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Background The vasodilatory calcitonin-gene related peptide (CGRP) is understood as pivotal mediator in migraine pathophysiology. Blocking CGRP with small molecules or monoclonal antibodies (CGRP-mAb) reduces migraine frequency. However, prescription of CGRP-mAbs is still regulated and possible predictive measures of therapeutic success would be useful. Methods Using standardized capsaicin-induced dermal blood flow model, 29 migraine patients underwent a laser speckle imaging measurement before and after administration of galcanezumab. At both sessions dermal blood flow before and after capsaicin stimulation as well as flare size were analyzed over all three trigeminal branches and the volar forearm for extracranial control. Long-term measures were repeated in 14 patients after continuous treatment ranging from 6 to 12 months. Results Resting dermal blood flow remained unchanged after administration of galcanezumab. Capsaicin-induced dermal blood flow decreased significantly after CGRP-mAb in all tested areas compared to baseline and this was consistent even after 12 months of treatment. However, following galcanezumab administration, the flare size decreased only in the three trigeminal dermatomes, not the arm and was therefore specific for the trigemino-vascular system. None of these two markers distinguished between responders and non-responders. Conclusion CGRP-mAb changed blood flow response to capsaicin stimulation profoundly and this effect did not change over a 12-month application. Neither capsaicin-induced flare nor dermal blood flow can be used as a predictor for treatment efficacy. These data suggest that the mechanism of headache development in migraine is not entirely CGRP-mediated.

Galcanezumab, a monoclonal antibody against calcitonin gene-related peptide, is an emerging migraine preventative. We hypothesized that the preventive effects are conveyed via the modulation of somatosensory processing and that certain sensory profiles may hence be associated with different clinical responses. We recruited migraine patients (n = 26), who underwent quantitative sensory tests over the right V1 dermatome and forearm at baseline (T0), 2 to 3 weeks (T1) and 1 year (T12) after monthly galcanezumab treatment. The clinical response was defined as a reduction of ≥30% in headache frequency based on the headache diary. Predictors for clinical response were calculated using binary logistical regression models. After galcanezumab (T1 vs T0), the heat pain threshold (°C, 44.9 ± 3.4 vs 43.0 ± 3.3, P = 0.013) and mechanical pain threshold (log mN, 1.60 ± 0.31 vs 1.45 ± 0.26, P = 0.042) were increased exclusively in the V1 dermatome but not the forearm. These changes were immediate, did not differ between responders and nonresponders, and did not last in 1 year of follow-up (T12 vs T0). However, baseline heat pain threshold (OR: 2.13, 95% CI: 1.08-4.19, P = 0.029) on the forearm was a robust predictor for a clinical response 3 months later. In summary, our data demonstrated that galcanezumab modulates pain thresholds specifically in the V1 dermatome, but this modulation is short-lasting and irrelevant to clinical response. Instead, the clinical response may be determined by individual sensibility even before the administration of medication.

Purpose of Review The diagnostic criteria of new daily persistent headache (NDPH) have been revised since 2013. The current review focused on the progress of NDPH research over the last few years. Recent Findings Various new triggers and different NDPH mimics have been reported. The association with both cephalic and extracephalic pathologies suggests that NDPH is rather a syndrome with more than one disease mechanism. Recent clinical studies confirmed that migrainous headache remained the most prominent phenotype of NDPH, echoing the change of the diagnostic criteria in 2013. Diagnostic workup, including imaging studies, was unremarkable, except serving to exclude secondary etiologies. Studies on treatment options have yet shown promising targets, and randomized clinical trials are still lacking. Summary Multiple mechanisms, both cranial and systemic, may be involved synergically in the generation of NDPH-like headaches. The search for effective treatment options should base on better understanding of disease mechanisms.

