Background and purpose Migraine is recognized as a vascular risk factor, especially in women. Presumably, migraine, stroke and cardiovascular events share pathophysiological mechanisms. Self... Show moreBackground and purpose Migraine is recognized as a vascular risk factor, especially in women. Presumably, migraine, stroke and cardiovascular events share pathophysiological mechanisms. Self-reported cold extremities were investigated as a marker for vascular dysfunction in migraine. Secondly, it was hypothesized that suffering from cold extremities affects sleep quality, possibly exacerbating migraine attack frequency.Methods In this case-control study, a random sample of 1084 migraine patients and 348 controls (aged 22-65 years) from the LUMINA migraine cohort were asked to complete questionnaires concerning cold extremities, sleep quality and migraine.Results A total of 594 migraine patients and 199 controls completed the questionnaires. In women, thermal discomfort and cold extremities (TDCE) were more often reported by migraineurs versus controls (odds ratio 2.3, 95% confidence interval 1.4-3.7; P < 0.001), but not significantly so in men (odds ratio 2.5, 95% confidence interval 0.9-6.9; P = 0.09). There was no difference in TDCE comparing migraine with or without aura. Female migraineurs who reported TDCE had higher attack frequencies compared to female migraineurs without TDCE (4 vs. 3 attacks per month; P = 0.003). The association between TDCE and attack frequency was mediated by the presence of difficulty initiating sleep (P = 0.02).Conclusion Women with migraine more often reported cold extremities compared with controls, possibly indicating a sex-specific vascular vulnerability. Female migraineurs with cold extremities had higher attack frequencies, partly resulting from sleep disturbances. Future studies need to demonstrate whether cold extremities in female migraineurs are a predictor for cardiovascular and cerebrovascular events. Show less
Hoogeveen, E.S.; Arkink, E.B.; Grond, J. van der; Buchem, M.A. van; Ferrari, M.D.; Terwindt, G.M.; ... ; PROSPER Study Grp 2020
Although white matter lesions are frequently detected in migraine patients, underlying mechanisms remain unclear. Low carotid artery endothelial shear stress has been associated with white matter... Show moreAlthough white matter lesions are frequently detected in migraine patients, underlying mechanisms remain unclear. Low carotid artery endothelial shear stress has been associated with white matter lesions. We aimed to investigate the association between carotid artery endothelial shear stress and white matter lesions in migraine. In 40 elderly migraine patients (n = 29 females, 75 years [SD 3]) and 219 controls (n = 80 females, 74 years [SD 3]) from the PROSPER-MRI study, carotid artery endothelial shear stress was estimated on 1.5 T gradient-echo phase contrast MRI. White matter lesion volumes were calculated from structural MRI scans. Analyses were adjusted for age, sex, cardiovascular risk factors and cardiovascular disease. Migraine patients had lower mean endothelial shear stress compared to controls (0.90 [SD 0.15] vs. 0.98 [SD 0.16] Pa; P = 0.03). The association between mean endothelial shear stress and white matter lesion volume was greater for the migraine group than control group (P for interaction = 0.05). Within the migraine group, white matter lesion volume increased with decreasing endothelial shear stress (beta-0.421; P = 0.01). In conclusion, migraine patients had lower endothelial shear stress which was associated with higher white matter lesion volume. Show less
Background and Purpose-To determine whether migraine, which has often been described as an inaugural manifestation in monogenic cerebrovascular syndromes, is associated with cerebral amyloid... Show moreBackground and Purpose-To determine whether migraine, which has often been described as an inaugural manifestation in monogenic cerebrovascular syndromes, is associated with cerebral amyloid pathology, we assessed migraine and its correlation with magnetic resonance imaging markers in Hereditary Dutch-Type Cerebral Amyloid Angiopathy (D-CAA or Hereditary Cerebral Hemorrhage With Amyloidosis-Dutch type).Methods-All D-CAA mutation carriers who visited our clinic between 2012 and 2018 were included. Migraine was diagnosed by an interview and classified according to the International Classification of Headache Disorders. Magnetic resonance imaging scans were scored for intracerebral hemorrhage (ICH) location(s) and presence of cortical superficial siderosis. Kaplan Meier survival analysis was used for age of ICH onset in carriers with and without migraine. Correlation with ICH location(s) and cortical superficial siderosis were calculated with Poisson regression analysis adjusted for confounders.Results-We included 86 D-CAA mutation carriers (57% women, mean age 57 years), 48 (56%) suffered from migraine, all with aura. Prevalence was higher than expected compared with the general population (women, P<0.05; men, P<0.001). Migraine was the inaugural symptom in 77% and an isolated symptom in 35% of the carriers. Carriers with and without migraine did not differ for age of first ICH, cortical superficial siderosis prevalence, or occipital ICH. Time between migraine onset and first ICH was 8.5 years. Aura attacks lasting >= 60 minutes signaled acute ICH in 55%.Conclusions-Migraine with aura is an important, often inaugural, symptom in D-CAA. Aura attacks lasting >= 60 minutes may signal acute ICH in D-CAA. Migraine with aura may be regarded as an early marker of disease in hereditary CAA preceding the occurrence of symptomatic ICH by several years. Show less
