Cerebrospinal Fluid and Plasma Amine Profiles in Interictal Migraine.

OBJECTIVE: Impaired amine metabolism has been associated with the etiology of migraine, that is, why patients continue to get migraine attacks. However, evidence from cerebrospinal fluid (CSF) is lacking. Here, we evaluated individual amine levels, global amine profiles, and amine pathways in CSF and plasma of interictal migraine patients and healthy controls. METHODS: CSF and plasma were sampled between 8:30 am and 1:00 pm, randomly and interchangeably over the time span to avoid any diurnal and seasonal influences, from healthy volunteers and interictal migraine patients, matched for age, sex, and sampling time. The study was approved by the local medical ethics committee. Individual amines (n = 31), global amine profiles, and specific amine pathways were analyzed using a validated ultraperformance liquid chromatography mass spectrometry platform. RESULTS: We analyzed n = 99 participants with migraine with aura, n = 98 with migraine without aura, and n = 96 healthy volunteers. Univariate analysis with Bonferroni correction indicated that CSF L-arginine was reduced in migraine with aura (10.4%, p < 0.001) and without aura (5.0%, p = 0.03). False discovery rate-corrected CSF L-phenylalanine was also lower in migraine with aura (6.9%, p = 0.011) and without aura (8.1%, p = 0.001), p = 0.088 after Bonferroni correction. Multivariate analysis revealed that CSF global amine profiles were similar for both types of migraine (p = 0.64), but distinct from controls (p = 0.009). Global profile analyses were similar in plasma. The strongest associated pathways with migraine were related to L-arginine metabolism. INTERPRETATION: L-Arginine was decreased in the CSF (but not in plasma) of interictal patients with migraine with or without aura, and associated pathways were altered. This suggests that dysfunction of nitric oxide signaling is involved in susceptibility to getting migraine attacks. ANN NEUROL 2023;93:715-728.

Hypothalamic functional MRI activity in the initiation phase of spontaneous and glyceryl trinitrate-induced migraine attacks.

The hypothalamus has been suggested to be important in the initiation cascade of migraine attacks based on clinical and biochemical observations. Previous imaging studies could not disentangle the changes due to the attack and those due to the trigger compound. With a novel approach, we assessed hypothalamic neuronal activity in early premonitory phases of glyceryl-trinitrate (GTN)-induced and spontaneous migraine attacks. We measured the hypothalamic blood oxygen level-dependent (BOLD) response to oral glucose ingestion with 3T-functional magnetic resonance imaging (MRI) in 27 women, 16 with migraine without aura and 11 controls group matched for age and body mass index (BMI), on 1 day without prior GTN administration and on a second day after GTN administration (to coincide with the premonitory phase of an induced attack). Interestingly, subgroups of patients with and without GTN-triggered attacks could be compared. Additionally, five migraineurs were investigated in a spontaneous premonitory phase. Linear mixed models were used to study between- and within-group effects. Without prior GTN infusion, the BOLD response to glucose was similar in migraine participants and controls (P = .41). After prior GTN infusion, recovery occurred steeper and faster in migraineurs (versus Day 1; P < .0001) and in those who developed an attack versus those who did not (P < .0001). Prior GTN infusion did not alter the glucose-induced response in controls (versus baseline; P = .71). Just before spontaneous attacks, the BOLD-response recovery was also faster (P < .0001). In this study, we found new and direct evidence of altered hypothalamic neuronal function in the immediate preclinical phase of both GTN-provoked and spontaneous migraine attacks.

Chronobiology and Sleep in Cluster Headache.

BACKGROUND: Cluster headache attacks follow a striking circadian rhythm with an intriguing influence of sleep. We aim to investigate differences in sleep quality, chronotype, and the ability to alter individual sleep rhythms in episodic and chronic cluster headache patients vs controls. METHODS: Cluster headache patients and non-headache controls from the Dutch Leiden University Cluster headache neuro-Analysis program aged 18 and above completed web-based questionnaires in a cross-sectional study. RESULTS: A total of 478 episodic, 147 chronic cluster headache patients and 367 controls participated. Chronic cluster headache patients had more often early chronotypes than controls, as measured by mid-sleep phase (P = .021 adjusted B -15.85 minutes CI -29.30; -2.40). Compared to controls, chronic cluster headache participants were less able to alter their sleep rhythms (P < .001 adjusted B -1.65 CI -2.55; 0.74), while episodic cluster headache participants reported more difficulty in coping with reduced sleep (P = .025 adjusted B 0.75 CI 0.09; 1.40). Sleep quality was reduced in both types of cluster headache compared to controls ("poor sleepers": 71.4% (105/147) in chronic and 48.3% (235/367) in episodic cluster headache vs 25.6% (94/367) in controls; both P < .001; episodic adjusted B -1.71 CI 0.10; 0.32; chronic adjusted B -0.93 CI 0.24; 0.65). CONCLUSION: Sleep quality is decreased in both episodic and chronic cluster headache, most likely caused by cluster headache attacks that strike during the night. Episodic cluster headache patients report more difficulty in coping with reduced sleep, while chronic patients are less able to alter their sleep rhythm. Although not directly proven, cluster headache patients will likely benefit from a structured, regular daily schedule.

