Background and purposeThe aim was to evaluate the effect of anti-calcitonin gene related peptide (CGRP) (ligand or receptor) antibodies on depressive symptoms in subjects with migraine and to... Show moreBackground and purposeThe aim was to evaluate the effect of anti-calcitonin gene related peptide (CGRP) (ligand or receptor) antibodies on depressive symptoms in subjects with migraine and to determine whether depressive symptoms predict treatment response.MethodsPatients with migraine treated with erenumab and fremanezumab at the Leiden Headache Centre completed daily E-headache diaries. A control group was included. Depressive symptoms were assessed using the Hospital Anxiety and Depression Scale (HADS) and the Center for Epidemiological Studies Depression Scale (CES-D) questionnaires at baseline (T0) and after 3 months (T1). First, the effect of treatment on the reduction in HADS-D and CES-D scores was assessed, with reduction in depression scores as the dependent variable and reduction in monthly migraine days (MMD) and treatment with anti-CGRP medication as independent variables. Second, depression as a predictor of treatment response was investigated, using the absolute reduction in MMD as a dependent variable and age, gender, MMD, active depression, impact, stress and locus of control scores as independent variables.ResultsIn total, n = 108 patients were treated with erenumab, n = 90 with fremanezumab and n = 68 were without active treatment. Treatment with anti-CGRP medication was positively associated with a reduction in the HADS-D (β = 1.65, p = 0.01) compared to control, independent of MMD reduction. However, the same effect was not found for the CES-D (β = 2.15, p = 0.21). Active depression predicted poorer response to erenumab (p = 0.02) but not to fremanezumab (p = 0.09).ConclusionAnti-CGRP (ligand or receptor) monoclonals lead to improvement of depressive symptoms in individuals with migraine, independent of migraine reduction. Depression may predict treatment response to erenumab but not to fremanezumab. Show less
Arend, B.W.H. van der; Bloemhof, M.M.; Schoor, A.G. van der; Zwet, E.W. van; Terwindt, G.M. 2023
BackgroundThis longitudinal cohort study aimed to investigate changes in migraine-related outcomes following COVID-19 infection and vaccination.MethodsWe identified 547 clinically diagnosed... Show moreBackgroundThis longitudinal cohort study aimed to investigate changes in migraine-related outcomes following COVID-19 infection and vaccination.MethodsWe identified 547 clinically diagnosed migraine patients from the Leiden Headache Center who kept a headache E-diary during the COVID-19 pandemic (February 2020 to August 2022). We sent a questionnaire to register their COVID-19 infection and/or vaccination dates. After applying inclusion criteria, n = 59 participants could be included in the infection analysis and n = 147 could be included in the vaccination analysis. Primary outcome was the change in monthly migraine days (MMD) between 1 month prior and 1 month post COVID-19 infection or vaccination. Secondary outcome variables were change in monthly headache days (MHD) and monthly acute medication days (MAMD).ResultsVaccination against COVID-19 was associated with an increase in MMD (1.06; 95% confidence interval [CI] = 0.57–1.55; p < 0.001), MHD (1.52; 95% CI = 0.91–2.14; p < 0.001) and MAMD (0.72; 95% CI = 0.33–1.12; p < 0.001) in the first month post-vaccination. COVID-19 infection solely increased the number of MAMD (1.11; 95% CI = 0.10–1.62; p < 0.027), but no statistically significant differences in MMD or MHD were observed.ConclusionsOur findings imply that vaccination against COVID-19 is associated with an increase in migraine, indicating a possible role of inflammatory mediators in migraine pathophysiology. Show less
ObjectiveTo evaluate the effect of treatment with anti-calcitonin gene–related peptide (CGRP; receptor) antibodies on visual hypersensitivity in patients with migraine.BackgroundIncreased visual... Show moreObjectiveTo evaluate the effect of treatment with anti-calcitonin gene–related peptide (CGRP; receptor) antibodies on visual hypersensitivity in patients with migraine.BackgroundIncreased visual sensitivity can be present both during and outside migraine attacks. CGRP has been demonstrated to play a key role in light-aversive behavior.MethodsIn this prospective follow-up study, patients treated for migraine with erenumab (n = 105) or fremanezumab (n = 100) in the Leiden Headache Center were invited