- Email: [email protected]
Brain lesions and cerebral functional impairment in migraine patients
Journal of the Neurological Sciences 283 (2009) 134–136
Contents lists available at ScienceDirect
Journal of the Neurological Sciences j o u r n a l h o m e p a g e : w w w. e l s ev i e r. c o m / l o c a t e / j n s
Brain lesions and cerebral functional impairment in migraine patients Koen Paemeleire ⁎ Headache Clinic, Department of Neurology, Ghent University Hospital, De Pintelaan 185, B-9000 Ghent, Belgium
a r t i c l e
i n f o
Available online 5 March 2009 Keywords: Migraine Risk factor White matter hyperintensities Stroke Cognitive decline Dementia
a b s t r a c t Migraine is an independent risk factor for ischemic stroke, mainly in the subpopulation of women with migraine with aura who are younger than 45 years, particularly those that use estrogen containing oral contraceptives. Migraine however should be considered a benign condition as the absolute increase of stroke risk is small. Migraine is also associated with a high prevalence of cerebral white matter hyperintensities, occurring in the deep and periventricular white matter as well as infratentorial, mainly pontine. The pathogenesis and clinical significance of these hyperintensities is unclear. We do not know whether migraine may be considered a progressive disorder in a subset of patients because of accumulation of these hyperintensities over time. Studies on the relationship between migraine and cognitive functioning yielded conflicting results. Two recent studies have provided reassuring news for the migraine patient. A population-based twin study showed that a lifetime migraine diagnosis was not associated with cognitive deficits in middle-aged subjects. A long-term prospective study, assessing cognitive and memory changes in ageing individuals with and without a history of migraine, showed that migraineurs do not exhibit more decline on cognitive tests over time versus controls. Migraine is certainly not a recognized risk factor for (vascular) dementia. © 2009 Elsevier B.V. All rights reserved.
1. Introduction
2. Migraine and ischemic stroke
Migraine affects about 12% of the population and is a primary disorder of the brain with a genetic foundation characterized primarily by recurrent head pain with associated features including nausea and/or vomiting and heightened sensitivity to stimuli such as light (photophobia), sound (phonophobia) and movement. The two main subtypes are migraine with aura and migraine without aura [1]. A literature search for migraine and vascular dementia yields mainly information on CADASIL (Cerebral Autosomal Dominant Arteriopathy with Subcortical Infarcts and Leukoencephalopathy), an autosomal dominant small-artery disease caused by mutations of the NOTCH3 gene and characterized by accumulating white matter lesions, mood disturbances, ischemic strokes and cognitive decline. At least one third of patients suffer from migraine with aura, which is usually the presenting symptom in such cases [2–4]. Although migraine certainly is not a recognized risk factor for dementia, several reports have emerged linking migraine with the presence of subclinical white matter lesions, less than average functioning in certain cognitive domains, and an increased risk of ischemic stroke. We will review literature on these topics and address the question whether migraine is associated with cognitive decline over time. The literature on reversible cognitive impairment during a migraine attack or in the peri-ictal period will not be covered [5–8].
