Pub Date : 2024-11-01DOI: 10.1016/j.neurol.2024.07.002
The past two decades have seen a considerable paradigm shift in the way autoimmune CNS disorders are considered, diagnosed, and treated; largely due to the discovery of novel autoantibodies directed at neuroglial surface or intracellular targets. This approach has enabled multiple bona fide CNS autoantibody-associated diseases to thoroughly infiltrate the sphere of clinical neurology, facilitating advances in patient outcomes. This review focusses on the fundamental immunological concepts behind CNS autoantibody-associated diseases. First, we briefly review the broad phenotypic profiles of these conditions. Next, we explore concepts around immune checkpoints and the related B cell lineage. Thirdly, the sources of autoantibody production are discussed alongside triggers of tolerance failure, including neoplasms, infections and iatrogenic therapies. Penultimately, the role of T cells and leucocyte trafficking into the CNS are reviewed. Finally, biological insights from responses to targeted immunotherapies in different CNS autoantibody-associated diseases are summarised. The continued and rapid expansion of the CNS autoantibody-associated field holds promise for further improved diagnostic and therapeutic paradigms, ultimately leading to further improvements in patient outcomes.
在过去二十年中，自身免疫性中枢神经系统疾病的考虑、诊断和治疗方式发生了巨大的范式转变，这主要归功于针对神经胶质细胞表面或细胞内靶点的新型自身抗体的发现。这种方法使多种真正的中枢神经系统自身抗体相关疾病彻底渗入临床神经病学领域，促进了患者治疗效果的改善。本综述重点探讨中枢神经系统自身抗体相关疾病背后的基本免疫学概念。首先，我们简要回顾了这些疾病的广泛表型特征。其次，我们探讨了免疫检查点和相关 B 细胞系的概念。第三，讨论自身抗体产生的来源以及耐受失败的诱因，包括肿瘤、感染和先天性疗法。最后，回顾了 T 细胞的作用和白细胞向中枢神经系统的迁移。最后，总结了不同中枢神经系统自身抗体相关疾病对靶向免疫疗法反应的生物学启示。中枢神经系统自身抗体相关领域的持续快速发展为进一步改进诊断和治疗范例带来了希望，最终将进一步改善患者的预后。
{"title":"The immunology underlying CNS autoantibody diseases","authors":"","doi":"10.1016/j.neurol.2024.07.002","DOIUrl":"10.1016/j.neurol.2024.07.002","url":null,"abstract":"<div><div>The past two decades have seen a considerable paradigm shift in the way autoimmune CNS disorders are considered, diagnosed, and treated; largely due to the discovery of novel autoantibodies directed at neuroglial surface or intracellular targets. This approach has enabled multiple <em>bona fide</em> CNS autoantibody-associated diseases to thoroughly infiltrate the sphere of clinical neurology, facilitating advances in patient outcomes. This review focusses on the fundamental immunological concepts behind CNS autoantibody-associated diseases. First, we briefly review the broad phenotypic profiles of these conditions. Next, we explore concepts around immune checkpoints and the related B cell lineage. Thirdly, the sources of autoantibody production are discussed alongside triggers of tolerance failure, including neoplasms, infections and iatrogenic therapies. Penultimately, the role of T cells and leucocyte trafficking into the CNS are reviewed. Finally, biological insights from responses to targeted immunotherapies in different CNS autoantibody-associated diseases are summarised. The continued and rapid expansion of the CNS autoantibody-associated field holds promise for further improved diagnostic and therapeutic paradigms, ultimately leading to further improvements in patient outcomes.</div></div>","PeriodicalId":21321,"journal":{"name":"Revue neurologique","volume":null,"pages":null},"PeriodicalIF":2.8,"publicationDate":"2024-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142256856","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-11-01DOI: 10.1016/j.neurol.2024.08.003
The concept that many neurologic and psychiatric disorders of unknown cause are immune-mediated has evolved fast during the past 20 years. The main contribution to the expansion of this field has been the discovery of antibodies that attack neuronal or glial cell-surface proteins or receptors, directly modifying their structure and function. These antibodies facilitate the diagnosis and prompt treatment of patients who often improve with immunotherapy. The identification of this group of diseases, collectively named “autoimmune encephalitides”, was preceded by many years of investigations on other autoimmune CNS disorders in which the antibodies are against intracellular proteins, occur more frequently with cancer, and associate with cytotoxic T-cell responses that are less responsive to immunotherapy. Here, we first trace the recent history of the autoimmune encephalitides and address how to assess the clinical value and implement in our practice the rapid pace of autoantibody discovery. In addition, we review recent developments in the post-acute stage of the two main autoimmune encephalitides (NMDAR and LGI1) focusing on symptoms that are frequently overlooked or missed, and therefore undertreated. Because a better understanding of the pathophysiology of these diseases relies on animal models, we examine currently available studies, recognizing the existing needs for better and all-inclusive neuro-immunobiological models. Finally, we assess the status of biomarkers of disease outcome, clinical scales, current treatment strategies, and emerging therapies including CAR T-cell technology. Altogether, this overview is intended to identify gaps of knowledge and provide suggestions for improvement and insights for future research.
