Global, regional, and national burden of disorders affecting the nervous system, 1990–2021: a systematic analysis for the Global Burden of Disease Study 2021

1990至2021影响神经系统疾病的全球、区域和国家负担: 全球疾病负担研究2021的系统分析

Disorders affecting the nervous system are diverse and include neurodevelopmental disorders, late-life neurodegeneration, and newly emergent conditions, such as cognitive impairment following COVID-19. Previous publications from the Global Burden of Disease, Injuries, and Risk Factor Study estimated the burden of 15 neurological conditions in 2015 and 2016, but these analyses did not include neurodevelopmental disorders, as defined by the International Classification of Diseases (ICD)-11, or a subset of cases of congenital, neonatal, and infectious conditions that cause neurological damage. Here, we estimate nervous system health loss caused by 37 unique conditions and their associated risk factors globally, regionally, and nationally from 1990 to 2021. As the leading cause of overall disease burden in the world, with increasing global DALY counts, effective prevention, treatment, and rehabilitation strategies for disorders affecting the nervous system are needed.

影响神经系统的疾病是多种多样的，包括神经发育障碍，晚年神经变性和新出现的疾病，例如新型冠状病毒肺炎后的认知障碍。全球疾病负担、损伤和危险因素研究的先前出版物估计了2015年和2016 15种神经系统疾病的负担，但这些分析不包括国际疾病分类 (ICD)-11定义的神经发育障碍，或先天性、新生儿、以及导致神经损伤的传染病。在这里，我们估计了1990年至2021年全球，区域和全国范围内由37种独特疾病及其相关风险因素引起的神经系统健康损失。作为全球总体疾病负担的主要原因，随着全球DALY计数的增加，需要针对影响神经系统的疾病的有效预防，治疗和康复策略。

REF: GBD 2021 Nervous System Disorders Collaborators. Global, regional, and national burden of disorders affecting the nervous system, 1990-2021: a systematic analysis for the Global Burden of Disease Study 2021 [published correction appears in Lancet Neurol. 2024 May;23(5):e9]. Lancet Neurol. 2024;23(4):344-381. doi:10.1016/S1474-4422(24)00038-3 PMID: 38493795 PMCID: PMC10949203

Safety and efficacy of atogepant for the preventive treatment of episodic migraine in adults for whom conventional oral preventive treatments have failed (ELEVATE): a randomised, placebo-controlled, phase 3b trial

atogepant在常规口服预防治疗失败的成人中预防性治疗阵发性偏头痛的安全性和有效性 (ELEVATE): 一项随机，安慰剂对照，3b期试验

Atogepant, an oral calcitonin gene-related peptide receptor antagonist, has been approved for the preventive treatment of migraine, but its efficacy and safety in people who have been failed by conventional oral preventive migraine treatments has not yet been evaluated in a dedicated clinical trial. The ELEVATE trial evaluated the safety, tolerability, and efficacy of atogepant for the preventive treatment of episodic migraine in participants for whom two to four classes of conventional oral preventive treatments have failed. Atogepant 60 mg once a day was safe, well tolerated, and showed significant and clinically relevant reductions in mean monthly migraine days compared with placebo across 12 weeks in patients with episodic migraine who had previously been failed by two to four classes of conventional oral preventive treatments. Atogepant might be an effective preventive treatment option for patients in this difficult-to-treat population.

Atogepant是一种口服降钙素基因相关肽受体拮抗剂，已被批准用于偏头痛的预防性治疗，但其在常规口服预防性偏头痛治疗失败的人群中的疗效和安全性尚未在专门的临床试验中进行评估。ELEVATE试验评估了atogepant在两到四类常规口服预防治疗失败的参与者中预防性治疗发作性偏头痛的安全性，耐受性和有效性。每天一次60 mg的Atogepant是安全的，耐受性良好，并且在12周内与安慰剂相比，平均每月偏头痛天数显着且临床相关的减少先前因两到四类常规口服预防治疗而失败的发作性偏头痛患者治疗。对于这种难以治疗的人群，Atogepant可能是一种有效的预防性治疗选择。

REF: Tassorelli C, Nagy K, Pozo-Rosich P, et al. Safety and efficacy of atogepant for the preventive treatment of episodic migraine in adults for whom conventional oral preventive treatments have failed (ELEVATE): a randomised, placebo-controlled, phase 3b trial. Lancet Neurol. 2024;23(4):382-392. doi:10.1016/S1474-4422(24)00025-5 PMID: 38364831