Objective The presence of aura is rare in cluster headache, and even rarer in other trigeminal autonomic cephalalgias. We hypothesized that the presence of aura in patients with trigeminal autonomic cephalalgias is frequently an epiphenomenon and mediated by comorbid migraine with aura. Methods The study retrospectively reviewed 480 patients with trigeminal autonomic cephalalgia in a tertiary medical center for 10 years. Phenotypes and temporal correlation of aura with headache were analyzed. Trigeminal autonomic cephalalgia patients with aura were further followed up in a structured telephone interview. Results Seventeen patients with aura (3.5%) were identified from 480 patients with trigeminal autonomic cephalalgia, including nine with cluster headache, one with paroxysmal hemicrania, three with hemicrania continua, and four with probable trigeminal autonomic cephalalgia. Compared to trigeminal autonomic cephalalgia patients without aura, trigeminal autonomic cephalalgia patients with aura were more likely to have a concomitant diagnosis of migraine with aura (odds ratio [OR] = 109.0, 95% CI 30.9–383.0, p Interpretation In most patients with trigeminal autonomic cephalalgia, the presence of aura is mediated by the comorbidity of migraine with aura. Aura directly related to trigeminal autonomic cephalalgia attack may exist but remains rare. Our results suggest that aura may not be involved in the pathophysiology of trigeminal autonomic cephalalgia.

Research on migraine usually focuses on the headache; however, accumulating evidence suggests that migraine not only changes the somatosensory system for nociception (pain), but also the other modalities of perception, such as visual, auditory or tactile sense. More importantly, the multisensory changes exist beyond the headache (ictal) phase of migraine and show cyclic changes, suggesting a central generator driving the multiple sensory changes across different migraine phases. This review summarizes the latest studies that explored the cyclic sensory changes of migraine.Considerable evidence from recent neurophysiological and functional imaging studies suggests that alterations in brain activation start at least 48 h before the migraine headache and outlast the pain itself for 24 h. Several sensory modalities are involved with cyclic changes in sensitivity that peak during the ictal phase.In many ways, migraine represents more than just vascular-mediated headaches. Migraine alters the propagation of sensory information long before the headache attack starts.

Objective Headache disorders like migraine show geographic and ethnic differences between Asian and European/North American countries. In cluster headache, these differences are rarely mentioned and discussed. This article aimed to review the characteristics of cluster headache in Asian countries and compare the clinical features to those in European and North American populations. Methods We conducted a narrative literature review on the demographics, clinical presentations, and treatments of cluster headache in Asian countries. Results Patients with cluster headache in Asian populations showed a stronger male predominance compared to European and North American populations. Chronic cluster headache was rare in Asian countries. The clinical presentation of restlessness was not as common in Asian as it was in European and North American countries, and Asian patients with aura were extremely rare. Patients in Asian countries may have a lower circadian rhythmicity of cluster headache and a lower headache load, as demonstrated by lower attack frequencies per day, bout frequencies, and bout durations. Conclusions Regional differences in the presentation of cluster headache exist. Greater awareness for cluster headache should be raised in Asian regions, and further studies are warranted to elucidate the mechanisms behind observed differences.

Cluster headache and migraine are regarded as distinct primary headaches. While cluster headache and migraine differ in multiple aspects such as gender-related and headache specific features (e.g., attack duration and frequency), both show clinical similarities in trigger factors (e.g., alcohol) and treatment response (e.g., triptans). Here, we review the similarities and differences in anatomy and pathophysiology that underlie cluster headache and migraine, discuss whether cluster headache and migraine should indeed be considered as two distinct primary headaches, and propose recommendations for future studies. Graphical Abstract Video recording of the debate held at the 1st International Conference on Advances in Migraine Sciences (ICAMS 2022, Copenhagen, Denmark) is available at https://www.youtube.com/watch?v=uUimmnDVTTE.

Background Accumulating evidence suggests various specific triggers may lead to new daily persistent headache (NDPH)-like presentations, suggesting that new daily persistent headache is a heterogenous syndrome, and challenging the concept that new daily persistent headache is a primary headache disorder. Method We searched the PubMed database up to August 2022 for keywords including persistent daily headache with both primary and secondary etiologies. We summarized the literature and provided a narrative review of the clinical presentation, diagnostic work-ups, possible pathophysiology, treatment response, and clinical outcomes. Results and conclusion New daily persistent headache is a controversial but clinically important topic. New daily persistent headache is likely not a single entity but a syndrome with different etiologies. The issue with past studies of new daily persistent headache is that patients with different etiologies/subtypes were pooled together. Different studies may investigate distinct subsets of patients, which renders the inter-study comparison, both positive and negative results, difficult. The identification (and removal) of a specific trigger might provide the opportunity for clinical improvement in certain patients, even when the disease has lasted for months or years. Nonetheless, if there is a specific trigger, it remains unknown or unidentified for a great proportion of the patients. We need to continue to study this unique headache population to better understand underlying pathogenesis and, most importantly, to establish effective treatment strategies that hopefully resolve the continuous cycle of pain.