A meta-analysis of studies published between 1966 and June 2004 regarding the risk of ischemic stroke in migraine patients concluded that migraine is an independent risk factor for ischemic stroke, especially in women of childbearing age suffering from migraine with aura and using contraceptives containing estrogen, albeit the absolute risk is small [9]. The average relative risk of ischemic stroke averages 2.16 and ranges between 1.89 and 2.48 in the 14 studies that were included (11 case control studies and 3 cohort studies). The increase of risk for ischemic stroke is higher in migraine with aura (average 2.27, range 1.61 to 3.19, 7 case–control studies) than for migraine without aura (average 1.83, range 1.06 to 3.15, 6 case–control studies). The relative risk in women aged less than 45 years and suffering from migraine rises to an average of 2.76 (range 2.17 to 3.52). Importantly, the risk for ischemic stroke is increased almost 9 times in migraine patients using oral contraceptives containing estrogen (average 8.72, range 5.05 to 15.05), although this number came from only 3 case–control studies. Additional lessons were learned from a methodological sound cross-sectional prevalence study in a population-based sample of Dutch adults aged 30 to 60 years [10]. The patient group included 134 patients with migraine without aura and 161 patients with migraine with aura. Their data were compared with 140 matched controls. Brain magnetic resonance imaging (MRI) studies were evaluated for the presence of infarcts and white matter lesions, both in the deep and periventricular white matter. All patients had a normal neurological examination and no history of transient ischemic attack or stroke. The percentage of patients with at least 1 radiographic brain infarct was not significantly increased in migraine patients versus
⁎ Tel.: +32 9 332 45 39; fax: +32 9 332 49 71. E-mail address: [email protected]. 0022-510X/$ – see front matter © 2009 Elsevier B.V. All rights reserved. doi:10.1016/j.jns.2009.02.333
K. Paemeleire / Journal of the Neurological Sciences 283 (2009) 134–136
controls (5% versus 8.1%), with the data controlled for cardiovascular risk factors and use of vasoconstrictive agents. When these data were subanalysed by vascular supply, a significantly increased risk for posterior circulation infarcts was observed in patients with migraine with aura (in 8.1% versus 0.7% of controls), although the absolute numbers of posterior circulation strokes were small (13 in migraine with aura versus 1 in controls). In a large prospective cohort study, the Women's Health Study, migraine was not associated with total, ischemic or hemorrhagic stroke in women [11]. After subgroup analysis, a statistically significant increased ischemic stroke risk was found in migraine patients with aura, although the absolute increase of stroke risk was small, with only 3.8 additional ischemic stroke cases per year per 10,000 women. The risk of stroke in migraine patients is smaller than the risk of stroke during pregnancy, even in patients with migraine with aura using oral contraceptives [12]. 3. Migraine and cerebral white matter hyperintensities White matter hyperintensities are more prevalent in migraineurs compared to the general population, and are found in 12–47% of all patients [13–16]. The overall relative risk for white matter hyperintensities in migraine patients versus controls was calculated to be close to 4, after meta-analysis of 7 studies [17]. They are typically seen on T2 and FLAIR MRI as multiple, small, punctuate lesions in the deep or periventricular white matter, as well as in the brainstem, mainly the pons [10,18]. These white matter hyperintensities occur more frequently in female patients with frequent attacks [10]. The pathogenesis and clinical significance of these hyperintensities is still unclear at present. A number of pathophysiological mechanisms have been put forward including oligemia [18] and mitochondrial dysfunction [19], but there are no neuropathological data. They are not associated with arterial hypertension, hypercholesterolemia and diabetes mellitus [17], or the presence of antiphospholipid antibodies (anticardiolipin antibodies and lupus anticoagulans) or abnormal coagulation parameters, including antithrombin-III, Protein S or Protein C [20]. Several questions remain unanswered regarding these hyperintensities, including whether they accumulate over time in migraine patients (and whether the use of migraine prevention strategies would prevent their accumulation), whether their presence constitutes a risk for stroke in migraine patients (and whether stroke prophylaxis is indicated), and whether they have an impact on cognitive functioning in migraine patients [21]. As such, white matter hyperintensities should be separated from white matter lesions, related to cerebral small-vessel disease on neuropathology, and silent brain infarcts that are both associated with a risk of future stroke, cognitive decline and dementia [22–25].