to complete a questionnaire on visual sensitivity (the Leiden Visual Sensitivity Scale [L-VISS]), pertaining to both their ictal and interictal state, before starting treatment (T0) and 3 months after treatment initiation (T1). Using a daily e-diary, treatment effectiveness was assessed in weeks 9–12 compared to a 4-week pre-treatment baseline period. L-VISS scores were compared between T0 and T1. Subsequently, the association between the reduction in L-VISS scores and the reduction in monthly migraine days (MMD) was investigated.ResultsAt 3 months, the visual hypersensitivity decreased, with a decrease in mean ± standard deviation (SD) ictal L-VISS (from 20.1 ± 7.7 to 19.2 ± 8.1, p = 0.042) and a decrease in mean ± SD interictal L-VISS (from 11.8 ± 6.6 to 11.1 ± 7.0, p = 0.050). We found a positive association between the reduction in MMD and the decrease in interictal L-VISS (β = 0.2, p = 0.010) and the reduction in ictal L-VISS (β = 0.3, p = 0.001).ConclusionA decrease in visual hypersensitivity in patients with migraine after treatment with anti-CGRP (receptor) antibodies is positively associated with clinical response on migraine. Show less
BackgroundThere is lack of data on opioid (over)use for migraine in Europe.MethodsWe performed a cross-sectional study in a large Dutch cohort using a web-based questionnaire to assess opioid use... Show moreBackgroundThere is lack of data on opioid (over)use for migraine in Europe.MethodsWe performed a cross-sectional study in a large Dutch cohort using a web-based questionnaire to assess opioid use in individuals with migraine. Primary outcome was to assess opioid use for the treatment of migraine attacks. As secondary outcomes we specified use of opioids (duration of use, type of opioids, prescriber) and compared between persons with episodic migraine versus chronic migraine. Descriptive statistics, unpaired T-tests, Chi-square and Mann-Whitney U tests were used.ResultsIn total n = 3712 patients participated, 13% ever used opioids for headache. In opioid users, 27% did this for >1 month, and 11% for >1 year, and 2% without prescription. The majority of prescribing physicians were general practitioners (46%), followed by neurologists (35%), other specialists (9%), or emergency room doctors (8%). Opioids were used as acute treatment in 63%, in 16% as preventive treatment, and in 21% for both indications. Chronic migraine patients reported more opioid use compared with episodic migraine (22% versus 12%, p < 0.001), with also more prolonged use (>1 month: 34% chronic migraine versus 24% episodic migraine, p < 0.003).ConclusionOpioid use is more frequent and prolonged in chronic migraine patients. Further education for both doctors and migraine subjects and providing multimodal pain management strategies are needed to reduce opioid use in persons with migraine. Show less
Verhagen, I.E.; Lentsch, S.D.; Arend, B.W.H. van der; Cessie, S. le; MaassenVanDenBrink, A.; Terwindt, G.M. 2023
Background and purpose Anti-calcitonin gene-related peptide (CGRP) (receptor) antibodies effectively reduce overall migraine attack frequency, but whether there are differences in effect between... Show moreBackground and purpose Anti-calcitonin gene-related peptide (CGRP) (receptor) antibodies effectively reduce overall migraine attack frequency, but whether there are differences in effect between perimenstrual and nonperimenstrual migraine days has not been investigated.Methods We performed a single-arm study among women with migraine. Participants were followed with electronic E-diaries during one (pretreatment) baseline month and 6 months of treatment with either erenumab or fremanezumab. Differences in treatment effect on perimenstrual and nonperimenstrual migraine days were assessed using a mixed effects logistic regression model, with migraine day as dependent variable; treatment, menstrual window, and an interaction term (treatment x menstrual window) as fixed effects; and patient as a random effect.Results There was no interaction between the menstrual window and treatment effect, indicating that the reduction in migraine days under treatment was similar during the menstrual window and the remainder of the menstrual cycle (odds ratio for treatment = 0.44, 95% confidence interval = 0.38-0.51).Conclusions Our findings support prophylactic use of anti-CGRP (receptor) antibodies for women with menstrual migraine, as this leads to consistent reductions in number of migraine days during the entire menstrual cycle. Show less
