Effect of erenumab on the reversion from chronic migraine to episodic migraine in an Asian population: A post hoc analysis of the DRAGON study.

BACKGROUND: Erenumab is a fully human monoclonal antibody that selectively targets the calcitonin gene-related peptide receptor. It has been proven to be safe and efficacious in patients with episodic migraine (EM) and chronic migraine (CM) as demonstrated in phase 2 and 3 clinical trials including patients from Europe, Japan, and the United States. Reversion from CM to EM, as indicated by a reduction in the frequency of headache days, is an important indicator for efficacy outcome, though it has not been analyzed widely in patients with CM to date. OBJECTIVE: Primary results of the DRAGON study demonstrated the efficacy and safety of erenumab in patients with CM from China and other Asian countries. This post hoc analysis evaluated the rate of reversion from CM to EM in the overall population and in subgroups of patients defined by baseline demographic and clinical characteristics (age, body mass index, gender, prior preventive treatment failure, medication overuse status, and disease duration). METHODS: Reversion from CM to EM was defined as a reduction in headache frequency to < 45 headache days over the 12 weeks of the double-blind treatment period. In addition, migraine-related disability and disease impact on functional impairment were assessed within each treatment group in reverters and non-reverters using the Headache Impact Test-6 (HIT-6), Migraine Physical Function Impact Diary (MPFID), and modified Migraine Disability Assessment (mMIDAS). RESULTS: Overall, 557 patients with CM were randomized to monthly erenumab 70 mg (n = 279) or placebo (n = 278), of whom 52.3% (146 of 279) treated with erenumab reverted from CM to EM compared to 41.0% (114 of 278) in the placebo group (odds ratio [OR] 1.59, 95% confidence interval: 1.1-2.2; p = 0.007). Treatment with erenumab resulted in a greater mean change (standard error) from baseline in the HIT-6 total score for reverters versus non-reverters compared to placebo (erenumab: -9.5 [0.6] vs. -5.1 [0.5]; placebo: -8.9 [0.7] vs. -4.9 [0.5]). A similar pattern was observed for mMIDAS score in erenumab treatment groups versus placebo (erenumab: -22.1 [1.2] vs. -6.3 [1.8]; placebo: -19.9 [1.3] vs. -7.9 [1.6]). Substantial improvements were reported in MPFID-Physical Impairment (PI) and Everyday Activities (EA) scores in reverters versus non-reverters in erenumab treatment groups (MPFID-PI: -5.9 [0.3] vs. -1.9 [0.6]; MPFID-EA: -7.9 [0.4] vs. -3.4 [0.6]) and in placebo (MPFID-PI: -5.4 [0.4] vs. -1.0 [0.5]; MPFID-EA: -7.1 [0.5] vs. -3.2 [0.5]). CONCLUSIONS: This analysis demonstrated that a greater proportion of patients treated with erenumab reverted from CM to EM compared to patients treated with placebo. The reversion from CM to EM was reflected by the greater improvements in patient-reported outcomes in the erenumab group.

Fecal microbiota transplantation significantly improved respiratory failure of amyotrophic lateral sclerosis.

Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease that leads to respiratory failure, and eventually death. However, there is a lack of effective treatments for ALS. Here we report the results of fecal microbiota transplantation (FMT) in two patients with late-onset classic ALS with a Japan ALS severity classification of grade 5 who required tracheostomy and mechanical ventilation. In both patients, significant improvements in respiratory function were observed following two rounds of FMT, leading to weaning off mechanical ventilation. Their muscle strength improved, allowing for assisted standing and mobility. Other notable treatment responses included improved swallowing function and reduced muscle fasciculations. Metagenomic and metabolomic analysis revealed an increase in beneficial Bacteroides species (Bacteroides stercoris, Bacteroides uniformis, Bacteroides vulgatus), and Faecalibacterium prausnitzii after FMT, as well as elevated levels of metabolites involved in arginine biosynthesis and decreased levels of metabolites involved in branched-chain amino acid biosynthesis. These findings offer a potential rescue therapy for ALS with respiratory failure and provide new insights into ALS in general.

Alleviation of migraine related pain and anxiety by inhibiting calcium-stimulating AC1-dependent CGRP in the insula of adult rats.