135
pain. It has been suggested that even if subtle cognitive problems would be reproducibly be identified in cross-sectional studies they would probably be common to chronic pain disorders in general [41]. It is therefore worthwhile to draw attention to two recent studies in this domain. The first one is a population-based study, with middle-aged subjects selected from the Danish twin registry [43]. Data from cognitive tests in 536 migraineurs were compared with non-migraineurs, and additional data from cognitive tests were compared within 139 monozygotic or dizygotic same sex twin pairs discordant for migraine. No significant differences were found on all cognitive tests for fluency, digit span, delayed word recall and symbol digit substitution test. The authors acknowledge that only a limited sample of tests has been performed and that differences in specific domains are not excluded. The second study is part of the Baltimore Epidemiologic Catchment Area Study [44]. Longitudinal data were obtained from waves III (1993–1996) and IV (2004–2005) of this study regarding cognitive functioning in migraine patients. The migraine diagnosis was made according to modified International Headache Society criteria. Data from immediate and delayed recall tests (using a modified Rey Verbal learning test), as well as Mini Mental State Examination (MMSE) were compared between 204 migraine patients and 1244 non-migraineurs. Surprisingly, migraineurs (especially those suffering from migraine with aura), showed less decline on cognitive tests over time versus non-migraineurs. For the MMSE the difference became only apparent among those more than 50 years old. These are the only long-term prospective data available from a community-based sample assessing the association between a lifetime history of migraine with cognitive functioning in middle-aged to older adults. 5. Conclusion Migraine is not an established risk factor for vascular dementia, although migraine is an independent risk factor for ischemic stroke. Migraine is a risk factor for white matter hyperintensities of unknown pathogenesis and clinical significance. It remains to be prospectively evaluated whether those people who have migraine and white matter hyperintensities are at greater risk of stroke than those with migraine without white matter hyperintensities. At present systematic neuroimaging of migraine patients is not recommended [45–47]. Systematic genetic testing for CADASIL is also not recommended in migraine patients with white matter hyperintensities on brain MRI [47]. More research is necessary in large population-based samples to more fully understand the effects of migraine headaches, both with and without aura, on an individual's cognitive trajectory over time.
4. Migraine and cognitive function
References
Studies on the relationship between migraine and cognitive functioning have come up with conflicting results. Some studies demonstrated a deleterious effect of migraine on several cognitive skills, including attention, verbal ability, memory and psychomotor ability [26–34], whereas other studies have shown no differences in cognitive skills [35–41]. One study showed that migraine patients may perform better in ‘low level’ visual processes, such orientation detection and temporal order judgement [42], but the results were not replicated [41]. A detailed description of all these studies is beyond the scope of this paper, but the explanation for this apparent contradiction lies in methodological differences between studies. The majority of these studies were cross-sectional, thus indicating an association rather than a causal relationship. Studies varied widely according to sample size, subject selection, headache diagnosis and test methodology. Most studies have included small groups of patients recruited from specialized headache clinics. It is furthermore hard to blind the subject or to correct for comorbid depression or anxiety, effect of medication (especially preventative drugs) and the influence of discomfort and
[1] Headache Classification Subcommittee of The International Headache Society. The International Classification of Headache Disorders, vol. 24 Suppl 1. Cephalalgia, 2nd edition; 2004. p. 9–160. [2] Lesnik Oberstein SA, van den Boom R, Middelkoop HA, Ferrari MD, Knaap YM, van Houwelingen HC, et al. Incipient CADASIL. Arch Neurol 2003;60(5):707–12. [3] Dichgans M, Mayer M, Uttner I, Brüning R, Müller-Höcker J, Rungger G, et al. The phenotypic spectrum of CADASIL: clinical findings in 102 cases. Ann Neurol Nov 1998;44(5):731–9. [4] Markus HS, Martin RJ, Simpson MA, Dong YB, Ali N, Crosby AH, et al. Diagnostic strategies in CADASIL. Neurology 2002;59(8):1134–8. [5] Farmer K, Cady R, Bleiberg J, Reeves D. A pilot study to measure cognitive efficiency during migraine. Headache 2000;40:657–61. [6] Blau JN. Migraine postdromes: symptoms after attacks. Cephalalgia 1991;11(5):229–31. [7] Sanchez A. Neuropsychologic symptoms in the migraine syndrome. Cephalalgia 1998;8:67–70. [8] Meyer JS, Thronby J, Crawford K, Rauch GM. Reversible cognitive decline accompanies migraine and cluster headaches. Headache 2000;40:638–46. [9] Etminan M, Takkouche B, Isorna FC, Samii A. Risk of ischaemic stroke in people with migraine: systematic review and meta-analysis of observational studies. BMJ 2005;330(7482):63. [10] Kruit MC, van Buchem MA, Hofman PA, Bakkers JT, Terwindt GM, Ferrari MD, et al. Migraine as a risk factor for subclinical brain lesions. JAMA 2004;291:427–34. [11] Kurth T, Slomke MA, Kase CS, Cook NR, Lee IM, Gaziano JM, et al. Migraine, headache, and the risk of stroke in women: a prospective study. Neurology 2005;64(6):1020–6.