Noninvasive vagus nerve stimulation (nVNS) is effective in several types of headache disorders. We sought to unravel the mechanism of how nVNS exhibits this efficacy. This study used a randomized, single-blind, sham-controlled, crossover design and comprised 3 projects with 3 independent cohorts of healthy participants. Project I (n = 15) was explorative. Six quantitative sensory test parameters, including mechanical pain threshold (MPT), were measured over the left V1 dermatome and forearm and compared before and after unilateral nVNS. Projects II (n = 20) and III (n = 21) were preregistered online ( https://osf.io/r4jb9 ). Quantitative sensory test parameters were compared over the left (Project II) or bilateral V1 and V3 dermatomes (Project III), respectively, in addition to the left forearm as a control. A secondary analysis of heart rate variability (HRV) using a historical control group was used to control for systemic effects of nVNS. Verum-nVNS induced trigeminal-specific modulation of pain threshold (ie, MPT) over the left V1 in Project I, left V1 and V3 in Project II, and bilateral V1 and V3 in Project III. Data pooled from Projects II and III demonstrated a greater increase in MPT in the V1 vs V3 dermatome. There were no differences associated with sham-nVNS in any projects. Heart rate variability parameters did not change after nVNS. Our results provide functional evidence of a long hypothesized functional trigemino-vagal system in humans and may explain why nVNS is effective in some headache disorders but not in somatic pain disorders. Because unilateral nVNS modulated the trigeminal thresholds bilaterally, this effect is probably indirect through a central top-down mechanism.

Background Migraine is associated with syncope. We investigated risk factors for syncope and burden of syncope in migraine patients. Methods Participants were recruited from a headache clinic. All participants provided information on lifestyle, co-morbidity, syncope, headache and suicide, and completed the MIDAS and HADS questionnaires. Genetic data were available for a subset of participants. Risk of syncope in relation to participant’s characteristics and migraine susceptibility loci, and risks of psychological disorders associated with syncope, were calculated using logistic regression. Results Underweight, regular tea intake, diabetes mellitus, and migraine with aura were associated with increased syncope risks, with adjusted ORs of 1.76 (95% CI 1.03–3.03), 1.84 (95% CI 1.22–2.79), 4.70 (95% CI 1.58–13.95), and 1.78 (95% CI 1.03–3.10), respectively. Preliminary results showed that rs11172113 in LRP1 was associated with syncope risks. Comorbid syncope in migraine patients was associated with increased risks of depression (OR 1.95, 95% CI 1.18–3.22) and suicide attempt (OR 2.85, 95% CI 1.48–5.48). Conclusion Our study showed the potential roles of vascular risk factors in the association between migraine and syncope. Modifiable risk factors for syncope in patients with migraine include body mass index and tea intake. The debilitating psychological impact of co-morbid syncope in migraine patients warrants clinical attention of treating physicians.

Migraine is defined by attacks of headache with a specific length and associated symptoms such as photophobia, phonophobia and nausea. It is long recognized that migraine is more than just the attacks and that migraine should be understood as a cycling brain disorder with at least 4 phases: interictal, preictal, ictal and postictal. However, unlike the pain phase, the other phases are less well defined, which renders studies focusing on these phases susceptible to bias. We herewith review the available clinical, electrophysiological, and neuroimaging data and propose that the preictal phase should be defined as up to 48 hours before the headache attack and the postictal phase as up to 24 hours following the ictal phase. This would allow future studies to specifically investigate these migraine phases and to make study results more comparable.

