported increased WMH prevalence in migraineurs. The variation of reported WMH prevalence in migraine was very large in these studies, varying from 5.5% [32] to 86% [30,31]. In one study, the prevalence fell from 16% of 185 patients to 6% following exclusion of 49 patients with cardiovascular risk factors [34]. These studies clearly demonstrated a need for larger, preferably longitudinal studies, applying matching of control participants, risk factor stratification and observer blinding, in order to clarify the possible role of WMHs in migraine. To date, three large population-based studies of WMHs in migraine have been carried out [35,36,37 ]. In the Cerebral Abnormalities in Migraine, an Epidemiological Risk Analysis 1 (CAMERA-1) study [35] (295 migraineurs and 140 matched controls), WMHs were prevalent in both groups (37% of patients, 39% of controls), and no overall difference was found. However, women with migraine had a higher risk of having a high load of deep, supratentorial WMHs (24% of patients, 13% of controls). This risk increased with increasing attack frequency, but it was not affected by the presence of migraine aura. In a subsequent study of these patients, a significant difference between patients and controls was found for infratentorial WMHs (4.4% of patients and 0.7% of controls) [35]. A 9-year follow-up study (CAMERA-2) reported progression only for deep supratentorial WMHs in women (with and without aura), and no progression in men [38]. The Epidemiology of Vascular Ageing (EVA) study (116 migraine patients, 617 non-headache controls, 47 non-migraine headache controls) found an overall association of migraine with WMHs (41% of patients and 31% of controls had a high WMH load). This relation was not specific to migraine, but extended to nonmigraine headaches [36]. The association with deep WMHs in this study was stronger for migraine with &
aura than for migraine without aura. Recently, the Atherosclerosis Risk in Communities (ARIC) study (175 migraine patients, 1617 non-headache controls, 165 non-migraine headache) reported increased WMH load in patients with migraine without aura only and no progression after 8–12 years of follow-up. This study was limited by WMH evaluation on a categorical scale, possibly causing a loss of sensitivity, and because the presence of aura was determined using a single question [37 ]. In addition, CAMERA featured a younger, healthier population that likely experienced more active headaches than in ARIC [37 ]. A recent metaanalysis, not including the ARIC study, showed an increased risk of WMHs [39 ] for migraine with aura patients [odds ratio (OR) 1.68, 95% confidence interval (CI) 1.07–2.65], but no significantly increased risk in migraine without aura patients (OR 1.34, 95% CI 0.96–1.87). &
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INFARCT-LIKE LESIONS Silent infarct-like lesions (ILLs), that is, non-mass brain parenchymal defects with the same intensity as cerebrospinal fluid and without symptoms, have also been associated with migraine. The ILL prevalence in the general population varies widely depending on the population studied, the imaging technique, and the infarct definition applied [40]. Most variation is explained by age, and prevalence has been reported to be around 10% at age 60 and 28% at 75 years of age [40]. Women generally have a 30–40% higher risk of ILLs than men [41,42], even though men more frequently have symptomatic infarcts [43]. Five reports on ILLs in migraine from population-based studies have been published, based on the CAMERA and EVA cohorts and the Icelandic Age Gene/Environment Susceptibility-Reykjavik Study (AGES-RS) cohort [44]. No overall increased ILL prevalence was found in migraine patients compared to controls in the CAMERA study, but increased prevalence was found for lesions in the posterior territory specifically, mostly in the cerebellum. This was especially true for patients with migraine with aura (13 out of 161 patients) compared to patients with migraine without aura (3 out of 134 patients) and healthy controls (1 out of 140). In accordance, Kurth et al. [36] reported an increased prevalence of ILLs only in patients with migraine with aura, but lesions were mostly located in deep grey matter structures, not the cerebellum or brainstem. Migraine patients in the AGES-RS cohort underwent MRI 26 years after the initial diagnosis [44]. The authors found an increased ILL prevalence in women with migraine with aura compared to
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controls (31 vs. 25%), mostly in the cerebellum, but no increased risk for men or migraine without aura sufferers. In disagreement with previous studies, 63% of patients in this cohort were classified as having migraine with aura, suggesting that the diagnosis was not in accordance with the International Headache Society criteria, which could potentially attenuate the association between ILLs and migraine with aura. Follow-up imaging after 9 years in CAMERA-2 [38] did not find an increased risk of progression of previously identified ILLs in migraineurs. Overall, no increased prevalence of ILLs was found in migraineurs compared to controls in a recent meta-analysis [39 ]. This analysis showed, however, an increased risk of ILLs in patients with migraine with aura compared to migraine without aura (OR 1.44, 95% CI 0.96–1.87). &&