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[12] Goadsby PJ. Is migraine a progressive disorder? Considering the clinical implications of new research data on migraine and brain lesions. Med J Aust 2005;182(3):103–4. [13] Cooney BS, Grossman RI, Farber RE, Goin JE, Galetta SL. Frequency of magnetic resonance imaging abnormalities in patients with migraine. Headache 1996;36 (10):616–21. [14] Fazekas F, Koch M, Schmidt R, Offenbacher H, Payer F, Freidl W, et al. The prevalence of cerebral damage varies with migraine type: a MRI study. Headache 1992;32(6):287–91. [15] Rocca MA, Colombo B, Pratesi A, Comi G, Filippi M. A magnetization transfer imaging study of the brain in patients with migraine. Neurology 2000;54:507–9. [16] De Benedettis G, Lorenzetti A, Sina C, Bernasconi V. Magnetic resonance imaging in migraine and tension-type headache. Headache 1995;35(5):264–8. [17] Swartz RH, Kern RZ. Migraine is associated with magnetic resonance imaging white matter abnormalities: a meta-analysis. Arch Neurol 2004;61(9):1366–8. [18] Kruit MC, Launer LJ, Ferrari MD, van Buchem MA. Brain stem and cerebellar hyperintense lesions in migraine. Stroke 2006;37(4):1109–12. [19] Speciali JG, Bigal ME. Subcortical lesions in migraine: are they related to mitochondrial dysfunction? Headache 2006;46(9):1461–2. [20] Intiso D, Di Rienzo F, Rinaldi G, Zarrelli MM, Giannatempo GM, Crociani P, et al. Brain MRI white matter lesions in migraine patients: is there a relationship with antiphospholipid antibodies and coagulation parameters? Eur J Neurol 2006;13 (12):1364–9. [21] Tietjen GE. Stroke and migraine linked by silent lesions. Lancet Neurol 2004;3 (5):267. [22] Vermeer SE, Hollander M, van Dijk EJ, Hofman A, Koudstaal PJ, Breteler MM. Rotterdam Scan Study. Silent brain infarcts and white matter lesions increase stroke risk in the general population: the Rotterdam Scan Study. Stroke 2003;34 (5):1126–9. [23] Schmidt R, Scheltens P, Erkinjuntti T, Pantoni L, Markus HS, Wallin A, et al. White matter lesion progression: a surrogate endpoint for trials in cerebral small-vessel disease. Neurology 2004;63(1):139–44. [24] Vermeer SE, Prins ND, den Heijer T, Hofman A, Koudstaal PJ, Breteler MM. Silent brain infarcts and the risk of dementia and cognitive decline. N Engl J Med 2003;348(13):1215–22. [25] Bernick C, Kuller L, Dulberg C, Longstreth Jr WT, Manolio T, Beauchamp N, et al. Silent MRI infarcts and the risk of future stroke: the cardiovascular health study. Neurology 2001;57(7):1222–9. [26] Zeitlin C, Oddy M. Cognitive impairment in patients with severe migraine. Br J Clin Psychol 1984;23(Pt1):27–35. [27] Le Pira F, Lanaia F, Zappalà G, Morana R, Panetta MR, Reggio E, et al. Relationship between clinical variables and cognitive performances in migraineurs with and without aura. Funct Neurology 2004;19(2):101–5. [28] Hooker WD, Raskin NH. Neuropsychologic alterations in classic and common migraine. Arch Neurol 1986;43(7):709–12. [29] Mulder EJCM, Linssen WHJP, Passchier J, Orlebeke JF, de Geus EJC. Interictal and postictal cognitive changes in migraine. Cephalalgia 1999;19:557–65.