BACKGROUND: Recent animal and clinical findings consistently highlight the critical role of calcitonin gene-related peptide (CGRP) in chronic migraine (CM) and related emotional responses. CGRP antibodies and receptor antagonists have been approved for CM treatment. However, the underlying CGRP-related signaling pathways in the pain-related cortex remain poorly understood. METHODS: The SD rats were used to establish the CM model by dural infusions of inflammatory soup. Periorbital mechanical thresholds were assessed using von-Frey filaments, and anxiety-like behaviors were observed via open field and elevated plus maze tests. Expression of c-Fos, CGRP and NMDA GluN2B receptors was detected using immunofluorescence and western blotting analyses. The excitatory synaptic transmission was detected by whole-cell patch-clamp recording. A human-used adenylate cyclase 1 (AC1) inhibitor, hNB001, was applied via insula stereotaxic and intraperitoneal injections in CM rats. RESULTS: The insular cortex (IC) was activated in the migraine model rats. Glutamate-mediated excitatory transmission and NMDA GluN2B receptors in the IC were potentiated. CGRP levels in the IC significantly increased during nociceptive and anxiety-like activities. Locally applied hNB001 in the IC or intraperitoneally alleviated periorbital mechanical thresholds and anxiety behaviors in migraine rats. Furthermore, CGRP expression in the IC decreased after the hNB001 application. CONCLUSIONS: Our study indicated that AC1-dependent IC plasticity contributes to migraine and AC1 may be a promising target for treating migraine in the future.

Association between Body Mass Index and Medication-Overuse Headache among Individuals with Migraine: A Cross-Sectional Study.

INTRODUCTION: Medication-overuse headache (MOH) is a secondary chronic headache disorder that occurs in individuals with a pre-existing primary headache disorder, particularly migraine disorder. Obesity is often combined with chronic daily headaches and is considered a risk factor for the transformation of episodic headaches into chronic headaches. However, the association between obesity and MOH among individuals with migraine has rarely been studied. The present study explored the association between body mass index (BMI) and MOH in people living with migraine. METHODS: This cross-sectional study is a secondary analysis of data from the Survey of Fibromyalgia Comorbidity with Headache study. Migraine and MOH were diagnosed using the criteria of the International Classification of Headache Disorders, 3rd Edition. BMI (kg/m2) is calculated by dividing the weight (kg) by the square of the height (m). Multivariable logistic regression analysis was used to evaluate the association between BMI and MOH. RESULTS: A total of 2,251 individuals with migraine were included, of whom 8.7% (195/2,251) had a concomitant MOH. Multivariable logistic regression analysis, adjusted for age, sex, education level, headache duration, pain intensity, headache family history, chronic migraine, depression, anxiety, insomnia, and fibromyalgia, demonstrated there was an association between BMI (odds ratio [OR], 1.05; 95% confidence interval [CI], 1.01-1.11; p = 0.031) and MOH. The results remained when the BMI was transformed into a category. Compared to individuals with Q2 (18.5 kg/m2 ≤ BMI ≤23.9 kg/m2), those with Q4 (BMI ≥28 kg/m2) had an adjusted OR for MOH of 1.81 (95% CI, 1.04-3.17; p = 0.037). In the subgroup analyses, BMI was associated with MOH among aged more than 50 years (OR, 1.13; 95%, 1.03-1.24), less than high school (OR, 1.08; 95%, 1.01-1.15), without depression (OR, 1.06; 95%, 1.01-1.12), and without anxiety (OR, 1.06; 95%, 1.01-1.12). An association between BMI and MOH was found in a sensitivity analysis that BMI was classified into four categories according to the World Health Organization guidelines. CONCLUSION: In this cross-sectional study, BMI was associated with MOH in Chinese individuals with migraine.

Clinical and structural characteristics of NEU1 variants causing sialidosis type 1.