Background: Non-dental orofacial pain disorders are not uncommon, but idiopathic or primary facial pain syndromes are rare. Inadequate recognition of these disorders usually leads to unsatisfactory and unmet treatment needs. Methods: We conducted a narrative review with a literature search in PubMed until December 2021, focusing on current guidelines and the recently published International Classification of Orofacial Pain (ICOP). Results: In this paper, we provide an updated overview of the common orofacial pain disorders following the ICOP, covering the classification, epidemiology, pathophysiology, clinical approaches, and treatment options. Additionally, we propose a pragmatic approach focusing on the attack duration to improve distinguishing orofacial disorders. Conclusion: The introduction of ICOP offers the opportunity to better coordinate and concentrate scientific efforts, which lays the foundation for the identification of the disease mechanism of facial pain disorders and the optimization of the currently still insufficient therapeutic strategies.

Migraine encompasses a broader spectrum of sensory symptoms than just headache. These "other" symptoms, eg, sensory phobias, cognitive and mood changes, allodynia, and many others indicate an altered sensitivity to sensory input which can be measured, in principle, by quantifying sensory threshold changes longitudinally over time. Photophobia, for example, can be quantified by investigating the discomfort thresholds towards the luminance of light. The aim of this review is to look into how thresholds change in patients with migraine. We performed a PubMed search up to June 2018 targeting all peer-reviewed articles evaluating the changes in threshold, sensory phobia, or sensitivity in patients with migraine. Migraineurs, in general, exhibit lower sensory thresholds compared with healthy controls. These threshold changes seem to follow the different phases during a migraine cycle. In general, thresholds reach a nadir when the headache starts (the ictal phase), rise after the headache ends, and then gradually descend towards the next attack. The sensory modality of measurement-mechanical, thermal, or nociceptive-and the location of measurement-trigeminal vs somatic dermatome-also influence the sensory threshold. Functional imaging studies provide evidence that the hypothalamo-thalamo-brainstem network may be the driving force behind the periodic threshold changes. In summary, there is evidence in the literature that migraine could be understood as a periodic sensory dysregulation originating from the brain. Nevertheless, the interstudy discrepancy is still high due to different study designs and a lack of focus on distinct migraine phases. Further well-designed and harmonized studies with an emphasis on the cyclic changes still need to be conducted.

Objective Whether migraine is associated with urinary calculi is an unresolved issue, although topiramate, a migraine-preventive agent, is known to contribute to this complication. This study investigates the association between migraine and the risk of urinary calculi. Methods We identified a total of 147,399 patients aged ≥18 years with migraine diagnoses recorded in the Taiwan National Health Insurance Research Database between 2005 and 2009. Each patient was randomly matched with one individual without headache using propensity scores. All participants were followed from the date of enrollment until urinary calculi development, death, or the end of 2010. Results The risk of urinary calculi was greater in the migraine than the control cohort (adjusted hazard ratio (aHR), 1.58; 95% confidence interval (CI), 1.52–1.63; p Conclusions Our study showed migraine was associated with an increased risk of urinary calculi, independent of topiramate use. A higher frequency of clinic visits was associated with a greater risk.

Background:Hormonal changes in natural menstrual cycles are known to modulate and even worsen headache symptoms in migraineurs; however, the impact of oral contraceptive pills (OCP), including combined oral contraceptive (COC) and progestogen-only pills on migraine symptomatology, is little investigated.Method:In this retrospective cohort study of 1758 migraine patients, data from 1032 female patients aged 15–45 years were accessed and their contraceptive methods, if any, were analyzed. Further comparisons were conducted between patients with OCP use and those without OCP use regarding the demographics, headache symptoms, and associated symptoms. Most OCP users in this study were assumed to have used COC, but information of individual hormone content of OCP was not collected. Patients with nonoral hormonal contraceptives were excluded for further comparison.Results:The use of OCP was common (47.8%) among the study cohort. Compared to those without OCP use ( n = 410), patients with OCP use ( n = 493) were younger (27.4 ± 7.0 vs. 32.8 ± 7.9, p < 0.001), had lower headache frequency (days per month, 11.1 ± 7.5 vs. 12.3 ± 8.8, p = 0.03), were less likely to have osmophobia (47.3 vs. 54.4%, p = 0.033) or cranial autonomic symptoms (44.8 vs. 53.2%, p = 0.013), and more commonly reported menstrually-related worsening of headache (52.3 vs. 42.4%, p = 0.012). The proportion of migraine with aura or other headache characteristics including severity, unilaterality, and pulsatile characteristic showed no differences between groups.Conclusion:Our data provide real-life information about contraceptive use among patients with migraine. The use of OCP is associated with differences in migraine symptomatology. Further studies are needed to determine whether this relationship is causal and any possible underlying mechanism.