SIGNIFICANCE OF STRUCTURAL CHANGES The existence and possible significance of grey matter abnormalities in migraine remain unclear, and present findings have had no implications for clinical practice. This relatively new area of research could, however, with more and larger studies and improved technology, provide valuable information about migraine pathophysiology. A role of WMHs and ILLs in migraine is clearly suggested by a large number of studies, but at present no firm conclusions can be made about this association. If a true association exists for both types of abnormalities, do they share the same pathophysiological causes? Presence of ILLs was not associated with deep WMH load in the CAMERA study, indicating that this might not be the case. Are women more affected than men or is it just more difficult to pick up the signal in the male population in which both the prevalence of migraine and of silent brain lesions is markedly lower? Is the increased risk confined to patients with aura or does it generalize to all migraine patients or even all patients with frequent headache? And above all, what is the relevance of these findings to the patients? Obviously, brain scan abnormalities are surrogate markers of disease that cannot replace the efficacy measures that we are really interested in, such as patient quality of life, disease burden and life expectancy. They can, however, serve as diagnostic and prognostic aids and increase the understanding of pathophysiological mechanisms. Since WMHs and ILLs are associated with increased risk of cognitive decline and stroke, an obvious question is if this higher risk also applies to migraine patients. Reassuringly, the CAMERA and EVA studies found no relationship between brain abnormalities and cognitive decline in persons 312
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with migraine or other severe headache. This is in accordance with large population-based studies that have shown no long-term effects of migraine on cognitive function [45–47]. Subtle cerebellar dysfunction in asymptomatic migraineurs has been reported, suggesting a possible functional significance of posterior circulation ILLs, but this seems of little clinical relevance [48]. Epidemiological studies have reported an association of migraine, mostly with aura, not only with ischaemic stroke but also with haemorrhagic stroke [49]. Systematic reviews estimate a relative risk of ischaemic stroke in migraine with aura patients of approximately 2 [49]. This risk is greater for those with a higher attack frequency [50,51]. It should be kept in mind, however, that the absolute risk is small, with a mean incidence of ischaemic stroke in young women of 10 in 100 000 life years [52]. The possible increased risk is not likely to be attributed to acute migraine treatment, as neither ergots nor triptans have been consistently linked to an increased risk of stroke or other ischaemic events [53], at least when taken at recommended doses [54]. Thus, in general, migraine patients can be reassured that the nature of the disorder is benign. However, it is possible that sub-populations of migraine patients with migraine with WMLs, ILLs, or grey matter abnormalities may be at an increased risk for stroke and transient ischaemic attacks. Migraine, especially migraine with aura, can develop secondarily to otherwise asymptomatic cerebrovascular disease, for example, carotid stenosis and arteriovascular malformations [55,56 ]. A more extreme example is the syndrome of cerebral autosomal-dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL), in which 40% of patients present with migraine with aura as the initial symptoms, many years before having the first strokes. Therefore, some migraine patients could suffer from more subtle pathology that at the same time is a cause of migraine symptoms and of an increased risk of structural brain abnormalities and stroke. Future studies of structural changes in migraine should seek to identify such sub-groups that could potentially benefit from a different clinical management than other migraine patients. &
CONCLUSION Migraine is currently best described as a disorder of brain and nociceptive function with possible associated structural abnormalities. The clinical and functional significance of migraine-associated structural brain changes is unclear. At present, migraineurs with a normal neurologic examination do not require routine MRI [39 ]. Incidental findings of &&
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ILLs or high WMH load should prompt screening for stroke risk factors in persons with or without migraine. Additional large longitudinal studies are needed to clarify the association between migraine and structural brain abnormalities. Brain structure changes could potentially serve as disease biomarkers, most likely based on grey matter findings, or they could aid in identifying sub-groups of patients with specific therapeutic needs and prognoses. Acknowledgements The work was supported by the University of Copenhagen, the Lundbeck Foundation Center for Neurovascular Signalling (LUCENS), the Danish Council for Independent Research-Medical Sciences (FSS) (grant 271-080446), the Novo Nordisk Foundation (grant R172A14333) and the Research Foundation of the Capital Region of Denmark. Conflicts of interest There are no conflicts of interest.