Verhagen, I.E.; Arend, B.W.H. van der; Casteren, D.S. van; Cessie, S. le; MaassenVanDenBrink, A.; Terwindt, G.M. 2023
Objective: In this prospective cohort study, characteristics of perimenstrual and non-perimenstrual migraine attacks in women were compared with migraine attacks in men.Background: Women report... Show moreObjective: In this prospective cohort study, characteristics of perimenstrual and non-perimenstrual migraine attacks in women were compared with migraine attacks in men.Background: Women report longer migraine attacks and more accompanying symptoms than men in cross-sectional questionnaire studies, but this has not been confirmed in longitudinal studies. Supposed differences could result from different characteristics specific to perimenstrual migraine attacks, or of attacks in women in general.Methods: This cohort study was performed among patients with migraine who were treated at the Leiden Headache Clinic. We assessed differences in migraine attack characteristics between men and women who were prospectively followed by a previously validated electronic headache diary. The primary outcome was "attack" duration. Differences between perimenstrual (Days -2 to +3 of the menstrual cycle) and non-perimenstrual attacks in women versus attacks in men were corrected for age, chronic migraine, and medication overuse headache.Results: A total of 1347 women and 284 men were included, reflecting the preponderance of women in migraine prevalence. Crude median (first and third quartile [Q1-Q3]) attack duration in men was 32.1 [17.7-53.6] h, compared to 36.7 [21.9-62.4] h for non-perimenstrual migraine attacks and 44.4 [17.9-79.0] h for perimenstrual migraine attacks in women. After correction for confounding, perimenstrual migraine attacks were 1.62 (95% confidence interval [CI] 1.47-1.79; p < 0.001) and non-perimenstrual 1.15 (95% CI 1.05-1.25; p = 0.003) times longer compared to migraine attacks in men. The mean relapse percentage in men was 9.2%, compared to 12.6% for non-perimenstrual migraine attacks, and 15.7% for perimenstrual migraine attacks. Relapse risk was greater for perimenstrual (odds ratio [OR] 2.39, 95% CI 1.93-2.95; p < 0.001), but not for non-perimenstrual (OR 1.18, 95% CI 0.97-1.45; p = 0.060) attacks. Migraine attacks in women were more often accompanied by photophobia, phonophobia, and nausea, but less often aura.Conclusion: Compared to attacks in men, both perimenstrual and non-perimenstrual migraine attacks are of longer duration and are more often accompanied by associated symptoms. A sex-specific approach to migraine treatment and research is needed. Show less
Introduction: Migraine is a highly prevalent and disabling neurological disease. Excessive use of acute medications can lead to medication-overuse headache (MOH), occurring when a patient... Show moreIntroduction: Migraine is a highly prevalent and disabling neurological disease. Excessive use of acute medications can lead to medication-overuse headache (MOH), occurring when a patient experiences an increasing number of headache and migraine days, despite taking greater amounts of acute medication. To treat MOH, a preventive migraine treatment and/or withdrawal of the overused medication(s) are advised. Brief Educational Intervention (BEI) has been shown to be an effective tool with promising results for MOH. Here, we report the design of a clinical trial that aims to evaluate the efficacy of eptinezumab, an anti-calcitonin gene-related peptide preventive migraine treatment, as an add-on to BEI for treatment of MOH in those with chronic migraine.Methods and analysis: RESOLUTION will be a phase 4, multi-national, randomized, double-blind, placebo-controlled study. This study will enroll approximately 570 participants with dual diagnoses of chronic migraine and MOH. Eligible patients will be randomly allocated to one of two treatment groups, BEI and eptinezumab (100 mg; n = 285) or BEI and placebo (n = 285), in a 1:1 ratio. The primary endpoint is the change from baseline in monthly migraine days over weeks 1–4. Secondary and exploratory endpoints will assess monthly migraine days over weeks 1–12, MOH remission, transition from chronic to episodic migraine, health-related quality of life, work productivity, and the safety and tolerability of eptinezumab in this patient population.Ethics and dissemination: This study will be conducted in accordance with good clinical practice. All patients will be fully informed about the study, including the risks and benefits of participation, and all participants will provide informed consent for participation in the trial and dissemination of results. Show less