[30] Calandre EP, Bembibre J, Arnedo ML, Becerra D. Cognitive disturbances and regional cerebral blood flow abnormalities in migraine patients: their relationship with the clinical manifestations of the illness. Cephalalgia 2002;22:291–302. [31] Waldie K, Hausmann M, Milne BJ, Poulton R. Migraine and cognitive function: a life course study. Neurology 2002;59:904–8. [32] Riva D, Aggio F, Vago C, Nichelli F, Andreucci E, Paruta N, et al. Cognitive and behavioral effects of migraine in childhood and adolescence. Cephalalgia 2006;26:596–603. [33] Le Pira F, Zappalà G, Giuffrida S, Lo Bartolo ML, Reggio E, Morana R, et al. Memory disturbances in migraine with and without aura: a strategy problem ? Cephalalgia 2000;20:475–8. [34] Scherer P, Bauer H, Baum K. Alternate finger tapping test in patients with migraine. Acta Neurol Scand 1997;96(6):392–6. [35] Sinforiani E, Farina S, Mancuso A, Manzoni GC, Bono G, Mazzuchi A. Analysis of higher nervous functions in migraine and cluster headache. Funct Neurology 1987;2(1):69–77. [36] Pearson AJ, Chronicle EP, Maylor EA, Bruce LAM. Cognitive function is not impaired in people with a long history of migraine: a blinded study. Cephalalgia 2006;26:74–80. [37] Leijdekkers ML, Passchier J, Goudswaard P, Menges LJ, Orlebeke JF. Migraine patients cognitively impaired? Headache 1990;30(6):352–8. [38] Jelicic MJ, van Boxtel MPJ, Houx PJ, Jolles J. Does migraine headache affect cognitive function in the elderly? Report from the Maastricht Aging Study (MAAS). Headache 2000;40:715–9. [39] Haverkamp F, Hönscheid A, Müller-Sinik K. Cognitive development in children with migraine and their healthy unaffected siblings. Headache 2002;42:776–9. [40] Bell BD, Primeau M, Sweet JJ, Lofland KR. Neuropsychological functioning in migraine headache, nonheadache chronic pain, and mild traumatic brain injury patients. Arch Clin Neuropsychol 1999;14(4):389–99. [41] Palmer JE, Chronicle EP. Cognitive processing in migraine: a failure to find facilitation in patients with aura. Cephalalgia 1998;18:125–32. [42] Wray SH, Mijović-Prelec D, Kosslyn SM. Visual processing in migraineurs. Brain 1995;118(Pt 1):25–35. [43] Gaist D, Pedersen L, Madsen C, Tsiropoulos I, Bak S, Sindrup S, et al. Long-term effects of migraine on cognitive function. Neurology 2005;64:600–7. [44] Kalaydjian A, Zandi PP, Swartz KL, Eaton WW, Lyketsos C. How migraines impact cognitive function. Findings from the Baltimore ECA. Neurology 2007;68(17):1417–24. [45] AAN. Practice parameter: the utility of neuroimaging in the evaluation of headache in patients with normal neurologic examinations (summary statement). Report of the Quality Standards Subcommittee of the American Academy of Neurology. Neurology 1994;44(7):1353–4. [46] Silberstein SD. Practice parameter: evidence-based guidelines for migraine headache (an evidence-based review): report of the Quality Standards Subcommittee of the American Academy of Neurology. Neurology 2000;55(6):754–62. [47] Bousser MG, Welch KM. Relation between migraine and stroke. Lancet Neurol 2005;4(9):533–42.