Purpose: Sialidosis type 2 has variants that are both catalytically inactive (severe), while sialidosis type 1 has at least one catalytically active (mild) variant. This study aimed to discuss the structural changes associated with these variants in a newly reported family carrying NEU1 variants and explore the clinical characteristics of different combinations of variants in sialidosis type 1. Methods: First, whole-exome sequencing and detailed clinical examination were performed on the family. Second, structural analysis, including energy, flexibility and polar contacts, was conducted for several NEU1 variants, and a sialidase activity assay was performed. Third, previous NEU1 variants were systematically reviewed, and the clinical characteristics of patients in the severe-mild and mild-mild groups with sialidosis type 1 were analyzed. Results: We report a novel family with sialidosis type 1 and the compound heterozygous variants S182G and V143E. The newly identified V143E variant was predicted to be a mild variant through structural analysis and was confirmed by sialidase activity assay. The cherry-red spot was more prevalent in the severe-mild group, and ataxia was more common in the mild-mild group. Impaired cognition was found only in the severe-mild group. Moreover, patients with cherry-red spots and abnormal EEGs and VEPs had a relatively early age of onset, whereas patients with myoclonus had a late onset. Conclusion: Changes in flexibility and local polar contacts may be indicators of the NEU1 pathogenicity. Sialidosis type 1 can be divided into two subgroups according to the variant combinations, and patients with these two subtypes have different clinical characteristics.

Magnetic molecularly imprinted polymers using ternary deep eutectic solvent as novel functional monomer for hydroxytyrosol separation.

In this work, magnetic molecularly imprinted polymers (MIPs) for specific recognition of Hydroxytyrosol (HT) were designed by vinyl-modified magnetic particles (Fe3O4@SiO2@VTEOs) as carrier, ternary deep eutectic solvent (DES) as functional monomer, while ethylene glycol dimethacrylate (EGDMA) as crosslinker. The optimum amount of DES was obtained by adsorption experiments (molar ratio, caffeic acid: choline chloride: formic acid = 1:6:3) which were 140 µL in total. Under the optimized amount of DES, the maximum adsorption capacity of the MIPs particles was 42.43 mg g-1, which was superior to non-imprinted polymer (4.64 mg g-1) and the imprinting factor (IF) is 9.10. Syringin and Oleuropicrin were used as two reference molecules to test the selectivity of the DES-MIPs particles. The adsorption capacity of HT was 40.11 mg g-1. Three repeated experiments show that the polymer has high stability and repeatability (RSD = 5.50).

Rimegepant orally disintegrating tablet 75 mg for acute treatment of migraine in adults from China: a subgroup analysis of a double-blind, randomized, placebo-controlled, phase 3 clinical trial.

BACKGROUND: Rimegepant orally disintegrating tablet (ODT), an oral small-molecule calcitonin gene-related peptide receptor antagonist, is indicated for acute and preventive treatment of migraine in the United States and other countries. Previously, a large clinical trial assessed the efficacy and safety of rimegepant ODT 75 mg for the acute treatment of migraine in adults living in China or South Korea. A post hoc subgroup analysis of this trial was performed to evaluate the efficacy and safety of rimegepant for acute treatment of migraine in adults living in China. METHODS: Eligible participants were ≥ 18 years of age and had a ≥ 1-year history of migraine, with 2 to 8 attacks of moderate or severe pain intensity per month and < 15 headache days per month during the 3 months before screening. Participants self-administered rimegepant ODT 75 mg or matching placebo to treat a single migraine attack of moderate or severe pain intensity. The co-primary endpoints were pain freedom and freedom from the most bothersome symptom (MBS) at 2 h post-dose. Key secondary endpoints included pain relief at 2 h post-dose, ability to function normally at 2 h post-dose, use of rescue medication within 24 h post-dose, and sustained pain freedom from 2 to 24 h and 2 to 48 h post-dose. All p values were nominal. Safety was assessed via treatment-emergent adverse events (TEAEs), electrocardiograms, vital signs, and routine laboratory tests. RESULTS: Overall, 1075 participants (rimegepant, n = 538; placebo, n = 537) were included in the subgroup analysis. Rimegepant was more effective than placebo for the co-primary endpoints of pain freedom (18.2% vs. 10.6%, p = 0.0004) and freedom from the MBS (48.0% vs. 31.8%, p <  0.0001), as well as all key secondary endpoints. The incidence of TEAEs was comparable between the rimegepant (15.2%) and placebo (16.4%) groups. No signal of drug-induced liver injury was observed, and no study drug-related serious TEAEs were reported in the rimegepant group. CONCLUSIONS: A single dose of rimegepant 75 mg rimegepant was effective for the acute treatment of migraine in adults living in China, with safety and tolerability similar to placebo. TRIAL REGISTRATION: Clinicaltrials.gov NCT04574362 Date registered: 2020-10-05.