Introduction: Migraine is a highly prevalent and disabling neurological disease. Excessive use of acute medications can lead to medication-overuse headache (MOH), occurring when a patient... Show moreIntroduction: Migraine is a highly prevalent and disabling neurological disease. Excessive use of acute medications can lead to medication-overuse headache (MOH), occurring when a patient experiences an increasing number of headache and migraine days, despite taking greater amounts of acute medication. To treat MOH, a preventive migraine treatment and/or withdrawal of the overused medication(s) are advised. Brief Educational Intervention (BEI) has been shown to be an effective tool with promising results for MOH. Here, we report the design of a clinical trial that aims to evaluate the efficacy of eptinezumab, an anti-calcitonin gene-related peptide preventive migraine treatment, as an add-on to BEI for treatment of MOH in those with chronic migraine.Methods and analysis: RESOLUTION will be a phase 4, multi-national, randomized, double-blind, placebo-controlled study. This study will enroll approximately 570 participants with dual diagnoses of chronic migraine and MOH. Eligible patients will be randomly allocated to one of two treatment groups, BEI and eptinezumab (100 mg; n = 285) or BEI and placebo (n = 285), in a 1:1 ratio. The primary endpoint is the change from baseline in monthly migraine days over weeks 1–4. Secondary and exploratory endpoints will assess monthly migraine days over weeks 1–12, MOH remission, transition from chronic to episodic migraine, health-related quality of life, work productivity, and the safety and tolerability of eptinezumab in this patient population.Ethics and dissemination: This study will be conducted in accordance with good clinical practice. All patients will be fully informed about the study, including the risks and benefits of participation, and all participants will provide informed consent for participation in the trial and dissemination of results. Show less
Migraine is a highly common and debilitating disorder that often affects individuals in their most productive years of life. Previous studies have identified both genetic variants and brain... Show moreMigraine is a highly common and debilitating disorder that often affects individuals in their most productive years of life. Previous studies have identified both genetic variants and brain morphometry differences associated with migraine risk. However, the relationship between migraine and brain morphometry has not been examined on a genetic level, and the causal nature of the association between brain structure and migraine risk has not been determined. Using the largest available genome-wide association studies to date, we examined the genome-wide genetic overlap between migraine and intracranial volume, as well as the regional volumes of nine subcortical brain structures. We further focused the identification and biological annotation of genetic overlap between migraine and each brain structure on specific regions of the genome shared between migraine and brain structure. Finally, we examined whether the size of any of the examined brain regions causally increased migraine risk using a Mendelian randomization approach. We observed a significant genome-wide negative genetic correlation between migraine risk and intracranial volume (rG = -0.11, P = 1 x 10(-3)) but not with any subcortical region. However, we identified jointly associated regional genomic overlap between migraine and every brain structure. Gene enrichment in these shared genomic regions pointed to possible links with neuronal signalling and vascular regulation. Finally, we provide evidence of a possible causal relationship between smaller total brain, hippocampal and ventral diencephalon volume and increased migraine risk, as well as a causal relationship between increased risk of migraine and a larger volume of the amygdala. We leveraged the power of large genome-wide association studies to show evidence of shared genetic pathways that jointly influence migraine risk and several brain structures, suggesting that altered brain morphometry in individuals with high migraine risk may be genetically mediated. Further interrogation of these results showed support for the neurovascular hypothesis of migraine aetiology and shed light on potentially viable therapeutic targets. Show less
