White Matter Lesions in Migraine
2021; Elsevier BV; Volume: 191; Issue: 11 Linguagem: Inglês
10.1016/j.ajpath.2021.02.007
ISSN1525-2191
AutoresKatharina Eikermann‐Haerter, Susie Y. Huang,
Tópico(s)Trigeminal Neuralgia and Treatments
ResumoMigraine, the third most common disease worldwide, is a well-known independent risk factor for subclinical focal deep white matter lesions (WMLs), even in young and otherwise healthy individuals with no cardiovascular risk factors. These WMLs are more commonly seen in migraine patients with transient neurologic symptoms preceding their headaches, the so-called aura, and those with a high attack frequency. The pathophysiology of migraine-related deep white matter hyperintensities remains poorly understood despite their prevalence. Characteristic differences in their distribution compared with those of common periventricular WMLs in the elderly suggest a different underlying mechanism. Both ischemic and inflammatory mechanisms have been proposed, as there is increased cerebral vulnerability to ischemia in migraineurs, whereas there is also evidence of blood–brain barrier disruption with associated release of proinflammatory substances during migraine attacks. An enhanced susceptibility to spreading depolarization, the electrophysiological event underlying migraine, may be the mechanism that causes repetitive episodes of cerebral hypoperfusion and neuroinflammation during migraine attacks. WMLs can negatively affect both physical and cognitive function, underscoring the public health importance of migraine, and suggesting that migraine is an important contributor to neurologic deficits in the general population. Migraine, the third most common disease worldwide, is a well-known independent risk factor for subclinical focal deep white matter lesions (WMLs), even in young and otherwise healthy individuals with no cardiovascular risk factors. These WMLs are more commonly seen in migraine patients with transient neurologic symptoms preceding their headaches, the so-called aura, and those with a high attack frequency. The pathophysiology of migraine-related deep white matter hyperintensities remains poorly understood despite their prevalence. Characteristic differences in their distribution compared with those of common periventricular WMLs in the elderly suggest a different underlying mechanism. Both ischemic and inflammatory mechanisms have been proposed, as there is increased cerebral vulnerability to ischemia in migraineurs, whereas there is also evidence of blood–brain barrier disruption with associated release of proinflammatory substances during migraine attacks. An enhanced susceptibility to spreading depolarization, the electrophysiological event underlying migraine, may be the mechanism that causes repetitive episodes of cerebral hypoperfusion and neuroinflammation during migraine attacks. WMLs can negatively affect both physical and cognitive function, underscoring the public health importance of migraine, and suggesting that migraine is an important contributor to neurologic deficits in the general population. Migraine is one of the most common neurologic disorders and is the third most common disease worldwide. It is characterized by throbbing/pulsatile unilateral headaches that last for 4 to 72 hours. Thirty percent of patients with migraine develop transient neurologic symptoms in the setting of an attack, the so-called migraine aura. Aura symptoms characteristically precede or overlap with the headache phase. The most common types of migraine aura involve visual impairment, followed by sensory, language, or motor symptoms.1Russell M.B. Rasmussen B.K. Thorvaldsen P. Olesen J. Prevalence and sex-ratio of the subtypes of migraine.Int J Epidemiol. 1995; 24: 612-618Crossref PubMed Scopus (360) Google Scholar Neuroimaging studies have identified a twofold to fourfold increased incidence of white matter hyperintensities suggestive of white matter lesions (WMLs) in migraineurs compared with control subjects.2Kruit M.C. Launer L.J. 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Migraine with aura and risk of silent brain infarcts and white matter hyperintensities: an MRI study.Brain. 