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Silent brain infarcts: a systematic review. Lancet Neurol 2007; 6:611–619. 41. Vermeer SE, Koudstaal PJ, Oudkerk M, Hofman A. Prevalence and risk factors of silent brain infarcts in the population-based Rotterdam Scan Study. Stroke 2002; 1:21–25. 42. Longstreth WT Jr, Bernick C, Manolio TA. Lacunar infarcts defined by magnetic resonance imaging of 3660 elderly people: the Cardiovascular Health Study. Arch Neurol 1998; 9:1217–1225. 43. Goldstein LB, Adams R, Becker K, et al. Primary prevention of ischemic stroke: a statement for healthcare professionals from the Stroke Council of the American Heart Association. Stroke 2001; 32:280–299. 44. Scher AI, Gudmundsson LS, Sigurdsson S, et al. Migraine headache in middle age and late-life brain infarcts. J Am Med Assoc 2009; 301:2563– 2570. 45. Gaist D, Pedersen L, Madsen C, et al. Long-term effects of migraine on cognitive function: a population-based study of Danish twins. Am Acad Neurol 2005; 64:600–607. 46. 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Migraine and structural abnormalities in the brain Anders Hougaard, Faisal Mohammad Amin, and Messoud Ashina
Purpose of review The aim is to provide an overview of recent studies of structural brain abnormalities in migraine and to discuss the potential clinical significance of their findings. Recent findings Brain structure continues to be a topic of extensive research in migraine. Despite advances in neuroimaging techniques, it is not yet clear if migraine is associated with grey matter changes. Recent large populationbased studies sustain the notion of increased prevalence of white matter abnormalities in migraine, and possibly of silent infarct-like lesions. The clinical relevance of this association is not clear. Structural changes are not related to cognitive decline, but a link to an increased risk of stroke, especially in patients with aura, cannot be ruled out. Summary Migraine may be a risk factor for structural changes in the brain. It is not yet clear how factors such as migraine sub-type, attack frequency, and sex affects this association. Additional longitudinal studies are needed to address these issues. Brain structure changes in migraine could potentially serve as disease biomarkers or as a mean of identifying sub-groups of patients with specific therapeutic needs and prognoses. Keywords brain structure, cortical thickness, migraine, MRI, voxel-based morphometry, white matter hyperintensities
INTRODUCTION Migraine has traditionally been considered a disorder caused by dysfunction of the brain and trigeminovascular nociception, not involving structural brain abnormalities. The natural history of migraine is usually non-progressive and without development of persisting symptoms. Therefore, in current clinical practice, brain imaging of migraine patients has the sole purpose of excluding structural causes of secondary migraine, and migraine-associated pathology. The advent of MRI has made it possible to non-invasively obtain high-resolution anatomical images, optimized for visualizing different tissues and features of the human brain. This has fostered extensive research into the brain structure of migraine patients, now suggesting abnormalities of grey and white matter as key characteristics of this disorder. The purpose of this review is to summarize the current literature on this subject.
GREY MATTER Voxel-based morphometry (VBM) [1] is probably the most widely used method for whole-brain evaluation of local grey matter morphology based on magnetic resonance (MR) images. It is not well
understood what VBM changes reflect. Histological measures, such as neuronal density, do not correlate with VBM grey matter probability maps [2] and changes in cerebral blood flow produce ‘apparent’ grey matter volume changes in VBM analyses [3 ]. In a typical whole-brain VBM analysis, there are more than 10 00 000 comparisons of grey matter voxels carried out. Correcting the statistics for multiple comparisons is therefore essential to avoid falsepositives, and efficient statistical methods have been developed to address this issue [4]. Only two [5,6] out of eight VBM studies [5–12] comparing migraine patients to healthy controls have reported significant differences on a whole-brain level following correction for multiple comparison. These were &
Danish Headache Center and Department of Neurology, Glostrup Hospital, Faculty of Health and Medical Sciences, University of Copenhagen, Denmark Correspondence to Messoud Ashina, MD, PhD, DMSc, Danish Headache Center and Department of Neurology, Glostrup Hospital, Faculty of Health and Medical Sciences, University of Copenhagen, Ndr. Ringvej 67, Building 14, DK-2600 Glostrup, Denmark. Tel: +45 38 63 30 54; fax: +45 38 63 38 39; e-mail: [email protected] Curr Opin Neurol 2014, 27:309–314 DOI:10.1097/WCO.0000000000000086
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Headache
KEY POINTS The existence, and possible significance, of structural grey matter abnormalities of the brain in migraine patients is presently uncertain, and more research into this topic is warranted. Migraine has been linked to a moderately increased prevalence of white matter abnormalities and silent infarct-like lesions on brain imaging evaluation, but the clinical significance of these changes is unclear. Increased white matter abnormalities and infarct-like lesions in migraine patients could be confined to certain sub-groups of patients with distinct pathophysiological characteristics. Migraineurs with a normal neurologic examination do not require routine MR. Incidental findings of infarct-like lesions or pronounced white matter abnormalities should prompt screening for stroke risk factors in persons with or without migraine.