Clinic-based headache registries collect data for a wide variety of purposes including delineating disease characteristics, longitudinal natural disease courses, headache management approaches,... Show moreClinic-based headache registries collect data for a wide variety of purposes including delineating disease characteristics, longitudinal natural disease courses, headache management approaches, quality of care, treatment safety and effectiveness, factors that predict treatment response, health care resource utilization, clinician adherence to guidelines, and cost-effectiveness. Registry data are valuable for numerous stakeholders, including individuals with headache disorders and their caregivers, healthcare providers, scientists, healthcare systems, regulatory authorities, pharmaceutical companies, employers, and policymakers. This International Headache Society document may serve as guidance for developing clinic-based headache registries. Use of registry data requires a formal research protocol that includes: 1) research aims; 2) methods for data collection, harmonization, analysis, privacy, and protection; 3) methods for human subject protection; and 4) publication and dissemination plans. Depending upon their objectives, headache registries should include validated headache-specific questionnaires, patient reported outcome measures, data elements that are used consistently across studies (i.e., "common data elements"), and medical record data. Amongst other data types, registries may be linked to healthcare and pharmacy claims data, biospecimens, and neuroimaging data. Headache diagnoses should be made according to the International Classification of Headache Disorders diagnostic criteria. The data from well-designed headache registries can provide wide-ranging and novel insights into the characteristics, burden, and treatment of headache disorders and ultimately lead to improvements in the management of patients with headache. Show less
Patients suffering from familial hemiplegic migraine type 1 (FHM1) may have a disproportionally severe outcome after head trauma, but the underlying mechanisms are unclear. Hence, we subjected... Show morePatients suffering from familial hemiplegic migraine type 1 (FHM1) may have a disproportionally severe outcome after head trauma, but the underlying mechanisms are unclear. Hence, we subjected knock-in mice carrying the severer S218L or milder R192Q FHM1 gain-of-function missense mutation in the CACNA1A gene that encodes the alpha(1A) subunit of neuronal voltage-gated Ca(V)2.1 (P/Q-type) calcium channels and their wild-type (WT) littermates to experimental traumatic brain injury (TBI) by controlled cortical impact and investigated cortical spreading depolarizations (CSDs), lesion volume, brain edema formation, and functional outcome. After TBI, all mutant mice displayed considerably more CSDs and seizures than WT mice, while S218L mutant mice had a substantially higher mortality. Brain edema formation and the resulting increase in intracranial pressure were more pronounced in mutant mice, while only S218L mutant mice had larger lesion volumes and worse functional outcome. Here, we show that gain of Ca(V)2.1 channel function worsens histopathological and functional outcome after TBI in mice. This phenotype was associated with a higher number of CSDs, increased seizure activity, and more pronounced brain edema formation. Hence, our results suggest increased susceptibility for CSDs and seizures as potential mechanisms for bad outcome after TBI in FHM1 mutation carriers. Show less
Background: Women are more affected by stroke than men. This might, in part, be explained by sex differences in stroke pathophysiology. The hemostasis system is influenced by sex hormones and... Show moreBackground: Women are more affected by stroke than men. This might, in part, be explained by sex differences in stroke pathophysiology. The hemostasis system is influenced by sex hormones and associated with female risk factors for stroke, such as migraine.Aim: To systematically review possible sex differences in hemostatic related factors in patients with ischemic stroke in general, and the influence of migraine on these factors in women with ischemic stroke.Results: We included 24 studies with data on sex differences of hemostatic factors in 7247 patients with ischemic stroke (mean age 57-72 years, 27-57% women) and 25 hemostatic related factors. Levels of several factors were