Unveiling the therapeutic potential of Dl-3-n-butylphthalide in NTG-induced migraine mouse: activating the Nrf2 pathway to alleviate oxidative stress and neuroinflammation.

BACKGROUND: Migraine stands as a prevalent primary headache disorder, with prior research highlighting the significant involvement of oxidative stress and inflammatory pathways in its pathogenesis and chronicity. Existing evidence indicates the capacity of Dl-3-n-butylphthalide (NBP) to mitigate oxidative stress and inflammation, thereby conferring neuroprotective benefits in many central nervous system diseases. However, the specific therapeutic implications of NBP in the context of migraine remain to be elucidated. METHODS: We established a C57BL/6 mouse model of chronic migraine (CM) using recurrent intraperitoneal injections of nitroglycerin (NTG, 10 mg/kg), and prophylactic treatment was simulated by administering NBP (30 mg/kg, 60 mg/kg, 120 mg/kg) by gavage prior to each NTG injection. Mechanical threshold was assessed using von Frey fibers, and photophobia and anxious behaviours were assessed using a light/dark box and elevated plus maze. Expression of c-Fos, calcitonin gene-related peptide (CGRP), Nucleus factor erythroid 2-related factor 2 (Nrf2) and related pathway proteins in the spinal trigeminal nucleus caudalis (SP5C) were detected by Western blotting (WB) or immunofluorescence (IF). The expression of IL-1ß, IL-6, TNF-α, Superoxide dismutase (SOD) and malondialdehyde (MDA) in SP5C and CGRP in plasma were detected by ELISA. A reactive oxygen species (ROS) probe was used to detect the expression of ROS in the SP5C. RESULTS: At the end of the modelling period, chronic migraine mice showed significantly reduced mechanical nociceptive thresholds, as well as photophobic and anxious behaviours. Pretreatment with NBP attenuated nociceptive sensitization, photophobia, and anxiety in the model mice, reduced expression levels of c-Fos and CGRP in the SP5C and activated Nrf2 and its downstream proteins HO-1 and NQO-1. By measuring the associated cytokines, we also found that NBP reduced levels of oxidative stress and inflammation. Most importantly, the therapeutic effect of NBP was significantly reduced after the administration of ML385 to inhibit Nrf2. CONCLUSIONS: Our data suggest that NBP may alleviate migraine by activating the Nrf2 pathway to reduce oxidative stress and inflammation in migraine mouse models, confirming that it may be a potential drug for the treatment of migraine.

Profile of Chinese Cluster Headache Register Individual Study (CHRIS): Clinical characteristics, diagnosis and treatment status data of 816 patients in China.

BACKGROUND: The clinical profile of cluster headache may differ among different regions of the world, warranting interest in the data obtained from the initial Chinese Cluster Headache Register Individual Study (CHRIS) for better understanding. METHODS: We conducted a multicenter, prospective, longitudinal cohort study on cluster headache across all 31 provinces of China, aiming to gather clinical characteristics, treatment approaches, imaging, electrophysiological and biological samples. RESULTS: In total 816 patients were enrolled with a male-to-female ratio of 4.33:1. The mean age at consultation was 34.98 ± 9.91 years, and 24.89 ± 9.77 years at onset. Only 2.33% were diagnosed with chronic cluster headache, and 6.99% had a family history of the condition. The most common bout was one to two times per year (45.96%), lasting two weeks to one month (44.00%), and occurring frequently in spring (76.23%) and winter (73.04%). Of these, 68.50% experienced one to two attacks per day, with the majority lasting one to two hours (45.59%). The most common time for attacks was between 9 am and 12 pm (75.86%), followed by 1 am and 3 am (43.48%). Lacrimation (78.80%) was the most predominant autonomic symptom reported. Furthermore, 39.22% of patients experienced a delay of 10 years or more in receiving a correct diagnosis. Only 35.67% and 24.26% of patients received common acute and preventive treatments, respectively. CONCLUSION: Due to differences in ethnicity, genetics and lifestyle conditions, CHRIS has provided valuable baseline data from China. By establishing a dynamic cohort with comprehensive multidimensional data, it aims to advance the management system for cluster headache in China.