2016; 139: 2015-2023Crossref PubMed Scopus (44) Google Scholar, 7Hamedani A.G. Rose K.M. Peterlin B.L. Mosley T.H. Coker L.H. Jack C.R. Knopman D.S. Alonso A. Gottesman R.F. Migraine and white matter hyperintensities: the ARIC MRI Study.Neurology. 2013; 81: 1308-1313Crossref PubMed Scopus (60) Google Scholar WMLs are focal lesions without associated mass effect within the deep, subcortical, periventricular, or infratentorial white matter.3Bashir A. Lipton R.B. Ashina S. Ashina M. Migraine and structural changes in the brain: a systematic review and meta-analysis.Neurology. 2013; 81: 1260-1268Crossref PubMed Scopus (186) Google Scholar,8Palm-Meinders I.H. Koppen H. Terwindt G.M. Launer L.J. Konishi J. Moonen J.M.E. Bakkers J.T.N. Hofman P.A.M. van Lew B. Middelkoop H.A.M. van Buchem M.A. Ferrari M.D. Kruit M.C. Structural brain changes in migraine.JAMA. 2012; 308: 1889-1897Crossref PubMed Scopus (141) Google Scholar, 9Kurth T. Mohamed S. Maillard P. Zhu Y.C. Chabriat H. Mazoyer B. Bousser M.G. Dufouil C. Tzourio C. Headache, migraine, and structural brain lesions and function: population based Epidemiology of Vascular Ageing-MRI study.BMJ. 2011; 342: c7357Crossref PubMed Scopus (178) Google Scholar, 10Kruit M.C. van Buchem M.A. Hofman P.A.M. Bakkers J.T.N. Terwindt G.M. Ferrari M.D. Launer L.J. Migraine as a risk factor for subclinical brain lesions.JAMA. 2004; 291: 427-434Crossref PubMed Scopus (812) Google Scholar, 11Kruit M.C. Launer L.J. Ferrari M.D. van Buchem M.A. Brain stem and cerebellar hyperintense lesions in migraine.Stroke. 2006; 37: 1109-1112Crossref PubMed Scopus (128) Google Scholar WMLs are typically seen on T2 and fluid-attenuated inversion recovery sequences, and are believed to occur due to gliosis, demyelination, and/or loss of axons, possibly resulting from microvascular damage.12Porter A. Gladstone J.P. Dodick D.W. Migraine and white matter hyperintensities.Curr Pain Headache Rep. 2005; 9: 289-293Crossref PubMed Scopus (50) Google Scholar WMLs exhibit a negative effect on both physical and cognitive function in older adults.13Longstreth Jr., W.T. Manolio T.A. Arnold A. Burke G.L. Bryan N. Jungreis C.A. Enright P.L. O'Leary D. Fried L. Clinical correlates of white matter findings on cranial magnetic resonance imaging of 3301 elderly people. The Cardiovascular Health Study.Stroke. 1996; 27: 1274-1282Crossref PubMed Scopus (1235) Google Scholar, 14Vermeer S.E. Prins N.D. den Heijer T. Hofman A. 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Age and hypertension are well-known risk factors for common periventricular WMLs in the elderly that are presumably caused by increased interstitial fluid and altered periventricular fluid dynamics.16Fazekas F. Kleinert R. Offenbacher H. Schmidt R. Kleinert G. Payer F. Radner H. Lechner H. Pathologic correlates of incidental MRI white matter signal hyperintensities.Neurology. 1993; 43: 1683-1689Crossref PubMed Google Scholar, 17Fernando M.S. Simpson J.E. Matthews F. Brayne C. Lewis C.E. Barber R. Kalaria R.N. Forster G. Esteves F. Wharton S.B. Shaw P.J. O'Brien J.T. Ince P.G. MRC Cognitive Function and Ageing Neuropathology Study GroupWhite matter lesions in an unselected cohort of the elderly: molecular pathology suggests origin from chronic hypoperfusion injury.Stroke. 2006; 37: 1391-1398Crossref PubMed Scopus (416) Google Scholar, 18Rostrup E. Gouw A.A. Vrenken H. van Straaten E.C.W. Ropele S. Pantoni L. Inzitari D. Barkhof F. Waldemar G. LADIS study groupThe spatial distribution of age-related white matter changes as a function of vascular risk factors—results from the LADIS study.Neuroimage. 2012; 60: 1597-1607Crossref PubMed Scopus (57) Google Scholar In contrast, migraine is mostly associated with deep WMLs9Kurth T. Mohamed S. Maillard P. Zhu Y.C. Chabriat H. Mazoyer B. Bousser M.G. Dufouil C. Tzourio C. Headache, migraine, and structural brain lesions and function: population based Epidemiology of Vascular Ageing-MRI study.BMJ. 2011; 342: c7357Crossref PubMed Scopus (178) Google Scholar,10Kruit M.C. van Buchem M.A. Hofman P.A.M. Bakkers J.T.N. Terwindt G.M. Ferrari M.D. Launer L.J. Migraine as a risk factor for subclinical brain lesions.JAMA. 2004; 291: 427-434Crossref PubMed Scopus (812) Google Scholar that present as early as in childhood migraineurs. In fact, WMLs are found in 10% of pediatric patients with migraine.19Eidlitz-Markus T. Zeharia A. Haimi-Cohen Y. Konen O. MRI white matter lesions in pediatric migraine.Cephalalgia. 