higher in women compared with men; FVII:C (116% +/- 30% vs. 104% +/- 30%), FXI (0.14 UI/mL higher in women), PAI-1 (125.35 +/- 49.37 vs. 96.67 +/- 38.90 ng/mL), D-dimer (1.25 +/- 0.31 vs. 0.95 +/- 0.24 mg/mL), and aPS (18.7% vs. 12.0% positive). In contrast, protein-S (86.2% +/- 23.0% vs. 104.7% +/- 19.8% antigen) and P-selectin (48.9 +/- 14.4 vs. 79.1 +/- 66.7 pg/mL) were higher in men. Most factors were investigated in single studies, at different time points after stroke, and in different stroke subtypes. Only one small study reported data on migraine and hemostatic factors in women with ischemic stroke. No differences in fibrinogen, D-dimer, t-PA, and PAI-1 levels were found between women with and without migraine.Conclusion: Our systematic review suggests that sex differences exist in the activation of the hemostatic system in ischemic stroke. Women seem to lean more toward increased levels of procoagulant factors whereas men exhibit increased levels of coagulation inhibitors. To obtain better insight in sex-related differences in hemostatic factors, additional studies are needed to confirm these findings with special attention for different stroke phases, stroke subtypes, and not in the least women specific risk factors, such as migraine. Show less
Background: An increased risk of stroke in patients with migraine has been primarily found for women. The sex-dependent mechanisms underlying the migraine-stroke association, however, remain... Show moreBackground: An increased risk of stroke in patients with migraine has been primarily found for women. The sex-dependent mechanisms underlying the migraine-stroke association, however, remain unknown. This study aims to explore these sex differences to improve our understanding of pathophysiological mechanisms behind the migraine-stroke association.Methods: We included 2,492 patients with ischemic stroke from the prospective multicenter Dutch Parelsnoer Institute Initiative study, 425 (17%) of whom had a history of migraine. Cardiovascular risk profile, stroke cause (TOAST classification), and outcome [modified Rankin scale (mRS) at 3 months] were compared with both sexes between patients with and without migraine.Results: A history of migraine was not associated with sex differences in the prevalence of conventional cardiovascular risk factors. Women with migraine had an increased risk of stroke at young age (onset < 50 years) compared with women without migraine (RR: 1.7; 95% CI: 1.3-2.3). Men with migraine tended to have more often stroke in the TOAST category other determined etiology (RR: 1.7; 95% CI: 1.0-2.7) in comparison with men without migraine, whereas this increase was not found in women with migraine. Stroke outcome was similar for women with or without migraine (mRS >= 3 RR 1.1; 95% CI 0.7-1.5), whereas men seemed to have a higher risk of poor outcome compared with their counterparts without migraine (mRS >= 3 RR: 1.5; 95% CI: 1.0-2.1).Conclusion: Our results indicate possible sex differences in the pathophysiology underlying the migraine-stroke association, which are unrelated to conventional cardiovascular risk factors. Further research in larger cohorts is needed to validate these findings. Show less
Background and purpose New prophylactics for migraine, targeting calcitonin gene-related peptide (CGRP), have recently emerged. Real-world data are important for a comprehensive understanding of... Show moreBackground and purpose New prophylactics for migraine, targeting calcitonin gene-related peptide (CGRP), have recently emerged. Real-world data are important for a comprehensive understanding of treatment response. We assessed the consistency of response to erenumab, a monoclonal CGRP receptor antibody, in a real-world setting, in order to determine which patients may be considered responders in clinical practice. Methods All erenumab-treated patients (n = 100) completed a time-locked daily electronic diary, and an automated algorithm was used to monitor treatment response. Monthly migraine days (MMD), non-migrainous headache days, days of acute medication use (MAMD), well-being and coping with pain were assessed for a 6-month period. The primary outcome was reduction in MMD compared to baseline. Results The numbers of MMD and MAMD decreased in all months, in both episodic and chronic migraine patients, compared to baseline (p < 0.001), while general well-being (p < 0.001) and coping with pain (p < 0.001) also improved. Of all patients, 36% had an MMD reduction of >= 50% in >= 