The crucial role of locus coeruleus noradrenergic neurons in the interaction between acute sleep disturbance and headache.

BACKGROUND: Both epidemiological and clinical studies have indicated that headache and sleep disturbances share a complex relationship. Although headache and sleep share common neurophysiological and anatomical foundations, the mechanism underlying their interaction remains poorly understood. The structures of the diencephalon and brainstem, particularly the locus coeruleus (LC), are the primary sites where the sleep and headache pathways intersect. To better understand the intricate nature of the relationship between headache and sleep, our study focused on investigating the role and function of noradrenergic neurons in the LC during acute headache and acute sleep disturbance. METHOD: To explore the relationship between acute headache and acute sleep disturbance, we primarily employed nitroglycerin (NTG)-induced migraine-like headache and acute sleep deprivation (ASD) models. Initially, we conducted experiments to confirm that ASD enhances headache and that acute headache can lead to acute sleep disturbance. Subsequently, we examined the separate roles of the LC in sleep and headache. We observed the effects of drug-induced activation and inhibition and chemogenetic manipulation of LC noradrenergic neurons on ASD-induced headache facilitation and acute headache-related sleep disturbance. This approach enabled us to demonstrate the bidirectional function of LC noradrenergic neurons. RESULTS: Our findings indicate that ASD facilitated the development of NTG-induced migraine-like headache, while acute headache affected sleep quality. Furthermore, activating the LC reduced the headache threshold and increased sleep latency, whereas inhibiting the LC had the opposite effect. Additional investigations demonstrated that activating LC noradrenergic neurons further intensified pain facilitation from ASD, while inhibiting these neurons reduced this pain facilitation. Moreover, activating LC noradrenergic neurons exacerbated the impact of acute headache on sleep quality, while inhibiting them alleviated this influence. CONCLUSION: The LC serves as a significant anatomical and functional region in the interaction between acute sleep disturbance and acute headache. The involvement of LC noradrenergic neurons is pivotal in facilitating headache triggered by ASD and influencing the effects of headache on sleep quality.

AMPK activation attenuates central sensitization in a recurrent nitroglycerin-induced chronic migraine mouse model by promoting microglial M2-type polarization.

BACKGROUND: Energy metabolism disorders and neurogenic inflammation play important roles in the central sensitization to chronic migraine (CM). AMP-activated protein kinase (AMPK) is an intracellular energy sensor, and its activation regulates inflammation and reduces neuropathic pain. However, studies on the involvement of AMPK in the regulation of CM are currently lacking. Therefore, this study aimed to explore the mechanism underlying the involvement of AMPK in the central sensitization to CM. METHODS: Mice with recurrent nitroglycerin (NTG)-induced CM were used to detect the expression of AMPK protein in the trigeminal nucleus caudalis (TNC). Following intraperitoneal injection of the AMPK activator 5-aminoimidazole-4-carboxyamide ribonucleoside (AICAR) and inhibitor compound C, the mechanical pain threshold, activity level, and pain-like behaviors in the mice were measured. The expression of calcitonin gene-related peptide (CGRP) and cytokines, M1/M2 microglia, and NF-κB pathway activation were detected after the intervention. RESULTS: Repeated NTG injections resulted in a gradual decrease in AMPK protein expression, and the negative regulation of AMPK by increased ubiquitin-like plant homeodomain and RING finger domain 1 (UHRF1) expression may counteract AMPK activation by increasing ADP/ATP. AICAR can reduce the hyperalgesia and pain-like behaviors of CM mice, improve the activity of mice, reduce the expression of CGRP, IL-1ß, IL-6, and TNF-α in the TNC region, and increase the expression of IL-4 and IL-10. Moreover, AMPK in TNC was mainly located in microglia. AICAR could reduce the expression of inducible NO synthase (iNOS) in M1 microglia and increase the expression of Arginase 1 (Arg1) in M2 microglia by inhibiting the activation of NF-κB pathway. CONCLUSIONS: AMPK was involved in the central sensitization of CM, and the activation of AMPK reduced neuroinflammation in NTG-induced CM mice. AMPK may provide new insights into interventions for energy metabolism disorders and neurogenic inflammation in migraine.