Objective To determine whether transgenic mouse models of migraine exhibit upper gastrointestinal dysmotility comparable to those observed in migraine patients. Background There is considerable... Show moreObjective To determine whether transgenic mouse models of migraine exhibit upper gastrointestinal dysmotility comparable to those observed in migraine patients. Background There is considerable evidence supporting the comorbidity of gastrointestinal dysmotility and migraine. Gastrointestinal motility, however, has never been investigated in transgenic mouse models of migraine. Methods Three transgenic mouse strains that express pathogenic gene mutations linked to monogenic migraine-relevant phenotypes were studied: CADASIL (Notch3-Tg88), FASP (CSNK1D-T44A), and FHM1 (CACNA1A-S218L). Upper gastrointestinal motility was quantified by measuring gastric emptying and small intestinal transit in mutant and control animals. Gastrointestinal motility was measured at baseline and after pretreatment with 10 mg/kg nitroglycerin (NTG). Results No significant differences were observed for gastric emptying or small intestinal transit at baseline for any of the 3 transgenic strains when compared to appropriate controls or after pretreatment with NTG when compared to vehicle. Conclusions We detected no evidence of upper gastrointestinal dysmotility in mice that express mutations in genes linked to monogenic migraine-relevant phenotypes. Future studies seeking to understand why humans with migraine experience delayed gastric emptying may benefit from pursuing other modifiers of gastrointestinal motility, such as epigenetic or microbiome-related factors. Show less
Magni, G.; Boccazzi, M.; Bodini, A.; Abbracchio, M.P.; Maagdenberg, A.M.J.M. van den; Ceruti, S. 2019
Background Gain-of-function missense mutations in the alpha(1A) subunit of neuronal Ca(V)2.1 channels, which define Familial Hemiplegic Migraine Type 1 (FHM1), result in enhanced cortical... Show moreBackground Gain-of-function missense mutations in the alpha(1A) subunit of neuronal Ca(V)2.1 channels, which define Familial Hemiplegic Migraine Type 1 (FHM1), result in enhanced cortical glutamatergic transmission and a higher susceptibility to cortical spreading depolarization. It is now well established that neurons signal to surrounding glial cells, namely astrocytes and microglia, in the central nervous system, which in turn become activated and in pathological conditions can sustain neuroinflammation. We and others previously demonstrated an increased activation of pro-algogenic pathways, paralleled by augmented macrophage infiltration, in both isolated trigeminal ganglia and mixed trigeminal ganglion neuron-satellite glial cell cultures of FHM1 mutant mice. Hence, we hypothesize that astrocyte and microglia activation may occur in parallel in the central nervous system. Methods We have evaluated signs of reactive glia in brains from naive FHM1 mutant mice in comparison with wild type animals by immunohistochemistry and Western blotting. Results Here we show for the first time signs of reactive astrogliosis and microglia activation in the naive FHM1 mutant mouse brain. Conclusions Our data reinforce the involvement of glial cells in migraine, and suggest that modulating such activation may represent an innovative approach to reduce pathology. Show less
Boer, I. de; Maagdenberg, A.M.J.M. van den; Terwindt, G.M. 2019
Several factors that modulate migraine, a common primary headache disorder, also affect susceptibility to cortical spreading depolarization (CSD). CSD is a wave of neuronal and glial depolarization... Show moreSeveral factors that modulate migraine, a common primary headache disorder, also affect susceptibility to cortical spreading depolarization (CSD). CSD is a wave of neuronal and glial depolarization and thought to underlie the migraine aura and possibly headache. Here, we tested whether caffeine, known to alleviate or trigger headache after acute exposure or chronic use/withdrawal, respectively, modulates CSD. We injected C57BL/6J mice with caffeine (30, 60, or 120 mg/kg; i.p.) once (acute) or twice per day for one or two weeks (chronic). Susceptibility to CSD was evaluated by measuring the electrical CSD threshold and by assessing KCl-induced CSD. Simultaneous laser Doppler flowmetry was used to assess CSD-induced cortical blood flow changes. Recordings were performed 15 min after caffeine/vehicle administration, or 24 h after the last dose of chronic caffeine in the withdrawal group. The latter paradigm was also tested in mice carrying the familial hemiplegic migraine type 1 R192Q missense mutation, considered a valid migraine model. Neither acute/chronic administration nor withdrawal of caffeine affected CSD susceptibility or related cortical blood flow changes, either in WT or R192Q mice. Hence, adverse or beneficial effects of caffeine on headache seem unrelated to CSD pathophysiology, consistent with the non-migrainous clinical presentation of caffeine-related headache. Show less
Familial hemiplegic migraine type 1 (FHM1) is a rare migraine subtype. Whereas transgenic knock-in mice with the human pathogenic FHM1 R192Q missense mutation in the Cacna1a gene reveal overall... Show moreFamilial hemiplegic migraine type 1 (FHM1) is a rare migraine subtype. Whereas transgenic knock-in mice with the human pathogenic FHM1 R192Q missense mutation in the Cacna1a gene reveal overall neuronal hyperexcitability, the effects on the trigeminovascular system and calcitonin gene-related peptide (CGRP) receptor are largely unknown. This gains relevance as blockade of CGRP and its receptor are therapeutic targets under development. Hence, we set out to test these effects in FHM1 mice. We characterized the trigeminovascular system of wild-type and FHM1 mice through: (i) in vivo capsaicin- and CGRP-induced dural vasodilation in a closed-cranial window; (ii) ex vivo KCl-induced CGRP release from isolated dura mater, trigeminal ganglion and trigeminal nucleus caudalis; and (iii) peripheral vascular function in vitro. In mutant mice, dural vasodilatory responses were significantly decreased compared to controls. The ex vivo release of CGRP was not different in the components of the trigeminovascular system between genotypes; however, sumatriptan diminished the release in the trigeminal ganglion, trigeminal nucleus caudalis and dura mater but only in wild-type mice. Peripheral vascular function was similar between genotypes. These data suggest that the R192Q mutation might be associated with trigeminovascular CGRP receptor desensitization. Novel antimigraine drugs should be able to revert this complex phenomenon. Show less