decreased grey matter in the anterior cingulate, frontal, temporal, and occipital cortex, and the cerebellum and brainstem [5,6]. Other VBM studies have reported grey matter decrease in a-priori designated areas of the brain, while correcting for multiple comparison of voxels in these areas specifically [5,8,11]. Notably, grey matter reduction of the cingulate cortex and insula, in migraine patients compared to controls, has been reported in two independent studies [11,13] using this approach. A recent longitudinal VBM study compared the grey matter of migraine patients before and after a 1-year period and found decreased grey matter volume in several cortical and sub-cortical brain areas, including the hippocampus, but not including the cingulate or insula [14 ]. Surface-based morphometry (SBM) is a more recent approach for automatically detecting white–grey matter boundaries, which allows detection of local differences in cortical thickness. When comparing whole-brain cortical thickness between groups, many comparisons are made, not of voxels as in VBM, but of thickness values at the vertices of the tessellated three-dimensional surface reconstruction. Six studies have applied SBM to compare migraine patients to healthy controls [15–18, 19 ,20]. One study reported an increase in grey matter thickness in the somatosensory cortex (SSC) in patients with migraine [16]. In addition, an increase in grey matter thickness in visual motion processing areas (V3A and MTþ) has been reported [15]. However, these findings could not be reproduced in a subsequent study of a large number of &
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patients [17]. One study reported a very small, but significant global increase of cortical thickness in migraine patients compared to controls (2.08 and 2.02 mm, respectively) [18]. Following correction for multiple comparisons, increased cortical thickness was observed specifically in the left temporooccipital incisure [18]. Maleki et al. [20] reported significantly thicker cortex in the precuneus and posterior insula in migraineurs compared to controls. In another study, demonstrating functional and structural differences between migraineurs with frequent and less frequent attacks, high-frequency migraineurs had a thinner cortex of the insula and cingulate and increased thickness of the somatosensory and temporal cortices compared to healthy controls, whereas low-frequency migraineurs had a thinner somatosensory and temporal cortex than controls [19 ]. Recently, studies of grey matter structure in migraine have focused on the basal ganglia. One study applied quantitative MR relaxometry to compare the structure of the thalamus between migraine patients with and without aura and healthy controls [21 ]. Relaxometry comprises mapping of magnetization transfer, and T1 and T2 relaxation. Magnetization transfer is considered a direct measurement of myelin, T1 relaxation is sensitive to tissue water, and T2 depends on iron content. The authors reported significant differences between patients with and without aura for all three measures, but found differences to controls only for T1 relaxation of the right thalamus. Another recent study, specifically investigating basal ganglia volume using automatic segmentation, reported volume reduction of the left caudate and right nucleus accumbens in migraineurs compared to controls [22]. In addition, increased hippocampal volume in low-frequency migraineurs, compared to both healthy controls and to high-frequency migraineurs, has been reported [23]. Collectively, the current literature does not leave a clear picture of grey matter structure in migraine. The reported abnormalities need confirmation from future studies, and more longitudinal studies are required to determine if potential changes develop or progress over time as a possible consequence of migraine. It is puzzling that VBM studies generally suggest decreased grey matter volume, whereas the opposite is the case for SBM studies. Concurrent VBM and SBM analyses in future studies could elucidate this issue. Structural images acquired for grey matter analysis could advantageously be accompanied by functional measurements, for example, of cerebral blood flow using arterial spin labelling, to circumvent possible confounding effects on the grey matter evaluation. &
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Migraine and structural abnormalities in the brain Hougaard et al.