2013; 33: 906-913Crossref PubMed Scopus (19) Google Scholar However, in pediatric patients with migraine with or without aura,WMLs are not more prevalent than in control subjects and that no silent infarct-like lesions are identified.20Mar S. Kelly J.E. Isbell S. Aung W.Y. Lenox J. Prensky A. Prevalence of white matter lesions and stroke in children with migraine.Neurology. 2013; 81: 1387-1391Crossref PubMed Scopus (23) Google Scholar Interestingly, associations between migraine and WMLs are stable over time, suggesting that they occur earlier in life.7Hamedani A.G. Rose K.M. Peterlin B.L. Mosley T.H. Coker L.H. Jack C.R. Knopman D.S. Alonso A. Gottesman R.F. Migraine and white matter hyperintensities: the ARIC MRI Study.Neurology. 2013; 81: 1308-1313Crossref PubMed Scopus (60) Google Scholar In the Cerebral Abnormalities in Migraine, an Epidemiological Risk Analysis (CAMERA) population-based study sample of 30- to 60-year–old Dutch adults, female patients with migraine, were at increased risk of high deep WML-load (top 20th percentile), independent of migraine subtype and risk factors (odds ratio, 2.0; 95% CI, 1.0-4.2). This risk was higher in those with high attack frequency (odds ratio, 2.6; 95% CI, 1.2-6.0), suggestive of a causal relationship. Concurrent smoking, hypertension, and long-term oral contraceptive use further increased the risk.10Kruit M.C. van Buchem M.A. Hofman P.A.M. Bakkers J.T.N. Terwindt G.M. Ferrari M.D. Launer L.J. Migraine as a risk factor for subclinical brain lesions.JAMA. 2004; 291: 427-434Crossref PubMed Scopus (812) Google Scholar A follow-up investigation using the same study population showed that hyperintense lesions are predominantly located in the brainstem and cerebellar vascular border zone. WMLs are more commonly seen in patients with migraine with aura than those without aura and in those with a high attack frequency. Again, cardiovascular risk factors are not more prevalent in migraineurs with WMLs. Notably, progression of WMLs in individuals with migraine is not associated with migraine attack frequency, duration, severity, or antimigraine treatments.21Kruit M.C. van Buchem M.A. Launer L.J. Terwindt G.M. Ferrari M.D. Migraine is associated with an increased risk of deep white matter lesions, subclinical posterior circulation infarcts and brain iron accumulation: the population-based MRI CAMERA Study.Cephalalgia. 2010; 30: 129-136Crossref PubMed Scopus (251) Google Scholar Another longitudinal magnetic resonance spectroscopy study showed evidence of progression of migraine-related WMLs over time, with signs of more severe axonal loss and glial hypocellularity, as well as decreased intracellular energy production within a 3-year period.22Erdélyi-Bótor S. Aradi M. Kamson D.O. Kovács N. Perlaki G. Orsi G. Nagy S.A. Schwarcz A. Dóczi T. Komoly S. Deli G. Trauninger A. Pfund Z. Changes of migraine-related white matter hyperintensities after 3 years: a longitudinal MRI study.Headache. 2015; 55: 55-70Crossref PubMed Scopus (42) Google Scholar The number of newly developed T2 hyperintensities exceeded the number of disappeared ones, further suggesting a progression of disease. In contrast, the Epidemiology of Vascular Aging (EVA) study, a population-based, cross-sectional study in 780 elderly participants (mean age, 69 years), showed that migraine with aura is strongly associated with the cumulative volume of hyperintense lesions predominantly outside the cerebellum and brainstem.9Kurth T. Mohamed S. Maillard P. Zhu Y.C. Chabriat H. Mazoyer B. Bousser M.G. Dufouil C. Tzourio C. Headache, migraine, and structural brain lesions and function: population based Epidemiology of Vascular Ageing-MRI study.BMJ. 2011; 342: c7357Crossref PubMed Scopus (178) Google Scholar Another study found that the number of WMLs also increased with the intensity of nausea and disability during attacks.23Negm M. Housseini A.M. Abdelfatah M. Asran A. Relation between migraine pattern and white matter hyperintensities in brain magnetic resonance imaging.Egypt J Neurol Psychiatr Neurosurg. 