A pilot study on a patient with refractory headache: Personalized deep brain stimulation through stereoelectroencephalography.

The integration of stereoelectroencephalography with therapeutic deep brain stimulation (DBS) holds immense promise as a viable approach for precise treatment of refractory disorders, yet it has not been explored in the domain of headache or pain management. Here, we implanted 14 electrodes in a patient with refractory migraine and integrated clinical assessment and electrophysiological data to investigate personalized targets for refractory headache treatment. Using statistical analyses and cross-validated machine-learning models, we identified high-frequency oscillations in the right nucleus accumbens as a critical headache-related biomarker. Through a systematic bipolar stimulation approach and blinded sham-controlled survey, combined with real-time electrophysiological data, we successfully identified the left dorsal anterior cingulate cortex as the optimal target for the best potential treatment. In this pilot study, the concept of the herein-proposed data-driven approach to optimizing precise and personalized treatment strategies for DBS may create a new frontier in the field of refractory headache and even pain disorders.

Adult-onset combined oxidative phosphorylation deficiency type 14 manifests as epileptic status: a new phenotype and literature review.

BACKGROUND: Combined oxidative phosphorylation deficiency (COXPD) is a severe disorder with early onset and autosomal recessive inheritance, and has been divided into 51 types (COXPD1-COXPD51). COXPD14 is caused by a mutation in the FARS2 gene, which encodes mitochondrial phenylalanyl-tRNA synthetase (mt-PheRS), an enzyme that transfers phenylalanine to its cognate tRNA in mitochondria. Since the first case was reported in 2012, an increasing number of FARS2 variations have been subsequently identified, which present three main phenotypic manifestations: early onset epileptic encephalopathy, hereditary spastic paraplegia, and juvenile-onset epilepsy. To our knowledge, no adult cases have been reported in the literature. METHODS: We report in detail a case of genetically confirmed COXPD14 and review the relevant literature. RESULTS: Approximately 58 subjects with disease-causing variants of FARS2 have been reported, including 31 cases of early onset epileptic encephalopathy, 16 cases of hereditary spastic paraplegia, 3 cases of juvenile-onset epilepsy, and 8 cases of unknown phenotype. We report a case of autosomal recessive COXPD14 in an adult with status epilepticus as the only manifestation with a good prognosis, which is different from that in neonatal or infant patients reported in the literature. c.467C > T (p.T156M) has been previously reported, while c.119_120del (p.E40Vfs*87) is novel, and, both mutations are pathogenic. CONCLUSIONS: This case of autosomal recessive COXPD14 in an adult only presented as status epilepticus, which is different from the patients reported previously. Our study expands the mutation spectrum of FARS2, and we tended to define the phenotypes based on the clinical manifestation rather than the age of onset.

Migraine-like headache in subjects with isolated Lambl's excrescences: a case series and literature review.

AIM: Lambl's excrescences are mobile, thin, fibrinous connective tissue strands typically found on left-sided cardiac values. Migraine is positively associated with structural cardiac anomalies. However, it remains unclear whether Lambl's excrescences are associated with migraine. METHODS: Retrospective review of 182 inpatients with Lambl's excrescences confirmed by transesophageal echocardiogram in Chinese PLA General Hospital since January 2010. Among them, those with isolated Lambl's excrescences presented with migraine-like headache were included. We collected information on the demographics and clinical profiles of all participants, and performed follow-up visits. RESULTS: A total of 8 patients presented with migraine-like headache among 15 patients with isolated Lambl's excrescences. They included 2 men and 6 women, with an average age of 44.63 ± 12.24 years. Among these patients, 3 had visual aura, and 6 manifested infarct-like lesions on magnetic resonance imaging, of which 2 developed lesions after first visit. During follow-up, 4 patients suffering from intervention for Lambl's excrescences dramatically reduced headache recurrence compared to the other 4 patients only receiving migraine preventive medications. CONCLUSIONS: This study supports the hypothesis that microemboli from isolated Lambl's excrescences could cause migraine-like headache. And intervention for Lambl's excrescences may be crucial for preventing headache recurrence.