WHITE MATTER Most MRI-based studies of white matter structure in migraine have focused on the prevalence of white matter hyperintensities (WMHs), which are small regions of high-signal intensity observed on T2-weighted MR images. In the general population, WMHs can be observed in 11–21% of adults aged around 64 and 94% at age 82 [24,25]. WMHs are more common in patients with cardiovascular risk factors [26], and they generally predict an increased risk of stroke, dementia and death [27]. The first study of the association between migraine and WMHs was published in 1988 by Soges et al. [28], who reported periventricular hyperintensities in 11 out of 24 (46%) migraine patients with and without aura. In the following decade, several clinic-based studies of WMHs in migraine were published; most [29–31], but not all [32,33], reported increased WMH prevalence in migraineurs. The variation of reported WMH prevalence in migraine was very large in these studies, varying from 5.5% [32] to 86% [30,31]. In one study, the prevalence fell from 16% of 185 patients to 6% following exclusion of 49 patients with cardiovascular risk factors [34]. These studies clearly demonstrated a need for larger, preferably longitudinal studies, applying matching of control participants, risk factor stratification and observer blinding, in order to clarify the possible role of WMHs in migraine. To date, three large population-based studies of WMHs in migraine have been carried out [35,36,37 ]. In the Cerebral Abnormalities in Migraine, an Epidemiological Risk Analysis 1 (CAMERA-1) study [35] (295 migraineurs and 140 matched controls), WMHs were prevalent in both groups (37% of patients, 39% of controls), and no overall difference was found. However, women with migraine had a higher risk of having a high load of deep, supratentorial WMHs (24% of patients, 13% of controls). This risk increased with increasing attack frequency, but it was not affected by the presence of migraine aura. In a subsequent study of these patients, a significant difference between patients and controls was found for infratentorial WMHs (4.4% of patients and 0.7% of controls) [35]. A 9-year follow-up study (CAMERA-2) reported progression only for deep supratentorial WMHs in women (with and without aura), and no progression in men [38]. The Epidemiology of Vascular Ageing (EVA) study (116 migraine patients, 617 non-headache controls, 47 non-migraine headache controls) found an overall association of migraine with WMHs (41% of patients and 31% of controls had a high WMH load). This relation was not specific to migraine, but extended to nonmigraine headaches [36]. The association with deep WMHs in this study was stronger for migraine with &
aura than for migraine without aura. Recently, the Atherosclerosis Risk in Communities (ARIC) study (175 migraine patients, 1617 non-headache controls, 165 non-migraine headache) reported increased WMH load in patients with migraine without aura only and no progression after 8–12 years of follow-up. This study was limited by WMH evaluation on a categorical scale, possibly causing a loss of sensitivity, and because the presence of aura was determined using a single question [37 ]. In addition, CAMERA featured a younger, healthier population that likely experienced more active headaches than in ARIC [37 ]. A recent metaanalysis, not including the ARIC study, showed an increased risk of WMHs [39 ] for migraine with aura patients [odds ratio (OR) 1.68, 95% confidence interval (CI) 1.07–2.65], but no significantly increased risk in migraine without aura patients (OR 1.34, 95% CI 0.96–1.87). &
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INFARCT-LIKE LESIONS Silent infarct-like lesions (ILLs), that is, non-mass brain parenchymal defects with the same intensity as cerebrospinal fluid and without symptoms, have also been associated with migraine. The ILL prevalence in the general population varies widely depending on the population studied, the imaging technique, and the infarct definition applied [40]. Most variation is explained by age, and prevalence has been reported to be around 10% at age 60 and 28% at 75 years of age [40]. Women generally have a 30–40% higher risk of ILLs than men [41,42], even though men more frequently have symptomatic infarcts [43]. Five reports on ILLs in migraine from population-based studies have been published, based on the CAMERA and EVA cohorts and the Icelandic Age Gene/Environment Susceptibility-Reykjavik Study (AGES-RS) cohort [44]. No overall increased ILL prevalence was found in migraine patients compared to controls in the CAMERA study, but increased prevalence was found for lesions in the posterior territory specifically, mostly in the cerebellum. This was especially true for patients with migraine with aura (13 out of 161 patients) compared to patients with migraine without aura (3 out of 134 patients) and healthy controls (1 out of 140). In accordance, Kurth et al. [36] reported an increased prevalence of ILLs only in patients with migraine with aura, but lesions were mostly located in deep grey matter structures, not the cerebellum or brainstem. Migraine patients in the AGES-RS cohort underwent MRI 26 years after the initial diagnosis [44]. The authors found an increased ILL prevalence in women with migraine with aura compared to
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controls (31 vs. 25%), mostly in the cerebellum, but no increased risk for men or migraine without aura sufferers. In disagreement with previous studies, 63% of patients in this cohort were classified as having migraine with aura, suggesting that the diagnosis was not in accordance with the International Headache Society criteria, which could potentially attenuate the association between ILLs and migraine with aura. Follow-up imaging after 9 years in CAMERA-2 [38] did not find an increased risk of progression of previously identified ILLs in migraineurs. Overall, no increased prevalence of ILLs was found in migraineurs compared to controls in a recent meta-analysis [39 ]. This analysis showed, however, an increased risk of ILLs in patients with migraine with aura compared to migraine without aura (OR 1.44, 95% CI 0.96–1.87). &&