2018; 54: 24Crossref PubMed Scopus (9) Google Scholar In contrast, a population-based sample of female twins aged 30 to 60 years identified through the Danish Twin Registry showed no association between silent brain infarcts, WMLs, and migraine with aura.6Gaist D. Garde E. Blaabjerg M. Nielsen H.H. Krøigård T. Østergaard K. Møller H.S. Hjelmborg J. Madsen C.G. Iversen P. Kyvik K.O. Siebner H.R. Ashina M. Migraine with aura and risk of silent brain infarcts and white matter hyperintensities: an MRI study.Brain. 2016; 139: 2015-2023Crossref PubMed Scopus (44) Google Scholar The discrepancies between these studies might be related to different study designs (population versus hospital-based; prospective versus retrospective), characteristics of the participants (age, sex, headache or aura frequency, and conventional vascular risk factors), ascertainment of diagnosis (diagnosed by physician interview versus self-report), and neuroimaging methods (in particular lack of standardization, such as high versus low magnetic field, scanner type, and selection of sequences or slice thickness). It is important to also note that the sensitivity to detect WMLs using 1.5- or 3-T magnetic resonance imaging (MRI) may be higher than the sensitivity to detect cortical lesions.24van Veluw S.J. Zwanenburg J.J. Engelen-Lee J. Spliet W.G.M. Hendrikse J. Luijten P.R. Biessels G.J. In vivo detection of cerebral cortical microinfarcts with high-resolution 7T MRI.J Cereb Blood Flow Metab. 2013; 33: 322-329Crossref PubMed Scopus (153) Google Scholar The common periventricular WMLs in elderly non-migraineurs are known to be associated with an increased risk of stroke, dementia, and cognitive decline. With respect to migraine patients, it is still not entirely clear whether deep WMLs have negative long-term functional consequences. In migraineurs, cerebral WMLs, but not subclinical infarcts or infratentorial lesions, are independently associated with syncope and orthostatic intolerance.25Kruit M.C. Thijs R.D. Ferrari M.D. Launer L.J. van Buchem M.A. van Dijk J.G. Syncope and orthostatic intolerance increase risk of brain lesions in migraineurs and controls.Neurology. 2013; 80: 1958-1965Crossref PubMed Scopus (32) Google Scholar There is no association between autonomic nervous system symptoms and the severity of migraine or migraine subtype. Cardiovascular measurements do not differ significantly between migraineurs and control subjects.21Kruit M.C. van Buchem M.A. Launer L.J. Terwindt G.M. Ferrari M.D. Migraine is associated with an increased risk of deep white matter lesions, subclinical posterior circulation infarcts and brain iron accumulation: the population-based MRI CAMERA Study.Cephalalgia. 2010; 30: 129-136Crossref PubMed Scopus (251) Google Scholar The CAMERA-2 study found no association between deep WML load and change in cognitive scores. In addition, longitudinal studies show no evidence of an association between a history of migraine and an increased risk of dementia.8Palm-Meinders I.H. Koppen H. Terwindt G.M. Launer L.J. Konishi J. Moonen J.M.E. Bakkers J.T.N. Hofman P.A.M. van Lew B. Middelkoop H.A.M. van Buchem M.A. Ferrari M.D. Kruit M.C. Structural brain changes in migraine.JAMA. 2012; 308: 1889-1897Crossref PubMed Scopus (141) Google Scholar This is in agreement with a prospective study by Rist et al,26Rist P.M. Dufouil C. Glymour M.M. Tzourio C. Kurth T. Migraine and cognitive decline in the population-based EVA Study.Cephalalgia. 2011; 31: 1291-1300Crossref PubMed Scopus (36) Google Scholar which found no link between cognitive changes and WMLs in migraineurs. In fact, in some studies, better cognition was noted in migraineurs.27Wen K. Nguyen N.T. Hofman A. Ikram M.A. Franco O.H. Migraine is associated with better cognition in the middle-aged and elderly: the Rotterdam Study.Eur J Neurol. 2016; 23: 1510-1516Crossref PubMed Scopus (17) Google Scholar, 28Baars M.A.E. van Boxtel M.P.J. Jolles J. Migraine does not affect cognitive decline: results from the Maastricht aging study.Headache. 2010; 50: 176-184Crossref PubMed Scopus (42) Google Scholar, 29Rist P.M. Kang J.H. Buring J.E. Glymour M.M. Grodstein F. Kurth T. Migraine and cognitive decline among women: prospective cohort study.BMJ. 2012; 345: e5027Crossref PubMed Scopus (26) Google Scholar The effect of WMLs on the clinical course of migraine is also not entirely clear. One study showed more frequent baseline WMLs in patients who did not report an improvement in migraine frequency after 3 years.30Xie H. Zhang Q. Huo K. Liu R. Jian Z.J. Bian Y.T. Li G.L. Zhu D. Zhang L.H. Yang J. Luo G.G. Association of white matter hyperintensities with migraine features and prognosis.BMC Neurol. 