Randomized controlled trial of the CGRP receptor antagonist telcagepant for prevention of headache in women with perimenstrual migraine.

AIM: The aim of this article is to evaluate the safety and efficacy of perimenstrual telcagepant, a CGRP receptor antagonist, for headache prophylaxis. METHODS: We conducted a randomized, double-blind, placebo-controlled, six-month trial in women with migraine for ≥ 3 months who experienced perimenstrual headaches. Women were randomized to telcagepant 140 mg or placebo (2:1 ratio) for seven consecutive days perimenstrually. Safety was assessed by adverse events and laboratory tests. The primary efficacy endpoint was mean monthly headache days in the subset of women reporting perimenstrual migraine (-2 days to +3 days of menses onset) and ≥ 5 moderate or severe migraines per month prior to entering the trial. RESULTS: Telcagepant was generally well tolerated: 66/2660 (2.5%) on telcagepant and 36/1326 (2.7%) on placebo discontinued because of a clinical adverse event. The percentages of patients with clinical adverse events, laboratory adverse events, or discontinuation because of a laboratory adverse event were also similar between treatments. Alanine aminotransferase elevations ≥ 3x normal occurred in 0.6% of women on telcagepant and 0.4% on placebo. Three women on telcagepant vs none on placebo had alanine aminotransferase elevations ≥ 8× normal. In the efficacy subset there was no significant effect of telcagepant (n = 887) vs placebo (n = 447) in mean monthly headache days (treatment difference -0.5 day (95% CI: -1.1, 0.1)). However, telcagepant was associated with a reduction in on-drug headache days (treatment difference -0.4 day (95% CI: -0.5, -0.2), nominal p < 0.001). CONCLUSIONS: Telcagepant 140 mg taken perimenstrually for seven days was generally well tolerated, but was associated with transaminase elevations. Telcagepant did not reduce monthly headache frequency, but did reduce perimenstrual headaches.

Cutaneous allodynia as a predictor of migraine chronification.

Cutaneous allodynia is a common feature accompanying migraine attacks and considered a clinical marker for central sensitization. In a longitudinal study, we wanted to investigate if allodynia in migraine patients is a predictor of increasing frequency of migraine days. We included 3029 well-defined, web-based migraine patients (86% female, mean age 42.8 ± 11.4 years, 61% migraine without aura). Questionnaires on migraine characteristics (including allodynia), depression and demographic factors were applied. The number of migraine days was measured twice. Multivariate regression models were used, with correction for other factors that are involved in the relation between allodynia and the number of migraine attacks or migraine days, with specific focus on depression. Of all 2331 eligible migraine patients, 1624 (70%) had allodynia. Lifetime depression was an independent risk factor for allodynia (odds ratio 1.52, 95% confidence interval 1.26-1.84), as well as female gender, low age at onset, and high migraine attack frequency. Analysis of the longitudinal data (in migraineurs with a follow-up period of >6 months) showed that, apart from the known risk factors (low age at onset, high baseline number of migraine days, and depression), allodynia was an independent predictor for increase in number of migraine days over a mean follow-up period of 93 ± 30 weeks (median 103 weeks, range 26-160 weeks). Cutaneous allodynia is a risk factor for migraine chronification and may warrant preventive treatment strategies.

Frequency and Clinical Features of Space Headache Experienced by Astronauts During Long-Haul Space Flights.