在过去的 20 年中，许多原因不明的神经和精神疾病都是由免疫介导的这一概念得到了快速发展。这一领域的发展主要得益于抗体的发现，这些抗体可以攻击神经元或神经胶质细胞表面蛋白或受体，直接改变它们的结构和功能。这些抗体为诊断和及时治疗患者提供了便利，这些患者往往在接受免疫疗法后病情有所好转。在发现这一类疾病（统称为 "自身免疫性脑炎"）之前，我们已对其他自身免疫性中枢神经系统疾病进行了多年研究，这些疾病的抗体针对细胞内蛋白，更常与癌症同时发生，并与对免疫疗法反应较弱的细胞毒性T细胞反应相关联。在此，我们首先回顾了自身免疫性脑病的近代史，并探讨了如何评估自身抗体的临床价值，以及如何在实践中快速应用自身抗体的发现。此外，我们还回顾了两种主要自身免疫性脑炎（NMDAR 和 LGI1）急性期后阶段的最新进展，重点关注那些经常被忽视或遗漏、因而治疗不足的症状。由于更好地了解这些疾病的病理生理学有赖于动物模型，我们审视了现有的研究，认识到目前需要更好的、包罗万象的神经免疫生物学模型。最后，我们评估了疾病结局生物标志物、临床量表、当前治疗策略以及包括 CAR T 细胞技术在内的新兴疗法的现状。总之，本综述旨在找出知识差距，为未来研究提供改进建议和见解。
{"title":"Predicting the future of autoimmune encephalitides","authors":"","doi":"10.1016/j.neurol.2024.08.003","DOIUrl":"10.1016/j.neurol.2024.08.003","url":null,"abstract":"<div><div>The concept that many neurologic and psychiatric disorders of unknown cause are immune-mediated has evolved fast during the past 20 years. The main contribution to the expansion of this field has been the discovery of antibodies that attack neuronal or glial cell-surface proteins or receptors, directly modifying their structure and function. These antibodies facilitate the diagnosis and prompt treatment of patients who often improve with immunotherapy. The identification of this group of diseases, collectively named “autoimmune encephalitides”, was preceded by many years of investigations on other autoimmune CNS disorders in which the antibodies are against intracellular proteins, occur more frequently with cancer, and associate with cytotoxic T-cell responses that are less responsive to immunotherapy. Here, we first trace the recent history of the autoimmune encephalitides and address how to assess the clinical value and implement in our practice the rapid pace of autoantibody discovery. In addition, we review recent developments in the post-acute stage of the two main autoimmune encephalitides (NMDAR and LGI1) focusing on symptoms that are frequently overlooked or missed, and therefore undertreated. Because a better understanding of the pathophysiology of these diseases relies on animal models, we examine currently available studies, recognizing the existing needs for better and all-inclusive neuro-immunobiological models. Finally, we assess the status of biomarkers of disease outcome, clinical scales, current treatment strategies, and emerging therapies including CAR T-cell technology. Altogether, this overview is intended to identify gaps of knowledge and provide suggestions for improvement and insights for future research.</div></div>","PeriodicalId":21321,"journal":{"name":"Revue neurologique","volume":null,"pages":null},"PeriodicalIF":2.8,"publicationDate":"2024-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142294305","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-11-01DOI: 10.1016/j.neurol.2024.08.007
Immune checkpoint inhibitors lead to effective antitumour responses but also to immune-related adverse events (irAEs), which affect the nervous system in 1–5% of patients. Encephalitis is the most frequent central nervous system irAE and is clinically relevant due to its high severity and mortality. Early diagnosis is crucial but is hampered by the broad list of alternative diagnoses, the lack of established diagnostic criteria, and the need of extensive diagnostic procedures (e.g., spinal tap, brain MRI) alongside expert neurological evaluation. Additionally, the response to corticosteroids is inconsistent, and the management of corticosteroid-refractory patients remains poorly defined. This mini-review discusses the role of various soluble biomarkers in the diagnosis, prognostication, and management of ICI-encephalitis. Neural antibodies, which are well-established biomarkers of autoimmune and paraneoplastic encephalitis, are found in only a subset of ICI-encephalitis, in which they can aid to establish the diagnosis. The most prevalent are paraneoplastic neurological syndromes (PNS)-associated antibodies, which are found almost exclusively in focal ICI-encephalitis syndromes and are associated with poor outcomes, possibly due to predominantly cytotoxic T cell involvement leading to irreversible neuronal loss. Beside antibodies, serum brain injury biomarkers such as NfL and S100B are elevated in ICI-encephalitis and, even if non-specific, may be useful as a routine test to quickly identify patients in whom neurological evaluation and second-level diagnostic procedures should be prioritized. Additionally, higher serum and CSF NfL levels have been associated with lack of treatment response in ICI-encephalitis, suggesting they may have a prognostic role. Among cytokines, elevated interleukin 6 (IL6) levels have been observed in serum and/or CSF samples of some patients with ICI-encephalitis, but the role of IL6 as a biomarker for response to IL6-directed therapies requires further investigation. Likewise, the value of other biomarkers, including T cells markers and HLA haplotypes, still needs to be evaluated in large cohorts. Overall, neural antibodies are important diagnostic and prognostic biomarkers in ICI-encephalitis, and other soluble biomarkers, especially NfL, deserve further investigation since they have a promising application in clinical practice.