2018; 18: 93Crossref PubMed Scopus (10) Google Scholar A variety of advanced MRI techniques have been applied to characterize the microstructural substrate of WMLs in migraineurs. Magnetization transfer imaging is a myelin-sensitive imaging technique that indirectly quantifies the myelin content of white matter through the exchange of free water protons with bound water protons attached to macromolecules such as proteins or lipids.31Sled J.G. Pike G.B. Quantitative imaging of magnetization transfer exchange and relaxation properties in vivo using MRI.Magn Reson Med. 2001; 46: 923-931Crossref PubMed Scopus (300) Google Scholar The magnetization transfer ratio (MTR) measures the amount of magnetization exchanged between the free and macromolecular-bound water protons, such that a ratio can be estimated from the signal intensities. MTR is lower in the presence of demyelination, and it may also be influenced by the elevated water content in tissues as a result of inflammation or edema as well as changes in axonal density.32Schmierer K. Scaravilli F. Altmann D.R. Barker G.J. Miller D.H. Magnetization transfer ratio and myelin in postmortem multiple sclerosis brain.Ann Neurol. 2004; 56: 407-415Crossref PubMed Scopus (548) Google Scholar Several studies using magnetization transfer imaging in patients with migraine have suggested the presence of migraine-related focal microstructural damage.33Granziera C. Daducci A. Romascano D. Roche A. 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Microstructural white matter changes preceding white matter hyperintensities in migraine.Neurology. 2019; 93: e688-e694Crossref PubMed Scopus (6) Google Scholar A recent study of participants from the CAMERA-1 and CAMERA-2 studies examined whether visible WMLs exhibited alterations in MTR values compared with baseline MTR measurements in the normal-appearing white matter on prior imaging, before the appearance of these lesions.36Arkink E.B. Palm-Meinders I.H. Koppen H. Milles J. van Lew B. Launer L.J. Hofman P.A.M. Terwindt G.M. van Buchem M.A. Ferrari M.D. Kruit M.C. Microstructural white matter changes preceding white matter hyperintensities in migraine.Neurology. 2019; 93: e688-e694Crossref PubMed Scopus (6) Google Scholar The normal-appearing white matter that later progressed to WMLs at 9-year follow-up had a lower mean MTR at baseline compared with the contralateral white matter, suggesting that occult changes in microstructural tissue integrity may precede the development of frank WMLs on conventional T2-weighted MRI. Diffusion-weighted imaging uses the Brownian motion of water molecules as a probe of brain tissue microstructure and has been applied to study white matter integrity in migraine. Diffusion tensor imaging models the diffusive motion of water as a tensor and offers several quantitative metrics for characterizing tissue microstructure: fractional anisotropy, mean diffusivity, axial diffusivity, and radial diffusivity. 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Volumetric brain changes in migraineurs from the general population.Neurology. 2017; 89: 2066-2074Crossref PubMed Scopus (23) Google Scholar The pathophysiological mechanisms leading to the development of WMLs in migraine and the histopathologic correlates of migraine-related WMLs are not fully understood. The proposed etiologic mechanism underlying WMLs includes ischemic microvascular disturbances with subsequent focal hypoperfusion of the cerebral parenchyma.43Colombo B. Dalla Libera D. Comi G. Brain white matter lesions in migraine: what's the meaning?.Neurol Sci. 2011; 32: S37-S40Crossref PubMed Scopus (37) Google Scholar In fact, reduced cerebrovascular reactivity to carbon dioxide precedes the development of WMLs in normal individuals without migraine.44Sam K. Crawley A.P. Conklin J. Poublanc J. Sobczyk O. Mandell D.M. Venkatraghavan L. Duffin J. Fisher J.A. Black S.E. Mikulis D.J. 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