Background.—The link between arterial thromboembolism and migraine is well-documented; however, few studies investigated the link between venous thromboembolism (VTE) and migraine. We aimed to evaluate the association between migraine and VTE and to examine whether demographics or comorbid risk factors modulate VTE development. Methods.—We conducted a cohort study accessing a nationwide claims-based database with an adult cohort of 102,159 neurologist-diagnosed migraine patients, and 102,159 nonheadache comparison subjects, matched on sex and propensity score for the diagnosis of migraine. Both cohorts were followed until the end of 2010, death, or VTE development. Adjusted hazard ratios (aHRs) and 95% confidence intervals (CIs) were calculated based on Cox proportional hazards regression analyses and compared between the two groups. Results.—During a mean follow-up period of 4.2 years, VTE developed in 226 patients (460,047 person-years) in the migraine cohort and in 203 subjects (462,401 person-years) in the comparison cohort. Overall, likelihood of VTE for the migraine cohort did not differ from that in the comparison cohort (aHR 1.12; 95% CI, 0.92–1.35; P = .251). However, subgroup analysis by migraine subtypes (P = .004 for interaction) revealed an elevated risk of VTE in patients with migraine with aura (aHR 2.42; 95% CI, 1.40–4.19; P = .002), but not in those with migraine without aura. The association was not altered in subsequent subgroup analyses and sensitivity analyses. Conclusions Risk of VTE development is elevated specifically in patients diagnosed with migraine with aura. This association suggests a linked disease mechanism and warrants further exploration.

Idiopathic intracranial hypertension (IIH) is a rare disorder that typically affects obese women of childbearing age, but can also occur in paediatric populations. Patients usually present with diffuse, daily headache and visual disturbances, but either symptom can occur in isolation. Patients with IIH often have papilloedema; however, IIH without papilloedema is fairly common in patients with chronic daily headache. The pathogenesis of IIH is unknown; the high incidence of comorbid bilateral transverse sinus stenosis (BTSS) in patients with IIH suggests that the two conditions are linked, although no direct causal relationship has been established. Cerebrospinal fluid (CSF) pressure monitoring or lumbar puncture-which provides immediate symptomatic relief-are important in making a diagnosis of IIH. Current treatments for IIH include weight reduction, medical treatment, CSF diversion surgery, optic nerve sheath fenestration and, potentially, endovascular stenting (in patients with BTSS). Prevention of visual loss (which can be substantial) is the main goal of treatment. Residual headache and IIH recurrence are not uncommon after treatment, and regular follow-up is, therefore, warranted even in patients who achieve remission. This Review provides an update of current knowledge of the aetiology, pathophysiology and treatment of IIH.

To evaluate the association between migraine and Bell palsy and to examine the effects of age, sex, migraine subtype, and comorbid risk factors for Bell palsy.This nationwide cohort study was conducted using data from the Taiwan National Health Insurance Research Database. Subjects aged 18 years or older with neurologist-diagnosed migraine from 2005 to 2009 were included. A nonheadache age- and propensity score-matched control cohort was selected for comparison. All subjects were followed until the end of 2010, death, or the occurrence of a Bell palsy event. Cox proportional hazards regression was used to calculate the adjusted hazard ratios and 95% confidence intervals to compare the risk of Bell palsy between groups.Both cohorts (n = 136,704 each) were followed for a mean of 3.2 years. During the follow-up period, 671 patients (424,372 person-years) in the migraine cohort and 365 matched control subjects (438,677 person-years) were newly diagnosed with Bell palsy (incidence rates, 158.1 and 83.2/100,000 person-years, respectively). The adjusted hazard ratio for Bell palsy was 1.91 (95% confidence interval, 1.68-2.17; p0.001). The association between migraine and Bell palsy remained significant in sensitivity analyses, and tests of interaction failed to reach significance in all subgroup analyses.Migraine is a previously unidentified risk factor for Bell palsy. The association between these 2 conditions suggests a linked disease mechanism, which is worthy of further exploration.