3/6 months, and 6% had such a reduction in all 6 months. For a >= 30% MMD reduction, the figures were 60% and 24%, respectively. Almost 90% of patients with an average MMD reduction of >= 30% over the first 3 months had a sustained response in the last 3 months. In addition, 20% of patients without an initial response (average <30%), had a delayed response (average >= 30%) in the last 3 months. Conclusion Erenumab was effective in migraine patients who were highly refractory to previous prophylactics. As a practical guideline, we propose that treatment be continued for at least 6 months and that patients with a >= 30% MMD reduction in at least half of the treatment period should be considered to be responders. Show less
Background and purpose This study was undertaken to investigate migraine prevalence in persons with hallucinogen persisting perception disorder (HPPD) presenting as visual snow syndrome (VSS)... Show moreBackground and purpose This study was undertaken to investigate migraine prevalence in persons with hallucinogen persisting perception disorder (HPPD) presenting as visual snow syndrome (VSS).Methods Persons with visual snow as a persisting symptom after illicit drug use (HPPD) were recruited via a Dutch consulting clinic for recreational drug use. A structured interview on (visual) perceptual symptomatology, details of drugs use, and medical and headache history was taken. As a control group, persons with visual snow who had never used illicit drugs prior to onset were included. The primary outcome was lifetime prevalence of migraine. Symptom severity was evaluated by the Visual Snow Handicap Inventory (VHI), a 25-item questionnaire.Results None of the 24 HPPD participants had migraine, whereas 20 of 37 (54.1%) controls had migraine (p < 0.001). VHI scores did not differ significantly between the two groups; in both groups, the median score was 38 of 100. In most HPPD cases (17/24, 70.9%), visual snow had started after intake of ecstasy; other psychedelic drugs reported included cannabis, psilocybin mushrooms, amphetamine, 4-fluoroamphetamine, 3-methylmethcathinone, 4-Bromo-2,5-dimethoxypenethylamine, and nitrous oxide.Conclusions Whereas none of the HPPD participants had migraine, more than half of the visual snow controls without prior use of illicit drugs had migraine. This suggests that at least partly different pathophysiological factors play a role in these disorders. Users of ecstasy and other hallucinogens should be warned of the risk of visual snow. Further studies are needed to enhance understanding of the underlying neurobiology of HPPD and VSS to enable better management of these conditions. Show less
Suleimanova, A.; Talanov, M.; Maagdenberg, A.M.J.M. van den; Giniatullin, R. 2021
Familial hemiplegic migraine type 3 (FHM3) is caused by gain-of-function mutations in the SCN1A gene that encodes the alpha 1 subunit of voltage-gated Na(V)1.1 sodium channels. The high level of... Show moreFamilial hemiplegic migraine type 3 (FHM3) is caused by gain-of-function mutations in the SCN1A gene that encodes the alpha 1 subunit of voltage-gated Na(V)1.1 sodium channels. The high level of expression of Na(V)1.1 channels in peripheral trigeminal neurons may lead to abnormal nociceptive signaling thus contributing to migraine pain. Na(V)1.1 dysfunction is relevant also for other neurological disorders, foremost epilepsy and stroke that are comorbid with migraine. Here we used computer modeling to test the functional role of FHM3-mutated Na(V)1.1 channels in mechanisms of trigeminal pain. The activation of A delta-fibers was studied for two algogens, ATP and 5-HT, operating through P2X3 and 5-HT3 receptors, respectively, at trigeminal nerve terminals. In WT A delta-fibers of meningeal afferents, Na(V)1.1 channels efficiently participate in spike generation induced by ATP and 5-HT supported by Na(V)1.6 channels. Of the various FHM3 mutations tested, the L263V missense mutation, with a longer activation state and lower activation voltage, resulted in the most pronounced spiking activity. In contrast, mutations that result in a loss of Na(V)1.1 function largely reduced firing of trigeminal nerve fibers. The combined activation of P2X3 and 5-HT3 receptors and branching of nerve fibers resulted in very prolonged and high-frequency spiking activity in the mutants compared to WT. We identified, in silico, key determinants of long-lasting nociceptive activity in FHM3-mutated A delta-fibers that naturally express P2X3 and 5-HT3 receptors and suggest mutant-specific correction options. Modeled trigeminal nerve firing was significantly higher for FHM3 mutations, compared to WT, suggesting that pronounced nociceptive signaling may contribute to migraine pain. Show less
