Pub Date : 2024-08-19DOI: 10.1038/s41582-024-01002-5
Patricia Pozo-Rosich, Alicia Alpuente, Stephen D. Silberstein, Rami Burstein
OnabotulinumtoxinA (BTX-A) was first linked to beneficial effects in migraine 25 years ago and was approved by the FDA for preventive treatment of chronic migraine in 2010. The treatment has since had a major impact on the well-being of people with chronic migraine. The clinical development programme for BTX-A and research since its approval have provided insights into the neuromodulatory sensory effect of BTX-A, how it can control chronic migraine despite its peripheral action, and the underlying biology of migraine as a disease. In this Review, we consider the impact that BTX-A has had on the management of chronic migraine and on the research field. We discuss the insights provided by clinical research, encompassing the clinical trials and subsequent real-world evidence, and the mechanistic insights provided by preclinical and translational research. We also provide an overview of future directions of research in the field BTX-A in migraine and the clinical translation of this research. OnabotulinumtoxinA was first linked to beneficial effects in migraine 25 years ago and has since become a widely used treatment for chronic migraine. In this Review, Pozo-Rosich and colleagues consider the impact that onabotulinumtoxinA has had on the management of chronic migraine and on the research field.
{"title":"Insights from 25 years of onabotulinumtoxinA in migraine — mechanisms and management","authors":"Patricia Pozo-Rosich, Alicia Alpuente, Stephen D. Silberstein, Rami Burstein","doi":"10.1038/s41582-024-01002-5","DOIUrl":"10.1038/s41582-024-01002-5","url":null,"abstract":"OnabotulinumtoxinA (BTX-A) was first linked to beneficial effects in migraine 25 years ago and was approved by the FDA for preventive treatment of chronic migraine in 2010. The treatment has since had a major impact on the well-being of people with chronic migraine. The clinical development programme for BTX-A and research since its approval have provided insights into the neuromodulatory sensory effect of BTX-A, how it can control chronic migraine despite its peripheral action, and the underlying biology of migraine as a disease. In this Review, we consider the impact that BTX-A has had on the management of chronic migraine and on the research field. We discuss the insights provided by clinical research, encompassing the clinical trials and subsequent real-world evidence, and the mechanistic insights provided by preclinical and translational research. We also provide an overview of future directions of research in the field BTX-A in migraine and the clinical translation of this research. OnabotulinumtoxinA was first linked to beneficial effects in migraine 25 years ago and has since become a widely used treatment for chronic migraine. In this Review, Pozo-Rosich and colleagues consider the impact that onabotulinumtoxinA has had on the management of chronic migraine and on the research field.","PeriodicalId":19085,"journal":{"name":"Nature Reviews Neurology","volume":"20 9","pages":"555-568"},"PeriodicalIF":28.2,"publicationDate":"2024-08-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142002760","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-08-12DOI: 10.1038/s41582-024-01013-2
Ian Fyfe
Antisense oligonucleotide treatment has therapeutic potential in a severe form of Charcot–Marie–Tooth disease, according to a new study.