BACKGROUND AND OBJECTIVES: Few anecdotal cases and 1 small retrospective study during short-duration space missions suggest that headache may occur early in flight, as part of the space motion syndrome. Whether headaches may also occur at later stages of space flights is unknown. We aimed to prospectively characterize the incidence, timing, clinical features, and management of space headaches during long-duration flights. METHODS: We prospectively evaluated the occurrence, characteristics, and evolution of space headaches and the effects of treatment and countermeasures during long-haul flights with onboard questionnaires and correlated them with prevailing temperature, pressure, and ambient O2 and CO2 levels, measured within the International Space Station. In addition, we analyzed retrospective headache data from a different astronaut cohort. Headache data were reported using descriptive statistics and correlation data with intraindividual logistic regression models. Astronauts were included through (inter)national aerospace organizations. RESULTS: In the prospective study, 22/24 (91.7%) astronauts (mean ± SD age: 46.6 ± 6.5 years, 95.8% male) experienced ≥1 episode of headache during a total of 3,596 space days. A total of 378 episodes were reported (median 9; range 1-128) with detailed information on 189. Phenotypically, 170/189 (89.9%) episodes were tension-type headache (TTH) and 19/189 (10.1%) were migraine. Episodes in the first week differed from those in later periods in terms of phenotype (migraine 12/51 [23.5%] vs 7/138 [5.1%]; TTH 39/51 [86.5%] vs 131/138 [94.9%]; overall p = 0.0002) and accompanying symptoms: nausea: 17.6% vs 6.9%, p = 0.05; vomiting: 9.8% vs 0.7%, p = 0.005; nasal congestion: 52.9% vs 29.7%, p = 0.004; facial edema: 41.2% vs 1.4%, p < 0.001; and duration (p = 0.001). Severity and treatments were similar: acute antiheadache medication: 55.6%; other medication: 22.4%; and alternative treatments: 41.1%. Headache occurrence was not associated with temperature or ambient pressure/levels of O2 and CO2 (all p > 0.05). In the retrospective study, 23/42 (54.8%) astronauts (43.5 ± 7.2 years, 90.5% male) reported experiencing ≥1 headache episode during mission. Nasal congestion was the most common (8/33; 24.2%) accompanying symptom. Seventeen of 42 astronauts have been previously described. DISCUSSION: Astronauts during space flights frequently experience headaches. These most often have characteristics of TTHs but sometimes have migrainous features, particularly during the first week of flight in astronauts without a history of recurrent headaches before or after the space flight.

Female sex hormones in men with migraine.

OBJECTIVE: To assess the role of estradiol and testosterone in men with migraine. METHODS: We measured 17ß-estradiol (E2) and calculated free testosterone (Tf) in serum of 17 medication-free men with migraine and 22 men without migraine group-matched for age and body mass index (BMI), targeted at 20 to 28 kg/m2. Blood was sampled on a single, for migraineurs interictal, day at 9 am, 12 pm, 3 pm, and 6 pm. Migraineurs were subsequently measured 3 to 4 times daily until an attack occurred. Clinical androgen deficiency was assessed with the Androgen Deficiency of Ageing Men questionnaire and the Aging Males' Symptoms (AMS) scale. We analyzed interictal data (mean ± standard error) with repeated-measures analysis of covariance and longitudinal data by generalized estimated equations models. RESULTS: Compared to controls, men with migraine had a lower interictal Tf/E2 ratio (3.9 ± 0.4 vs 5.0 ± 0.3, p = 0.03) due to higher E2 (96.8 ± 6.1 vs 69.1 ± 5.6 pmol/L, p = 0.001) and similar Tf (357.5 ± 21.4 vs 332.6 ± 18.7 pmol/L, p = 0.35) levels. Preictal Tf levels were increased in men with migraine reporting premonitory symptoms (p = 0.03). Men with migraine more frequently reported symptoms of androgen deficiency (11 of 18 [61.1%] vs 6 of 22 [27.3%], p = 0.031), which were also more frequently severe (p = 0.006); their age- and BMI-adjusted AMS scores were higher (27.0 ± 1.2 vs 21.0 ± 1.0, p = 0.002). CONCLUSIONS: In this study, nonobese men with migraine exhibited increased levels of the sex hormone estradiol and showed clinical evidence of relative androgen deficiency. The role of estradiol in modulating migraine susceptibility and activity in men deserves further investigations.

Primary headache syndromes in the elderly: epidemiology, diagnosis and treatment.