Headache disorder is a major public health issue and is a great burden for the person, the health care system, and society. This article reviews epidemiological surveys of primary headache disorders including migraine and tension-type headache (TTH) among adults in the Asia-Pacific region using the International Classification of Headache Disorders (ICHD), first or second edition. Chronic daily headache (CDH), which is not an official diagnosis in the ICHD, was also reviewed. In the Asia-Pacific region, the median (range) 1-year prevalence of primary headache disorders was 9.1% (1.5-22.8%) for migraine, 16.2% (10.8-33.8%) for TTH, and 2.9% (1.0-3.9%) for CDH. The 1-year prevalence of migraine and TTH were rather consistent; however, the extremes in the 1-year prevalence of migraine in earlier studies from Hong Kong (1.5%) and South Korea (22.3%) were not repeated in later surveys (Hong Kong: 12.5%; South Korea: 6%). According to the United Nations, the estimated population of the Asia-Pacific region was 3.85 billion in 2010, equaling to headache suffers of 350 million patients with migraine, 624 million with TTH, and 112 million with CDH; many remain to be treated. The prevalence of headache disorders has remained stable over the last 2 decades in this region, where the diversity of geography, race, and development is wide. Thus, the pursuit of better headache care in this region might be our next challenge.

Background The International Burden of Migraine Study (IBMS) showed chronic migraine (CM) was associated with a higher disease burden than episodic migraine (EM). However, in this study Asians with CM were underrepresented. Objectives We investigated if CM and EM differed in headache-related disability, health-related quality of life (HRQoL) and health care resource utilization in Taiwan. Methods This study recruited patients with EM and CM from two headache clinics in Taiwan. Diagnosis was made by physicians based on Silberstein-Lipton criteria. Participants completed a questionnaire including sociodemographics, Migraine Disability Assessment (MIDAS), EuroQol five-dimensions (EQ-5D), Migraine-Specific Quality of Life v2.1 (MSQ), Patient Health Questionnaire-4 (PHQ-4), productivity and health care resource utilization. Results A total of 331 patients (EM, n = 164 (49.5%); CM, n = 167 (50.5%)) completed the study. CM patients reported a significantly higher MIDAS score, lower generic (EQ-5D visual analogue scale score and EQ-5D index score) and migraine-specific (all three domains of MSQ) HRQoL, higher levels of anxiety and depression (PHQ-4 ≥ 6) and greater health care resource utilization and productivity loss than those with EM. Positive correlations were found between these instruments and levels of anxiety and depression. Conclusion Compared to EM, CM was significantly associated with higher disability, lower HRQoL and greater health care resource utilization and productivity loss.

Introduction: International Classification of Headache Disorders (ICHD-2) criteria for new daily persistent headache (NDPH) require tension-type headache features. Many patients with ‘new-onset persistent’ headache fail to fulfil such criteria due to prominent migrainous features. Subjects and methods: We reviewed all NDPH patients in our headache clinic, using the definition of persistent headache 3 months. The patients were dichotomised: patients meeting ICHD-2 criteria (NDPH-S) and patients failing to meet ICHD-2 criteria due to prominent migrainous features (NDPH-M). All patients had completed a structured intake form including demographics, headache profiles, Beck Depression Inventory (BDI), Short Form 36 (SF-36) Health Survey, and Migraine Disability Assessment (MIDAS). A telephone interview was conducted for follow-up. Results: A total of 92 NDPH patients were enrolled (59 (64.1%) NDPH-M, 33 (35.9%) NDPH-S). Between the two subgroups, the sociodemographics were indistinguishable, but the patients with NDPH-M had higher headache intensity, BDI scores, MIDAS scores, and lower scores of most SF-36 subscales. After an average of 2 years of follow-up, 57 (66%) had a good outcome (≥ 50% reduction in headache frequency). Cox proportional analysis showed that disease duration ≤ 6 months and NDPH-S diagnosis predicted good outcomes. Conclusion: Migrainous features were common in patients with NDPH. Unlike prior studies, our study showed NDPH-M represented a more severe subgroup with a poorer outcome compared with NDPH-S.