Contents lists available at ScienceDirect
Journal of the Neurological Sciences j o u r n a l h o m e p a g e : w w w. e l s ev i e r. c o m / l o c a t e / j n s
Brain lesions and cerebral functional impairment in migraine patients Koen Paemeleire ⁎ Headache Clinic, Department of Neurology, Ghent University Hospital, De Pintelaan 185, B-9000 Ghent, Belgium
a r t i c l e
i n f o
Available online 5 March 2009 Keywords: Migraine Risk factor White matter hyperintensities Stroke Cognitive decline Dementia
a b s t r a c t Migraine is an independent risk factor for ischemic stroke, mainly in the subpopulation of women with migraine with aura who are younger than 45 years, particularly those that use estrogen containing oral contraceptives. Migraine however should be considered a benign condition as the absolute increase of stroke risk is small. Migraine is also associated with a high prevalence of cerebral white matter hyperintensities, occurring in the deep and periventricular white matter as well as infratentorial, mainly pontine. The pathogenesis and clinical significance of these hyperintensities is unclear. We do not know whether migraine may be considered a progressive disorder in a subset of patients because of accumulation of these hyperintensities over time. Studies on the relationship between migraine and cognitive functioning yielded conflicting results. Two recent studies have provided reassuring news for the migraine patient. A population-based twin study showed that a lifetime migraine diagnosis was not associated with cognitive deficits in middle-aged subjects. A long-term prospective study, assessing cognitive and memory changes in ageing individuals with and without a history of migraine, showed that migraineurs do not exhibit more decline on cognitive tests over time versus controls. Migraine is certainly not a recognized risk factor for (vascular) dementia. © 2009 Elsevier B.V. All rights reserved.
1. Introduction
2. Migraine and ischemic stroke
Migraine affects about 12% of the population and is a primary disorder of the brain with a genetic foundation characterized primarily by recurrent head pain with associated features including nausea and/or vomiting and heightened sensitivity to stimuli such as light (photophobia), sound (phonophobia) and movement. The two main subtypes are migraine with aura and migraine without aura [1]. A literature search for migraine and vascular dementia yields mainly information on CADASIL (Cerebral Autosomal Dominant Arteriopathy with Subcortical Infarcts and Leukoencephalopathy), an autosomal dominant small-artery disease caused by mutations of the NOTCH3 gene and characterized by accumulating white matter lesions, mood disturbances, ischemic strokes and cognitive decline. At least one third of patients suffer from migraine with aura, which is usually the presenting symptom in such cases [2–4]. Although migraine certainly is not a recognized risk factor for dementia, several reports have emerged linking migraine with the presence of subclinical white matter lesions, less than average functioning in certain cognitive domains, and an increased risk of ischemic stroke. We will review literature on these topics and address the question whether migraine is associated with cognitive decline over time. The literature on reversible cognitive impairment during a migraine attack or in the peri-ictal period will not be covered [5–8].
A meta-analysis of studies published between 1966 and June 2004 regarding the risk of ischemic stroke in migraine patients concluded that migraine is an independent risk factor for ischemic stroke, especially in women of childbearing age suffering from migraine with aura and using contraceptives containing estrogen, albeit the absolute risk is small [9]. The average relative risk of ischemic stroke averages 2.16 and ranges between 1.89 and 2.48 in the 14 studies that were included (11 case control studies and 3 cohort studies). The increase of risk for ischemic stroke is higher in migraine with aura (average 2.27, range 1.61 to 3.19, 7 case–control studies) than for migraine without aura (average 1.83, range 1.06 to 3.15, 6 case–control studies). The relative risk in women aged less than 45 years and suffering from migraine rises to an average of 2.76 (range 2.17 to 3.52). Importantly, the risk for ischemic stroke is increased almost 9 times in migraine patients using oral contraceptives containing estrogen (average 8.72, range 5.05 to 15.05), although this number came from only 3 case–control studies. Additional lessons were learned from a methodological sound cross-sectional prevalence study in a population-based sample of Dutch adults aged 30 to 60 years [10]. The patient group included 134 patients with migraine without aura and 161 patients with migraine with aura. Their data were compared with 140 matched controls. Brain magnetic resonance imaging (MRI) studies were evaluated for the presence of infarcts and white matter lesions, both in the deep and periventricular white matter. All patients had a normal neurological examination and no history of transient ischemic attack or stroke. The percentage of patients with at least 1 radiographic brain infarct was not significantly increased in migraine patients versus
⁎ Tel.: +32 9 332 45 39; fax: +32 9 332 49 71. E-mail address: [email protected]. 0022-510X/$ – see front matter © 2009 Elsevier B.V. All rights reserved. doi:10.1016/j.jns.2009.02.333
K. Paemeleire / Journal of the Neurological Sciences 283 (2009) 134–136