Safety and efficacy of givinostat in boys with Duchenne muscular dystrophy (EPIDYS): a multicentre, randomised, double-blind, placebo-controlled, phase 3 trial

givinostat对杜氏肌营养不良症 (EPIDYS) 男孩的安全性和有效性: 一项多中心，随机，双盲，安慰剂对照的3期试验

Duchenne muscular dystrophy, the most common childhood muscular dystrophy, is caused by dystrophin deficiency. Preclinical and phase 2 study data have suggested that givinostat, a histone deacetylase inhibitor, might help to counteract the effects of this deficiency. We aimed to evaluate the safety and efficacy of givinostat in the treatment of Duchenne muscular dystrophy. Among ambulant boys with Duchenne muscular dystrophy, results of the four-stair climb assessment worsened in both groups over the study period; however, the decline was significantly smaller with givinostat than with placebo. The dose of givinostat was reduced after an interim safety analysis, but no new safety signals were reported. An ongoing extension study is evaluating the long-term safety and efficacy of givinostat in patients with Duchenne muscular dystrophy.

杜氏肌营养不良症是最常见的儿童肌营养不良症，由肌营养不良蛋白缺乏引起。临床前研究和2期研究数据表明，组蛋白去乙酰化酶抑制剂givinostat可能有助于抵消这种缺陷的影响。我们旨在评估givinostat治疗杜氏肌营养不良症的安全性和有效性。在患有Duchenne肌营养不良症的走动男孩中，在研究期间，两组的四层楼梯攀爬评估结果均恶化; 然而，吉维司他的下降幅度明显小于安慰剂。givinostat的剂量在中期安全性分析后减少，但未报告新的安全性信号。一项正在进行的扩展研究正在评估givinostat在杜氏肌营养不良症患者中的长期安全性和有效性。

REF: Mercuri E, Vilchez JJ, Boespflug-Tanguy O, et al. Safety and efficacy of givinostat in boys with Duchenne muscular dystrophy (EPIDYS): a multicentre, randomised, double-blind, placebo-controlled, phase 3 trial [published correction appears in Lancet Neurol. 2024 Apr 18;:]. Lancet Neurol. 2024;23(4):393-403. doi:10.1016/S1474-4422(24)00036-X PMID: 38508835

Secondary stroke prevention in people with atrial fibrillation: treatments and trials

心房颤动患者的二级卒中预防: 治疗和试验

Atrial fibrillation is one of the most common cardiac arrhythmias and is a major cause of ischaemic stroke. Recent findings indicate the importance of atrial fibrillation burden (device-detected, subclinical, or paroxysmal and persistent or permanent) and whether atrial fibrillation was known before stroke onset or diagnosed after stroke for the risk of recurrence. Secondary prevention in patients with atrial fibrillation and stroke aims to reduce the risk of recurrent ischaemic stroke. Findings from randomised controlled trials assessing the optimal timing to introduce direct oral anticoagulant therapy after a stroke show that early start (ie, within 48 h for minor to moderate strokes and within 4-5 days for large strokes) seems safe and could reduce the risk of early recurrence. Other promising developments regarding early rhythm control, left atrial appendage occlusion, and novel factor XI inhibitor oral anticoagulants suggest that these therapies have the potential to further reduce the risk of stroke. Secondary prevention strategies in patients with atrial fibrillation who have a stroke despite oral anticoagulation therapy is an unmet medical need. Research advances suggest a heterogeneous spectrum of causes, and ongoing trials are investigating new approaches for secondary prevention in this vulnerable patient group. In patients with atrial fibrillation and a history of intracerebral haemorrhage, the latest data from randomised controlled trials on stroke prevention shows that oral anticoagulation reduces the risk of ischaemic stroke but more data are needed to define the safety profile.

心房颤动是最常见的心律失常之一，是缺血性中风的主要原因。最近的研究结果表明心房颤动负担 (装置检测，亚临床或阵发性和持续性或永久性) 的重要性，以及是否在卒中发作前或卒中后诊断出心房颤动对复发风险的重要性。房颤和卒中患者的二级预防旨在降低缺血性卒中复发的风险。评估中风后引入直接口服抗凝治疗的最佳时机的随机对照试验的结果表明，早期开始 (即，轻度至中度中风在48小时内，大中风在4-5天内) 似乎是安全的，可以降低早期复发的风险。关于早期节律控制、左心耳封堵和新型凝血因子XI抑制剂口服抗凝剂的其他有希望的进展表明，这些疗法有可能进一步降低中风风险。尽管口服抗凝治疗但仍有卒中的房颤患者的二级预防策略是未满足的医疗需求。研究进展表明，病因是多种多样的，正在进行的试验正在研究在这一脆弱患者群体中进行二级预防的新方法。在房颤和脑出血病史的患者中，来自卒中预防的随机对照试验的最新数据显示，口服抗凝药可降低缺血性卒中的风险，但需要更多的数据来确定安全性。