一项新的研究表明，反义寡核苷酸疗法对一种严重的夏科-玛丽-牙病具有治疗潜力。
{"title":"Antisense oligonucleotide shows potential in Charcot–Marie–Tooth disease","authors":"Ian Fyfe","doi":"10.1038/s41582-024-01013-2","DOIUrl":"10.1038/s41582-024-01013-2","url":null,"abstract":"Antisense oligonucleotide treatment has therapeutic potential in a severe form of Charcot–Marie–Tooth disease, according to a new study.","PeriodicalId":19085,"journal":{"name":"Nature Reviews Neurology","volume":"20 9","pages":"505-505"},"PeriodicalIF":28.2,"publicationDate":"2024-08-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141918749","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-08-09DOI: 10.1038/s41582-024-01001-6
Meabh O’Hare, Amanda C. Guidon
Immune checkpoint inhibitors have revolutionized cancer therapy and are increasingly used to treat a wide range of oncological conditions, with dramatic benefits for many patients. Unfortunately, the resulting increase in T cell effector function often results in immune-related adverse events (irAEs), which can involve any organ system, including the central nervous system (CNS) and peripheral nervous system (PNS). Neurological irAEs involve the PNS in two-thirds of affected patients. Muscle involvement (immune-related myopathy) is the most common PNS irAE and can be associated with neuromuscular junction involvement. Immune-related peripheral neuropathy most commonly takes the form of polyradiculoneuropathy or cranial neuropathies. Immune-related myopathy (with or without neuromuscular junction involvement) often occurs along with immune-related myocarditis, and this overlap syndrome is associated with substantially increased mortality. This Review focuses on PNS adverse events associated with immune checkpoint inhibition. Underlying pathophysiological mechanisms are discussed, including antigen homology between self and tumour, epitope spreading and activation of pre-existing autoreactive T cells. An overview of current approaches to clinical management is provided, including cytokine-directed therapies that aim to decouple anticancer immunity from autoimmunity and emerging treatments for patients with severe (life-threatening) presentations. Some patients who are treated with checkpoint inhibitors experience peripheral nervous system (PNS) immune-related adverse events (irAEs). O’Hare and Guidon describe the spectrum of PNS irAE phenotypes, discuss their underlying mechanisms and outline a consensus-based, pathophysiology-driven approach to their clinical management.
免疫检查点抑制剂彻底改变了癌症疗法，越来越多地用于治疗各种肿瘤疾病，给许多患者带来了巨大的益处。不幸的是，T细胞效应器功能的增强往往会导致免疫相关不良事件（irAEs），这些不良事件可能涉及任何器官系统，包括中枢神经系统（CNS）和外周神经系统（PNS）。三分之二的受影响患者的神经系统不良事件涉及 PNS。肌肉受累（免疫相关肌病）是最常见的 PNS irAE，可能与神经肌肉接头受累有关。免疫相关周围神经病变最常见的形式是多发性神经元病变或颅内神经病变。免疫相关性肌病（伴有或不伴有神经肌肉接头受累）通常与免疫相关性心肌炎同时发生，这种重叠综合征与死亡率大幅上升有关。本综述侧重于与免疫检查点抑制相关的 PNS 不良事件。其中讨论了潜在的病理生理学机制，包括自身与肿瘤之间的抗原同源性、表位扩散和原有自反应 T 细胞的激活。综述了目前的临床治疗方法，包括旨在使抗癌免疫与自身免疫脱钩的细胞因子导向疗法，以及针对重症（危及生命）患者的新兴疗法。
{"title":"Peripheral nervous system immune-related adverse events due to checkpoint inhibition","authors":"Meabh O’Hare, Amanda C. Guidon","doi":"10.1038/s41582-024-01001-6","DOIUrl":"10.1038/s41582-024-01001-6","url":null,"abstract":"Immune checkpoint inhibitors have revolutionized cancer therapy and are increasingly used to treat a wide range of oncological conditions, with dramatic benefits for many patients. Unfortunately, the resulting increase in T cell effector function often results in immune-related adverse events (irAEs), which can involve any organ system, including the central nervous system (CNS) and peripheral nervous system (PNS). Neurological irAEs involve the PNS in two-thirds of affected patients. Muscle involvement (immune-related myopathy) is the most common PNS irAE and can be associated with neuromuscular junction involvement. Immune-related peripheral neuropathy most commonly takes the form of polyradiculoneuropathy or cranial neuropathies. Immune-related myopathy (with or without neuromuscular junction involvement) often occurs along with immune-related myocarditis, and this overlap syndrome is associated with substantially increased mortality. This Review focuses on PNS adverse events associated with immune checkpoint inhibition. Underlying pathophysiological mechanisms are discussed, including antigen homology between self and tumour, epitope spreading and activation of pre-existing autoreactive T cells. An overview of current approaches to clinical management is provided, including cytokine-directed therapies that aim to decouple anticancer immunity from autoimmunity and emerging treatments for patients with severe (life-threatening) presentations. Some patients who are treated with checkpoint inhibitors experience peripheral nervous system (PNS) immune-related adverse events (irAEs). O’Hare and Guidon describe the spectrum of PNS irAE phenotypes, discuss their underlying mechanisms and outline a consensus-based, pathophysiology-driven approach to their clinical management.","PeriodicalId":19085,"journal":{"name":"Nature Reviews Neurology","volume":"20 9","pages":"509-525"},"PeriodicalIF":28.2,"publicationDate":"2024-08-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141909111","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-08-08DOI: 10.1038/s41582-024-01004-3
Nicolas Villain, Vincent Planche
In recent years, we have seen a shift towards defining sporadic neurodegenerative diseases as a biological continuum. Here, we discuss the risks associated with this shift, emphasize the importance of maintaining a strong connection between disease definitions and subsequent clinical outcomes, and suggest clinicobiological frameworks to disentangle multiple discrete nosological entities.