controls (5% versus 8.1%), with the data controlled for cardiovascular risk factors and use of vasoconstrictive agents. When these data were subanalysed by vascular supply, a significantly increased risk for posterior circulation infarcts was observed in patients with migraine with aura (in 8.1% versus 0.7% of controls), although the absolute numbers of posterior circulation strokes were small (13 in migraine with aura versus 1 in controls). In a large prospective cohort study, the Women's Health Study, migraine was not associated with total, ischemic or hemorrhagic stroke in women [11]. After subgroup analysis, a statistically significant increased ischemic stroke risk was found in migraine patients with aura, although the absolute increase of stroke risk was small, with only 3.8 additional ischemic stroke cases per year per 10,000 women. The risk of stroke in migraine patients is smaller than the risk of stroke during pregnancy, even in patients with migraine with aura using oral contraceptives [12]. 3. Migraine and cerebral white matter hyperintensities White matter hyperintensities are more prevalent in migraineurs compared to the general population, and are found in 12–47% of all patients [13–16]. The overall relative risk for white matter hyperintensities in migraine patients versus controls was calculated to be close to 4, after meta-analysis of 7 studies [17]. They are typically seen on T2 and FLAIR MRI as multiple, small, punctuate lesions in the deep or periventricular white matter, as well as in the brainstem, mainly the pons [10,18]. These white matter hyperintensities occur more frequently in female patients with frequent attacks [10]. The pathogenesis and clinical significance of these hyperintensities is still unclear at present. A number of pathophysiological mechanisms have been put forward including oligemia [18] and mitochondrial dysfunction [19], but there are no neuropathological data. They are not associated with arterial hypertension, hypercholesterolemia and diabetes mellitus [17], or the presence of antiphospholipid antibodies (anticardiolipin antibodies and lupus anticoagulans) or abnormal coagulation parameters, including antithrombin-III, Protein S or Protein C [20]. Several questions remain unanswered regarding these hyperintensities, including whether they accumulate over time in migraine patients (and whether the use of migraine prevention strategies would prevent their accumulation), whether their presence constitutes a risk for stroke in migraine patients (and whether stroke prophylaxis is indicated), and whether they have an impact on cognitive functioning in migraine patients [21]. As such, white matter hyperintensities should be separated from white matter lesions, related to cerebral small-vessel disease on neuropathology, and silent brain infarcts that are both associated with a risk of future stroke, cognitive decline and dementia [22–25].
135
pain. It has been suggested that even if subtle cognitive problems would be reproducibly be identified in cross-sectional studies they would probably be common to chronic pain disorders in general [41]. It is therefore worthwhile to draw attention to two recent studies in this domain. The first one is a population-based study, with middle-aged subjects selected from the Danish twin registry [43]. Data from cognitive tests in 536 migraineurs were compared with non-migraineurs, and additional data from cognitive tests were compared within 139 monozygotic or dizygotic same sex twin pairs discordant for migraine. No significant differences were found on all cognitive tests for fluency, digit span, delayed word recall and symbol digit substitution test. The authors acknowledge that only a limited sample of tests has been performed and that differences in specific domains are not excluded. The second study is part of the Baltimore Epidemiologic Catchment Area Study [44]. Longitudinal data were obtained from waves III (1993–1996) and IV (2004–2005) of this study regarding cognitive functioning in migraine patients. The migraine diagnosis was made according to modified International Headache Society criteria. Data from immediate and delayed recall tests (using a modified Rey Verbal learning test), as well as Mini Mental State Examination (MMSE) were compared between 204 migraine patients and 1244 non-migraineurs. Surprisingly, migraineurs (especially those suffering from migraine with aura), showed less decline on cognitive tests over time versus non-migraineurs. For the MMSE the difference became only apparent among those more than 50 years old. These are the only long-term prospective data available from a community-based sample assessing the association between a lifetime history of migraine with cognitive functioning in middle-aged to older adults. 5. Conclusion Migraine is not an established risk factor for vascular dementia, although migraine is an independent risk factor for ischemic stroke. Migraine is a risk factor for white matter hyperintensities of unknown pathogenesis and clinical significance. It remains to be prospectively evaluated whether those people who have migraine and white matter hyperintensities are at greater risk of stroke than those with migraine without white matter hyperintensities. At present systematic neuroimaging of migraine patients is not recommended [45–47]. Systematic genetic testing for CADASIL is also not recommended in migraine patients with white matter hyperintensities on brain MRI [47]. More research is necessary in large population-based samples to more fully understand the effects of migraine headaches, both with and without aura, on an individual's cognitive trajectory over time.