REF: Seiffge DJ, Cancelloni V, Räber L, et al. Secondary stroke prevention in people with atrial fibrillation: treatments and trials. Lancet Neurol. 2024;23(4):404-417. doi:10.1016/S1474-4422(24)00037-1 PMID: 38508836

Dysphagia after stroke: research advances in treatment interventions

脑卒中后吞咽障碍的治疗干预研究进展

After a stroke, most patients have dysphagia, which can lead to aspiration pneumonia, malnutrition, and adverse functional outcomes. Protective interventions aimed at reducing these complications remain the cornerstone of treatment. Dietary adjustments and oral hygiene help mitigate the risk of aspiration pneumonia, and nutritional supplementation, including tube feeding, might be needed to prevent malnutrition. Rehabilitative interventions aim to enhance swallowing function, with different behavioural strategies showing promise in small studies. Investigations have explored the use of pharmaceutical agents such as capsaicin and other Transient-Receptor-Potential-Vanilloid-1 (TRPV-1) sensory receptor agonists, which alter sensory perception in the pharynx. Neurostimulation techniques, such as transcranial direct current stimulation, repetitive transcranial magnetic stimulation, and pharyngeal electrical stimulation, might promote neuroplasticity within the sensorimotor swallowing network. Further advancements in the understanding of central and peripheral sensorimotor mechanisms in patients with dysphagia after a stroke, and during their recovery, will contribute to optimising treatment protocols.

中风后，大多数患者有吞咽困难，这可能导致误吸肺炎，营养不良和不良功能结局。旨在减少这些并发症的保护性干预仍然是治疗的基石。饮食调整和口腔卫生有助于降低误吸肺炎的风险，可能需要营养补充，包括管饲，以预防营养不良。康复干预旨在增强吞咽功能，不同的行为策略在小型研究中显示出希望。研究探索了诸如辣椒素和其他Transient-Receptor-Potential-Vanilloid-1 (TRPV-1) 感觉受体激动剂之类的药物的使用，这些药物会改变咽部的感觉。神经刺激技术，例如经颅直流电刺激，重复经颅磁刺激和咽部电刺激，可能会促进感觉运动吞咽网络内的神经可塑性。中风后吞咽困难患者及其康复过程中，对中枢和外周感觉运动机制的进一步了解将有助于优化治疗方案。

REF: Labeit B, Michou E, Trapl-Grundschober M, et al. Dysphagia after stroke: research advances in treatment interventions. Lancet Neurol. 2024;23(4):418-428. doi:10.1016/S1474-4422(24)00053-X PMID: 38508837

Genetics of migraine: complexity, implications, and potential clinical applications

偏头痛的遗传学: 复杂性、影响和潜在的临床应用

Migraine is a common neurological disorder with large burden in terms of disability for individuals and costs for society. Accurate diagnosis and effective treatments remain priorities. Understanding the genetic factors that contribute to migraine risk and symptom manifestation could improve individual management. Migraine has a strong genetic basis that includes both monogenic and polygenic forms. Some distinct, rare, familial migraine subtypes are caused by pathogenic variants in genes involved in ion transport and neurotransmitter release, suggesting an underlying vulnerability of the excitatory-inhibitory balance in the brain, which might be exacerbated by disruption of homoeostasis and lead to migraine. For more prevalent migraine subtypes, genetic studies have identified many susceptibility loci, implicating genes involved in both neuronal and vascular pathways. Genetic factors can also reveal the nature of relationships between migraine and its associated biomarkers and comorbidities and could potentially be used to identify new therapeutic targets and predict treatment response.

偏头痛是一种常见的神经系统疾病，在个人残疾和社会成本方面负担沉重。准确的诊断和有效的治疗仍然是优先事项。了解导致偏头痛风险和症状表现的遗传因素可以改善个体管理。偏头痛具有强大的遗传基础，包括单基因和多基因形式。一些独特的，罕见的家族性偏头痛亚型是由参与离子转运和神经递质释放的基因的致病性变异引起的，这表明大脑中兴奋性-抑制性平衡的潜在脆弱性，这可能因稳态的破坏而加剧并导致偏头痛。对于更普遍的偏头痛亚型，遗传研究已经确定了许多易感性基因座，涉及神经元和血管途径的基因。遗传因素还可以揭示偏头痛及其相关生物标志物和合并症之间关系的性质，并有可能用于识别新的治疗靶点和预测治疗反应。