{"title":"Disentangling clinical and biological trajectories of neurodegenerative diseases","authors":"Nicolas Villain, Vincent Planche","doi":"10.1038/s41582-024-01004-3","DOIUrl":"https://doi.org/10.1038/s41582-024-01004-3","url":null,"abstract":"In recent years, we have seen a shift towards defining sporadic neurodegenerative diseases as a biological continuum. Here, we discuss the risks associated with this shift, emphasize the importance of maintaining a strong connection between disease definitions and subsequent clinical outcomes, and suggest clinicobiological frameworks to disentangle multiple discrete nosological entities.","PeriodicalId":19085,"journal":{"name":"Nature Reviews Neurology","volume":"51 1","pages":""},"PeriodicalIF":38.1,"publicationDate":"2024-08-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141904615","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-08-07DOI: 10.1038/s41582-024-01000-7
Lahiru Handunnetthi, Maheshi N. Ramasamy, Lance Turtle, David P. J. Hunt
Vaccines protect against many infectious diseases, including some that can directly or indirectly cause nervous system damage. Serious neurological consequences of immunization are typically extremely rare, although they have the potential to jeopardize vaccination programmes, as demonstrated most recently during the COVID-19 pandemic. Neurologists have an important role in identifying safety signals at population and individual patient levels, as well as providing advice on the benefit–risk profile of vaccination in cohorts of patients with diverse neurological conditions. This article reviews the links between vaccination and neurological disease and considers how emerging signals can be evaluated and their mechanistic basis identified. We review examples of neurotropic infections with live attenuated vaccines, as well as neuroimmunological and neurovascular sequelae of other types of vaccines. We emphasize that such risks are typically dwarfed by neurological complications associated with natural infection and discuss how the risks can be further mitigated. The COVID-19 pandemic has highlighted the need to rapidly identify and minimize neurological risks of vaccination, and we review the structures that need to be developed to protect public health against these risks in the future. Vaccination has transformed the global fight against infectious diseases and has a highly favourable benefit–risk profile in most people, although adverse events, including neurological complications, can occasionally occur. This article reviews the links between vaccination and neurological disease and considers the role of neurologists in identifying safety signals and managing risk.