4. Migraine and cognitive function
References
Studies on the relationship between migraine and cognitive functioning have come up with conflicting results. Some studies demonstrated a deleterious effect of migraine on several cognitive skills, including attention, verbal ability, memory and psychomotor ability [26–34], whereas other studies have shown no differences in cognitive skills [35–41]. One study showed that migraine patients may perform better in ‘low level’ visual processes, such orientation detection and temporal order judgement [42], but the results were not replicated [41]. A detailed description of all these studies is beyond the scope of this paper, but the explanation for this apparent contradiction lies in methodological differences between studies. The majority of these studies were cross-sectional, thus indicating an association rather than a causal relationship. Studies varied widely according to sample size, subject selection, headache diagnosis and test methodology. Most studies have included small groups of patients recruited from specialized headache clinics. It is furthermore hard to blind the subject or to correct for comorbid depression or anxiety, effect of medication (especially preventative drugs) and the influence of discomfort and
[1] Headache Classification Subcommittee of The International Headache Society. The International Classification of Headache Disorders, vol. 24 Suppl 1. Cephalalgia, 2nd edition; 2004. p. 9–160. [2] Lesnik Oberstein SA, van den Boom R, Middelkoop HA, Ferrari MD, Knaap YM, van Houwelingen HC, et al. Incipient CADASIL. Arch Neurol 2003;60(5):707–12. [3] Dichgans M, Mayer M, Uttner I, Brüning R, Müller-Höcker J, Rungger G, et al. The phenotypic spectrum of CADASIL: clinical findings in 102 cases. Ann Neurol Nov 1998;44(5):731–9. [4] Markus HS, Martin RJ, Simpson MA, Dong YB, Ali N, Crosby AH, et al. Diagnostic strategies in CADASIL. Neurology 2002;59(8):1134–8. [5] Farmer K, Cady R, Bleiberg J, Reeves D. A pilot study to measure cognitive efficiency during migraine. Headache 2000;40:657–61. [6] Blau JN. Migraine postdromes: symptoms after attacks. Cephalalgia 1991;11(5):229–31. [7] Sanchez A. Neuropsychologic symptoms in the migraine syndrome. Cephalalgia 1998;8:67–70. [8] Meyer JS, Thronby J, Crawford K, Rauch GM. Reversible cognitive decline accompanies migraine and cluster headaches. Headache 2000;40:638–46. [9] Etminan M, Takkouche B, Isorna FC, Samii A. Risk of ischaemic stroke in people with migraine: systematic review and meta-analysis of observational studies. BMJ 2005;330(7482):63. [10] Kruit MC, van Buchem MA, Hofman PA, Bakkers JT, Terwindt GM, Ferrari MD, et al. Migraine as a risk factor for subclinical brain lesions. JAMA 2004;291:427–34. [11] Kurth T, Slomke MA, Kase CS, Cook NR, Lee IM, Gaziano JM, et al. Migraine, headache, and the risk of stroke in women: a prospective study. Neurology 2005;64(6):1020–6.
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