This study supports the hypothesis that microemboli from isolated Lambl's excrescences could cause migraine-like headache.The small sample size study fails to make management recommendations.

The World Health Organization Intersectoral Global Action Plan on Epilepsy and Other Neurological Disorders and the headache revolution: from headache burden to a global action plan for headache disorders.

The World Health Organization (WHO) Intersectoral Global Action Plan on Epilepsy and Other Neurological Disorders was developed by WHO to address the worldwide challenges and gaps in provision of care and services for people with epilepsy and other neurological disorders and to ensure a comprehensive, coordinated response across sectors to the burden of neurologic diseases and to promote brain health across life-course. Headache disorders constitute the second most burdensome of all neurological diseases after stroke, but the first if young and midlife adults are taken into account. Despite the availability of a range of treatments, disability associated with headache disorders, and with migraine, remains very high. In addition, there are inequalities between high-income and low and middle income countries in access to medical care. In line with several brain health initiatives following the WHOiGAP resolution, herein we tailor the main pillars of the action plan to headache disorders: (1) raising policy prioritization and strengthen governance; (2) providing effective, timely and responsive diagnosis, treatment and care; (3) implementing strategies for promotion and prevention; (4) fostering research and innovation and strengthen information systems. Specific targets for future policy actions are proposed. The Global Action Plan triggered a revolution in neurology, not only by increasing public awareness of brain disorders and brain health but also by boosting the number of neurologists in training, raising research funding and making neurology a public health priority for policy makers. Reducing the burden of headache disorders will not only improve the quality of life and wellbeing of people with headache but also reduce the burden of neurological disorders increasing global brain health and, thus, global population health.

Mortality from cerebrovascular diseases in China: Exploration of recent and future trends.

BACKGROUND: Cerebrovascular disease (CVD) ranks among the foremost factors responsible for mortality on a global scale. The mortality patterns of CVDs and temporal trends in China need to be well-illustrated and updated. METHODS: We collected mortality data on patients with CVD from Chinese Center for Disease Control and Prevention's Disease Surveillance Points (CDC-DSP) system. The mortality of CVD in 2020 was described by age, sex, residence, and region. The temporal trend from 2013 to 2019 was evaluated using joinpoint regression, and estimated rates of decline were extrapolated until 2030 using time series models. RESULTS: In 2019, the age-standardized mortality in China (ASMRC) per 100,000 individuals was 113.2. The ASMRC for males (137.7/10 5 ) and rural areas (123.0/10 5 ) were both higher when stratified by gender and urban/rural residence. The central region had the highest mortality (126.5/10 5 ), the western region had a slightly lower mortality (123.5/10 5 ), and the eastern region had the lowest mortality (97.3/10 5 ). The age-specific mortality showed an accelerated upward trend from aged 55-59 years, with maximum mortality observed in individuals over 85 years of age. The age-standardized mortality of CVD decreased by 2.43% (95% confidence interval, 1.02-3.81%) annually from 2013 to 2019. Notably, the age-specific mortality of CVD increased from 2013 to 2019 for the age group of over 85 years. In 2020, both the absolute number of CVD cases and the crude mortality of CVD have increased compared to their values in 2019. The estimated total deaths due to CVD were estimated to reach 2.3 million in 2025 and 2.4 million in 2030. CONCLUSION: The heightened focus on the burden of CVD among males, rural areas, the central and western of China, and individuals aged 75 years and above has emerged as a pivotal determinant in further decreasing mortalities, consequently presenting novel challenges to strategies for disease prevention and control.

Dopaminergic Projections from the Hypothalamic A11 Nucleus to the Spinal Trigeminal Nucleus Are Involved in Bidirectional Migraine Modulation.