Mehboob, R.; Marchenkova, A.; Maagdenberg, A.M.J.M. van den; Nistri, A. 2021
Trigeminal sensory neurons of transgenic knock-in (KI) mice expressing the R192Q missense mutation in the alpha 1A subunit of neuronal voltage-gated Ca(V)2.1 Ca2+ channels, which leads to familial... Show moreTrigeminal sensory neurons of transgenic knock-in (KI) mice expressing the R192Q missense mutation in the alpha 1A subunit of neuronal voltage-gated Ca(V)2.1 Ca2+ channels, which leads to familial hemiplegic migraine type 1 (FHM1) in patients, exhibit a hyperexcitability phenotype. Here, we show that the expression of Na(V)1.7 channels, linked to pain states, is upregulated in KI primary cultures of trigeminal ganglia (TG), as shown by increased expression of its alpha 1 subunit. In the majority of TG neurons, Na(V)1.7 channels are co-expressed with ATP-gated P2X3 receptors (P2X3R), which are important nociceptive sensors. Reversing the trigeminal phenotype with selective Ca(V)2.1 channel inhibitor omega-agatoxin IVA inhibited Na(V)1.7 overexpression. Functionally, KI neurons revealed a TTX-sensitive inward current of larger amplitude that was partially inhibited by selective Na(V)1.7 blocker Tp1a. Under current-clamp condition, Tp1a raised the spike threshold of both wild-type (WT) and KI neurons with decreased firing rate in KI cells. Na(V)1.7 activator OD1 accelerated firing in WT and KI neurons, a phenomenon blocked by Tp1a. Enhanced expression and function of Na(V)1.7 channels in KI TG neurons resulted in higher excitability and facilitated nociceptive signaling. Co-expression of Na(V)1.7 channels and P2X3Rs in TGs may explain how hypersensitivity to local stimuli can be relevant to migraine. Show less
Diener, H.C.; Ashina, M.; Durand-Zaleski, I.; Kurth, T.; Lanteri-Minet, M.; Lipton, R.B.; ... ; Terwindt, G. 2021
The Clinical Trials Subcommittee of the International Headache Society presents the first Health Technology Assessment for the Acute Treatment of Migraine Attacks and Prevention of Migraine. Health... Show moreThe Clinical Trials Subcommittee of the International Headache Society presents the first Health Technology Assessment for the Acute Treatment of Migraine Attacks and Prevention of Migraine. Health technology assessments are systematic evaluations of the properties, effects, and consequences of healthcare technologies; this position statement is designed to inform decision makers about access to and reimbursement for medications and devices for the acute and preventive treatment of migraine. This position statement extends beyond the already available guidelines on randomized controlled trials for migraine to incorporate real-world evidence and a synthetic approach for considering multiple data sources and modelling methods when assessing the value of migraine treatments. Show less
Boer, I. de; MaassenVanDenBrink, A.; Terwindt, G.M. 2020
Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is an inherited small vessel disease characterised by recurrent ischemic stroke, cognitive... Show moreCerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is an inherited small vessel disease characterised by recurrent ischemic stroke, cognitive decline progressing to dementia, psychiatric disturbances and apathy. More than half of mutation carriers suffer from migraine, most often migraine with aura. Recently, a CADASIL patient was treated with a monoclonal antibody targeting the calcitonin gene-related peptide (CGRP) receptor. Monoclonal antibodies targeting the CGRP system have been demonstrated to be safe, well tolerated, and effective in reducing migraine attacks. There is, however, abundant evidence that CGRP is important in maintaining cardiovascular homeostasis under (patho)physiological conditions. CGRP may act as a vasodilatory safeguard during cerebral and cardiac ischemia and blockage of the system could, therefore, potentially worsen ischemic events. Therefore, we caution against treating patients with small vessel diseases, such as the monogenic disorder CADASIL, with these drugs until relevant safety data and long term follow up results are available. Alternative preventive migraine treatments in CADASIL may be acetazolamide, sodium valproate, lamotrigine, topiramate, verapamil, or flunarizine. Show less