Although secondary headaches due to e.g. temporal arteritis or a brain tumor are common among the elderly, primary headache disorders also occur in this age group, albeit less frequently than in younger individuals. A different presentation in the older age groups often makes a diagnosis difficult. Some headache syndromes, such as hypnic headache, are typical for the elderly. Furthermore, age-related physiologic changes, co-morbidities and contra indications require appropriate and targeted treatment in the elderly. Although treatments for the most common primary headaches are available, many limitations hamper their use in this group. For many headaches syndromes randomized controlled treatment trials in elderly are not available. In this article we review the clinical aspects of common primary headaches and medication overuse headache in the elderly and their treatments, with emphasis on age-specific problems. Relevance for patients: Primary headache syndromes in older patients ask for specific treatment considerations due to comorbidity, polypharmacy and an increased risk of side effects. Clinically, the headaches can be different and atypical. Results from clinical trials cannot be generalized to the elderly because these groups usually are not included in studies. In migraine, non-pharmacologic treatment should be considered, with depression and cerebrovascular disease as major comorbidities. Tension type headache, being the most common headache presentation in elderly, also includes a relatively large proportion of patients with a secondary headache warranting further testing. Trigeminal autonomous cephalalgias are rare, and can present with pseudo dementia. Medication overuse and medication-induced headaches are relatively common, for which patient education, ceasing drugs and withdrawal from caffeine containing substances are pivotal. Furthermore, hypnic headache, exploding head syndrome and benign thunderclap headache are specific for this patient group and require specific treatment.

Headache under simulated microgravity is related to endocrine, fluid distribution, and tight junction changes.

Head-down-tilted bed rest (HDTBR) induces headaches similar to headaches during space flights. The objective of this investigation was to study hematological, endocrinological, fluid changes and tight junctions in HDTBR-induced headaches as a proxy for space headache. The randomized crossover HDTBR design by the European Space Agency included 12 healthy, nonheadache male subjects. Before, during, and after confined HDTBR periods, epinephrine (urine), cortisol (saliva), hematological, endothelium markers, and fluid distribution parameters were measured. Headaches were assessed with a validated headache questionnaire. Compared with baseline, HDTBR in all subjects was associated with higher hematocrit, hemoglobin, and epinephrine levels, higher erythrocyte counts, and lower relative plasma volumes (all P < 0.05). In total, 26 headache episodes occurred. In subjects with headaches during HDTBR, epinephrine levels were exaggerated (vs headache-free subjects; HDTBR day 3; 5.1 ± 1.7 vs 3.4 ± 2.4; P = 0.023), cortisol levels were decreased (vs headache-free subjects; HDTBR day 1; 0.37 ± 0.16 vs 0.50 ± 0.20; P < 0.001) and the tight junction marker zonulin was elevated (vs headache-free subjects in HDTBR days 1, 3, 5; P < 0.05). HDTBR induces hemoconcentration and fluid redistribution in all subjects. During headache episodes, endocrinological changes, fluid distribution, and tight junctions were more pronounced, suggesting an additional role in headache pathophysiology.

Prevalence of lifetime depression in a large hemiplegic migraine cohort.

OBJECTIVE: To determine the prevalence of depression and determinants associated with depression in a large population of hemiplegic migraine (HM) patients. METHODS: We conducted a cross-sectional, validated questionnaire study among 89 well-defined HM patients and 235 headache-free controls. The prevalence of lifetime depression and its relation to migraine characteristics was assessed. RESULTS: HM patients had increased odds for lifetime depression (odds ratio 3.73, 95% confidence interval 2.18-6.38) compared with controls. Use of acute antimigraine medication was associated with lifetime depression. CONCLUSIONS: Depression is part of the monogenic hemiplegic migraine phenotype. Further studies are needed to elucidate the pathophysiologic role of HM genes in comorbid depression. For now, clinicians should take comorbid depression into consideration when starting prophylactic treatment of HM.

Cluster headache and depression.

OBJECTIVE: As cluster headache (CH) is often referred to as "suicide headache," we wanted to assess the prevalence of depression in CH patients, and to investigate determinants of depression such as sleep disturbances. METHODS: In a cross-sectional, web-based, validated questionnaire study among 462 well-defined CH patients and 177 controls, we diagnosed CH according to the ICHD-III. We assessed depression using the Hospital Anxiety and Depression Scale (HADS-D) and the Center for Epidemiologic Studies Depression scale (CES-D) with supplementary questions to assess lifetime depression. Data were analyzed with logistic and linear regression models. RESULTS: Lifetime depression showed almost 3 times higher odds in CH patients (n = 462) than controls (n = 177) (odds ratio 2.77; 95% confidence interval 1.70-4.51). Chronic (n = 67) vs episodic (n = 394) patients had a higher prevalence of lifetime depression and more sleeping problems. Current depression was associated with having active attacks (last attack <1 month) (adjusted p = 0.02), but no effect remained after correction for sleep disturbances. CONCLUSIONS: CH is associated with an almost 3 times increased odds of lifetime depression. Current depression is highly prevalent in patients with active disease, in part related to sleep disturbances due to current nocturnal attacks.