REF: Sutherland HG, Jenkins B, Griffiths LR. Genetics of migraine: complexity, implications, and potential clinical applications. Lancet Neurol. 2024;23(4):429-446. doi:10.1016/S1474-4422(24)00026-7 PMID: 38508838

The expanding burden of neurological disorders

不断扩大的神经系统疾病负担

New estimates of the global, regional, and national burden of disorders affecting the nervous system are reported in an updated analysis from the Global Burden of Diseases, Injuries, and Risk Factors Study (GBD) 2021. 1 In their Article in The Lancet Neurology, the GBD 2021 Nervous System Disorders Collaborators report mortality, prevalence, years lived with disability (YLDs), years of life lost (YLLs), and disability-adjusted life-years (DALYs) attributable to diseases and conditions that cause dysfunction of the nervous system. The new report builds upon previous GBD analyses, 2 which have established global standards for the estimation of the burden of diseases, by including data up to 2021 and by expanding the number of studied conditions substantially, from 15 to 37.

全球疾病，伤害和危险因素负担研究 (GBD) 2021的最新分析报告了影响神经系统的全球，区域和国家疾病负担的新估计。1在《柳叶刀神经病学》上的文章中，GBD 2021神经系统疾病合作者报告了死亡率，患病率，残疾寿命 (YLDs)，丧失寿命 (YLLs) 和可归因于导致神经系统功能障碍的疾病和状况的残疾调整寿命年 (DALYs)。新报告以先前的GBD分析2为基础，通过纳入截至2021年的数据，并将研究条件的数量从15个大幅增加到37个，建立了估计疾病负担的全球标准。

REF: Grisold W. The expanding burden of neurological disorders. Lancet Neurol. 2024;23(4):326-327. doi:10.1016/S1474-4422(24)00086-3 PMID: 38493794

Addressing neurological burden in the Americas

解决美洲的神经系统负担

Expanding on previous analyses of the Global Burden of Diseases, Injuries, and Risk Factors Study (GBD), the GBD 2021 Nervous System Disorders Collaborators present one of the most comprehensive estimates of neurological burden available to date. Their study, published in The Lancet Neurology, 1 follows the historic adoption by the 75th World Health Assembly of the Intersectoral Global Action Plan on Epilepsy and Other Neurological Disorders 2022–2031 (IGAP), which aims “to improve access to care and treatment for people living with neurological disorders, while preventing new cases and promoting brain health and development across the life course”. 2 The Article by the GBD 2021 Nervous System Disorders Collaborators reinforces the importance and timeliness of the IGAP as a global framework through which to urgently address the burden of neurological disorders. Furthermore, the authors provide a valuable opportunity for reflection and analysis on the issue at the regional level.

在对全球疾病，伤害和危险因素研究 (GBD) 的先前分析的基础上，GBD 2021神经系统疾病合作者提出了迄今为止最全面的神经系统负担估计之一。他们的研究发表在《柳叶刀神经病学》上，1继第75届世界卫生大会历史性地通过了《2022-2031癫痫和其他神经系统疾病部门间全球行动计划》 (IGAP) 之后，该计划旨在 “改善神经系统疾病患者获得护理和治疗的机会，同时预防新病例并在整个生命过程中促进大脑健康和发育。GBD 2021神经系统疾病合作者的文章强调了IGAP作为紧急解决神经系统疾病负担的全球框架的重要性和及时性。此外，作者为在区域一级思考和分析这一问题提供了宝贵的机会。

REF: Tausch A, Thakur KT, Oliveira E Souza R. Addressing neurological burden in the Americas. Lancet Neurol. 2024;23(4):327-328. doi:10.1016/S1474-4422(24)00085-1 PMID: 38493796

ELEVATEd hope for patients after migraine treatment failure

偏头痛治疗失败后患者的希望提高

The emergence of calcitonin gene-related peptide (CGRP)-related medications has heralded a new era in migraine treatment. Numerous randomised controlled trials and real-world studies attest to the efficacy of anti-CGRP monoclonal antibodies and small-molecule CGRP receptor antagonists (gepants) in migraine preventive treatment, while gepants are also efficacious in acute treatment.

降钙素基因相关肽 (CGRP) 相关药物的出现预示着偏头痛治疗的新纪元。许多随机对照试验和现实世界研究证明了抗CGRP单克隆抗体和小分子CGRP受体拮抗剂 (gepants) 在偏头痛预防性治疗中的功效，而gepants在急性治疗中也有效。

REF: Xu X, Dong L, Zhou J. ELEVATEd hope for patients after migraine treatment failure. Lancet Neurol. 2024;23(4):328-330. doi:10.1016/S1474-4422(24)00072-3 PMID: 38364830