SIGNIFICANCE OF STRUCTURAL CHANGES The existence and possible significance of grey matter abnormalities in migraine remain unclear, and present findings have had no implications for clinical practice. This relatively new area of research could, however, with more and larger studies and improved technology, provide valuable information about migraine pathophysiology. A role of WMHs and ILLs in migraine is clearly suggested by a large number of studies, but at present no firm conclusions can be made about this association. If a true association exists for both types of abnormalities, do they share the same pathophysiological causes? Presence of ILLs was not associated with deep WMH load in the CAMERA study, indicating that this might not be the case. Are women more affected than men or is it just more difficult to pick up the signal in the male population in which both the prevalence of migraine and of silent brain lesions is markedly lower? Is the increased risk confined to patients with aura or does it generalize to all migraine patients or even all patients with frequent headache? And above all, what is the relevance of these findings to the patients? Obviously, brain scan abnormalities are surrogate markers of disease that cannot replace the efficacy measures that we are really interested in, such as patient quality of life, disease burden and life expectancy. They can, however, serve as diagnostic and prognostic aids and increase the understanding of pathophysiological mechanisms. Since WMHs and ILLs are associated with increased risk of cognitive decline and stroke, an obvious question is if this higher risk also applies to migraine patients. Reassuringly, the CAMERA and EVA studies found no relationship between brain abnormalities and cognitive decline in persons 312
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with migraine or other severe headache. This is in accordance with large population-based studies that have shown no long-term effects of migraine on cognitive function [45–47]. Subtle cerebellar dysfunction in asymptomatic migraineurs has been reported, suggesting a possible functional significance of posterior circulation ILLs, but this seems of little clinical relevance [48]. Epidemiological studies have reported an association of migraine, mostly with aura, not only with ischaemic stroke but also with haemorrhagic stroke [49]. Systematic reviews estimate a relative risk of ischaemic stroke in migraine with aura patients of approximately 2 [49]. This risk is greater for those with a higher attack frequency [50,51]. It should be kept in mind, however, that the absolute risk is small, with a mean incidence of ischaemic stroke in young women of 10 in 100 000 life years [52]. The possible increased risk is not likely to be attributed to acute migraine treatment, as neither ergots nor triptans have been consistently linked to an increased risk of stroke or other ischaemic events [53], at least when taken at recommended doses [54]. Thus, in general, migraine patients can be reassured that the nature of the disorder is benign. However, it is possible that sub-populations of migraine patients with migraine with WMLs, ILLs, or grey matter abnormalities may be at an increased risk for stroke and transient ischaemic attacks. Migraine, especially migraine with aura, can develop secondarily to otherwise asymptomatic cerebrovascular disease, for example, carotid stenosis and arteriovascular malformations [55,56 ]. A more extreme example is the syndrome of cerebral autosomal-dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL), in which 40% of patients present with migraine with aura as the initial symptoms, many years before having the first strokes. Therefore, some migraine patients could suffer from more subtle pathology that at the same time is a cause of migraine symptoms and of an increased risk of structural brain abnormalities and stroke. Future studies of structural changes in migraine should seek to identify such sub-groups that could potentially benefit from a different clinical management than other migraine patients. &
CONCLUSION Migraine is currently best described as a disorder of brain and nociceptive function with possible associated structural abnormalities. The clinical and functional significance of migraine-associated structural brain changes is unclear. At present, migraineurs with a normal neurologic examination do not require routine MRI [39 ]. Incidental findings of &&
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Migraine and structural abnormalities in the brain Hougaard et al.
ILLs or high WMH load should prompt screening for stroke risk factors in persons with or without migraine. Additional large longitudinal studies are needed to clarify the association between migraine and structural brain abnormalities. Brain structure changes could potentially serve as disease biomarkers, most likely based on grey matter findings, or they could aid in identifying sub-groups of patients with specific therapeutic needs and prognoses. Acknowledgements The work was supported by the University of Copenhagen, the Lundbeck Foundation Center for Neurovascular Signalling (LUCENS), the Danish Council for Independent Research-Medical Sciences (FSS) (grant 271-080446), the Novo Nordisk Foundation (grant R172A14333) and the Research Foundation of the Capital Region of Denmark. Conflicts of interest There are no conflicts of interest.
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