Metabolomic changes in CSF of migraine patients measured with 1H-NMR spectroscopy.

BACKGROUND: Migraine is a common episodic brain disorder. Treatment options and diagnosis are hampered by an incomplete understanding of disease pathophysiology and the lack of objective diagnostic markers. The aim of this study was to identify biochemical differences characteristic for different subtypes of migraine in cerebrospinal fluid (CSF) of migraine patients using an exploratory 1H-NMR-based metabolomics approach. METHODS: CSF was obtained, in between migraine attacks, via lumbar puncture from patients with hemiplegic migraine, migraine with aura, migraine without aura, and healthy controls. Metabolite concentrations were measured by quantitative 1H-NMR spectroscopy. Multivariate data analysis was used to find the optimal set of predictors, generalized linear models (GLM) were used to ascertain the differential significance of individual metabolites. RESULTS: In CSF samples from 18 patients with hemiplegic migraine, 38 with migraine with aura, 27 migraine without aura, and 43 healthy controls, nineteen metabolites were identified and quantified. Hemiplegic migraine patients could be discriminated from healthy controls using supervised multivariate modelling with 2-hydroxybutyrate and 2-hydroxyisovalerate as the most discriminant metabolites. Univariate GLM analysis showed 2-hydroxybutyrate to be lower in hemiplegic migraine compared with healthy controls; no significant differences were observed for other metabolites. It was not possible to discriminate migraine with and without aura from healthy controls based on their metabolic profile. CONCLUSIONS: Using an exploratory 1H-NMR metabolomics analysis we identified metabolites that were able to discriminate hemiplegic migraine patients from healthy controls. The lower levels of 2-hydroxybutyrate found in patients with hemiplegic migraine could indicate a dysregulation of the brain's energy metabolism. An experimental confirmation in vitro or in animal models will be required to confirm or discard this hypothesis. Migraine with and migraine without aura patients did not reveal a metabolic profile different from healthy controls.

[Footballer's migraine instead of concussion]. / Geen hersenschudding maar voetballersmigraine.

CASE DESCRIPTION: Our patient, a 27-year-old amateur soccer player, was hit hard against the head by a ball. Within a few minutes he developed visual and sensory symptoms followed by headache, nausea, vomiting, photophobia and phonophobia. After treatment with paracetamol and metoclopramide, he was free of symptoms within 24 hours. CONCLUSION: This picture is stereotypically associated with migraine provoked by minor head injury. TTM may also occur without aura. Trauma triggered migraine is seen more frequently in children, adolescents and young adults. The cause of trauma triggered migraine is unknown. Treatment of the headache and nausea with common analgesics and anti-emetic drugs might be effective. Proper explanation and reassurance are most important.

Genome-wide association analysis identifies susceptibility loci for migraine without aura.

Migraine without aura is the most common form of migraine, characterized by recurrent disabling headache and associated autonomic symptoms. To identify common genetic variants associated with this migraine type, we analyzed genome-wide association data of 2,326 clinic-based German and Dutch individuals with migraine without aura and 4,580 population-matched controls. We selected SNPs from 12 loci with 2 or more SNPs associated with P values of <1 × 10(-5) for replication testing in 2,508 individuals with migraine without aura and 2,652 controls. SNPs at two of these loci showed convincing replication: at 1q22 (in MEF2D; replication P = 4.9 × 10(-4); combined P = 7.06 × 10(-11)) and at 3p24 (near TGFBR2; replication P = 1.0 × 10(-4); combined P = 1.17 × 10(-9)). In addition, SNPs at the PHACTR1 and ASTN2 loci showed suggestive evidence of replication (P = 0.01; combined P = 3.20 × 10(-8) and P = 0.02; combined P = 3.86 × 10(-8), respectively). We also replicated associations at two previously reported migraine loci in or near TRPM8 and LRP1. This study identifies the first susceptibility loci for migraine without aura, thereby expanding our knowledge of this debilitating neurological disorder.