{"title":"Identifying and reducing risks of neurological complications associated with vaccination","authors":"Lahiru Handunnetthi, Maheshi N. Ramasamy, Lance Turtle, David P. J. Hunt","doi":"10.1038/s41582-024-01000-7","DOIUrl":"10.1038/s41582-024-01000-7","url":null,"abstract":"Vaccines protect against many infectious diseases, including some that can directly or indirectly cause nervous system damage. Serious neurological consequences of immunization are typically extremely rare, although they have the potential to jeopardize vaccination programmes, as demonstrated most recently during the COVID-19 pandemic. Neurologists have an important role in identifying safety signals at population and individual patient levels, as well as providing advice on the benefit–risk profile of vaccination in cohorts of patients with diverse neurological conditions. This article reviews the links between vaccination and neurological disease and considers how emerging signals can be evaluated and their mechanistic basis identified. We review examples of neurotropic infections with live attenuated vaccines, as well as neuroimmunological and neurovascular sequelae of other types of vaccines. We emphasize that such risks are typically dwarfed by neurological complications associated with natural infection and discuss how the risks can be further mitigated. The COVID-19 pandemic has highlighted the need to rapidly identify and minimize neurological risks of vaccination, and we review the structures that need to be developed to protect public health against these risks in the future. Vaccination has transformed the global fight against infectious diseases and has a highly favourable benefit–risk profile in most people, although adverse events, including neurological complications, can occasionally occur. This article reviews the links between vaccination and neurological disease and considers the role of neurologists in identifying safety signals and managing risk.","PeriodicalId":19085,"journal":{"name":"Nature Reviews Neurology","volume":"20 9","pages":"541-554"},"PeriodicalIF":28.2,"publicationDate":"2024-08-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141902471","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-08-06DOI: 10.1038/s41582-024-00999-z
Ellen Hertz, Yu Chen, Ellen Sidransky
An exciting development in the field of neurodegeneration is the association between the rare monogenic disorder Gaucher disease and the common complex disorder Parkinson disease (PD). Gaucher disease is a lysosomal storage disorder resulting from an inherited deficiency of the enzyme glucocerebrosidase, encoded by GBA1, which hydrolyses the glycosphingolipids glucosylceramide and glucosylsphingosine. The observation of parkinsonism in a rare subgroup of individuals with Gaucher disease first directed attention to the role of glucocerebrosidase deficiency in the pathogenesis of PD. PD occurs more frequently in people heterozygous for Gaucher GBA1 mutations, and 3–25% of people with Parkinson disease carry a GBA1 variant. However, only a small percentage of individuals with GBA1 variants develop parkinsonism, suggesting that the penetrance is low. Despite over a decade of intense research in this field, including clinical and radiological evaluations, genetic studies and investigations using model systems, the mechanism underlying GBA1-PD is still being pursued. Insights from this association have emphasized the role of lysosomal pathways in parkinsonism. Furthermore, different therapeutic strategies considered or developed for Gaucher disease can now inform drug development for PD. The association between the rare, monogenic lysosomal storage disorder Gaucher disease and Parkinson disease has provided insights into the pathogenesis of this far more common neurodegenerative disease. Here, Sidransky and colleagues review the knowledge gained from decades of Gaucher disease research and explore the relationship between GBA1 and parkinsonism.
{"title":"Gaucher disease provides a unique window into Parkinson disease pathogenesis","authors":"Ellen Hertz, Yu Chen, Ellen Sidransky","doi":"10.1038/s41582-024-00999-z","DOIUrl":"10.1038/s41582-024-00999-z","url":null,"abstract":"An exciting development in the field of neurodegeneration is the association between the rare monogenic disorder Gaucher disease and the common complex disorder Parkinson disease (PD). Gaucher disease is a lysosomal storage disorder resulting from an inherited deficiency of the enzyme glucocerebrosidase, encoded by GBA1, which hydrolyses the glycosphingolipids glucosylceramide and glucosylsphingosine. The observation of parkinsonism in a rare subgroup of individuals with Gaucher disease first directed attention to the role of glucocerebrosidase deficiency in the pathogenesis of PD. PD occurs more frequently in people heterozygous for Gaucher GBA1 mutations, and 3–25% of people with Parkinson disease carry a GBA1 variant. However, only a small percentage of individuals with GBA1 variants develop parkinsonism, suggesting that the penetrance is low. Despite over a decade of intense research in this field, including clinical and radiological evaluations, genetic studies and investigations using model systems, the mechanism underlying GBA1-PD is still being pursued. Insights from this association have emphasized the role of lysosomal pathways in parkinsonism. Furthermore, different therapeutic strategies considered or developed for Gaucher disease can now inform drug development for PD. The association between the rare, monogenic lysosomal storage disorder Gaucher disease and Parkinson disease has provided insights into the pathogenesis of this far more common neurodegenerative disease. Here, Sidransky and colleagues review the knowledge gained from decades of Gaucher disease research and explore the relationship between GBA1 and parkinsonism.","PeriodicalId":19085,"journal":{"name":"Nature Reviews Neurology","volume":"20 9","pages":"526-540"},"PeriodicalIF":28.2,"publicationDate":"2024-08-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141897891","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
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