Clinical imaging studies have revealed that the hypothalamus is activated in migraine patients prior to the onset of and during headache and have also shown that the hypothalamus has increased functional connectivity with the spinal trigeminal nucleus. The dopaminergic system of the hypothalamus plays an important role, and the dopamine-rich A11 nucleus may play an important role in migraine pathogenesis. We used intraperitoneal injections of glyceryl trinitrate to establish a model of acute migraine attack and chronicity in mice, which was verified by photophobia experiments and von Frey experiments. We explored the A11 nucleus and its downstream pathway using immunohistochemical staining and neuronal tracing techniques. During acute migraine attack and chronification, c-fos expression in GABAergic neurons in the A11 nucleus was significantly increased, and inhibition of DA neurons was achieved by binding to GABA A-type receptors on the surface of dopaminergic neurons in the A11 nucleus. However, the expression of tyrosine hydroxylase and glutamic acid decarboxylase proteins in the A11 nucleus of the hypothalamus did not change significantly. Specific destruction of dopaminergic neurons in the A11 nucleus of mice resulted in severe nociceptive sensitization and photophobic behavior. The expression levels of the D1 dopamine receptor and D2 dopamine receptor in the caudal part of the spinal trigeminal nucleus candalis of the chronic migraine model were increased. Skin nociceptive sensitization of mice was slowed by activation of the D2 dopamine receptor in SP5C, and activation of the D1 dopamine receptor reversed this behavioral change. GABAergic neurons in the A11 nucleus were activated and exerted postsynaptic inhibitory effects, which led to a decrease in the amount of DA secreted by the A11 nucleus in the spinal trigeminal nucleus candalis. The reduced DA bound preferentially to the D2 dopamine receptor, thus exerting a defensive effect against headache.

Efficacy and safety of eptinezumab in patients with chronic migraine and medication-overuse headache: a randomized, double-blind, placebo-controlled study.

BACKGROUND: For some people with migraine, despite taking greater amounts of acute headache medication (AHM), they develop an increase in monthly headache days. This cycle of increasing headache days, and in turn AHM use, can lead to a secondary headache disorder called medication-overuse headache (MOH). Preventive medications can prevent migraine from occurring and reduce reliance on AHMs, thereby preventing the cycle of MOH. This study was performed to evaluate the efficacy and safety of eptinezumab to prevent migraine/headache in a mainly Asian patient population with a dual diagnosis of chronic migraine and MOH. METHODS: SUNLIGHT was a phase 3, multicenter, double-blind, parallel-group, placebo-controlled trial. Patients aged 18-75 years with ≥ 8 migraine days/month and a diagnosis of MOH were randomly allocated (1:1) to one of two treatment groups: eptinezumab 100 mg or placebo. Monthly migraine days (MMDs) were captured using a daily electronic diary; the change from baseline in the number of MMDs over Weeks 1-12 was the primary efficacy endpoint. RESULTS: Patients were randomized to eptinezumab 100 mg (n = 93) or placebo (n = 100). Over Weeks 1-12, eptinezumab reduced mean MMDs more than placebo (difference between treatments was -1.2; p = 0.1484). Differences between treatment groups with p-values below 0.05 favoring eptinezumab were observed in 3 out of the 6 key secondary endpoints. CONCLUSION: All endpoints numerically favored eptinezumab treatment when compared to placebo; however, this study did not meet its primary endpoint and is therefore negative. No new safety signals were identified in this study, like previous reports that confirmed the safety and tolerability of eptinezumab treatment. TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT04772742 (26/02/2021).

Annexin A1 exerts analgesic effect in a mouse model of medication overuse headache.

Medication overuse headache (MOH) is a serious global condition. The interaction between headache attacks and medication overuse complicates the understanding of its pathophysiology. In this study, we developed a preclinical MOH model that incorporates these two key factors by overusing rizatriptan benzoate (RIZ, 4 mg/kg, i.g.) in a glyceryl trinitrate (GTN, 10 mg/kg, i.p.) induced chronic migraine mouse model. We observed that RIZ overuse aggravated GTN-induced cutaneous allodynia and caused a prolonged state of latent sensitization. We also detected a significant upregulation of Annexin-A1 (ANXA1), a protein mainly expressed in the microglia of the spinal trigeminal nucleus caudalis (SPVC), in GTN+RIZ mice. Intracerebroventricular injection of ANXA1-derived peptide Ac2-26 trifluoroacetic acid (TFA) (5 µg/mouse) inhibited bright light stress (BLS) induced acute allodynia via the formyl peptide receptor (FPR) in GTN+RIZ mice. These results suggest that ANXA1 may have an analgesic effect in triptan-associated MOH and could potentially serve as a therapeutic target.