{"title":"Soluble biomarkers for immune checkpoint inhibitor-related encephalitis: A mini-review","authors":"","doi":"10.1016/j.neurol.2024.08.007","DOIUrl":"10.1016/j.neurol.2024.08.007","url":null,"abstract":"<div><div>Immune checkpoint inhibitors lead to effective antitumour responses but also to immune-related adverse events (irAEs), which affect the nervous system in 1–5% of patients. Encephalitis is the most frequent central nervous system irAE and is clinically relevant due to its high severity and mortality. Early diagnosis is crucial but is hampered by the broad list of alternative diagnoses, the lack of established diagnostic criteria, and the need of extensive diagnostic procedures (e.g., spinal tap, brain MRI) alongside expert neurological evaluation. Additionally, the response to corticosteroids is inconsistent, and the management of corticosteroid-refractory patients remains poorly defined. This mini-review discusses the role of various soluble biomarkers in the diagnosis, prognostication, and management of ICI-encephalitis. Neural antibodies, which are well-established biomarkers of autoimmune and paraneoplastic encephalitis, are found in only a subset of ICI-encephalitis, in which they can aid to establish the diagnosis. The most prevalent are paraneoplastic neurological syndromes (PNS)-associated antibodies, which are found almost exclusively in focal ICI-encephalitis syndromes and are associated with poor outcomes, possibly due to predominantly cytotoxic T cell involvement leading to irreversible neuronal loss. Beside antibodies, serum brain injury biomarkers such as NfL and S100B are elevated in ICI-encephalitis and, even if non-specific, may be useful as a routine test to quickly identify patients in whom neurological evaluation and second-level diagnostic procedures should be prioritized. Additionally, higher serum and CSF NfL levels have been associated with lack of treatment response in ICI-encephalitis, suggesting they may have a prognostic role. Among cytokines, elevated interleukin 6 (IL6) levels have been observed in serum and/or CSF samples of some patients with ICI-encephalitis, but the role of IL6 as a biomarker for response to IL6-directed therapies requires further investigation. Likewise, the value of other biomarkers, including T cells markers and HLA haplotypes, still needs to be evaluated in large cohorts. Overall, neural antibodies are important diagnostic and prognostic biomarkers in ICI-encephalitis, and other soluble biomarkers, especially NfL, deserve further investigation since they have a promising application in clinical practice.</div></div>","PeriodicalId":21321,"journal":{"name":"Revue neurologique","volume":null,"pages":null},"PeriodicalIF":2.8,"publicationDate":"2024-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142294306","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-11-01DOI: 10.1016/j.neurol.2024.09.002
Over the past 30 years, about 20 antibodies have been identified in immune-mediated neuropathies, recognizing membrane or intracellular proteins or glycolipids of neuron and Schwann cells. This article reviews the different methods used for their detection, what we know about their pathogenic role, how they have helped identify several disorders, and how they are essential for diagnosis. Despite sustained efforts, some immune-mediated disorders still lack identified autoantibodies, notably the classical form of Guillain-Barré syndrome and chronic inflammatory demyelinating polyneuropathy. The reasons for this are discussed. The article also tries to determine potential future developments in antibody research, particularly the use of omic approaches and the search for other types of biomarkers beyond diagnostic ones, such as those that can identify patients who will respond to a given treatment.
{"title":"Antibodies in immune-mediated peripheral neuropathies. Where are we in 2024?","authors":"","doi":"10.1016/j.neurol.2024.09.002","DOIUrl":"10.1016/j.neurol.2024.09.002","url":null,"abstract":"<div><div>Over the past 30 years, about 20 antibodies have been identified in immune-mediated neuropathies, recognizing membrane or intracellular proteins or glycolipids of neuron and Schwann cells. This article reviews the different methods used for their detection, what we know about their pathogenic role, how they have helped identify several disorders, and how they are essential for diagnosis. Despite sustained efforts, some immune-mediated disorders still lack identified autoantibodies, notably the classical form of Guillain-Barré syndrome and chronic inflammatory demyelinating polyneuropathy. The reasons for this are discussed. The article also tries to determine potential future developments in antibody research, particularly the use of omic approaches and the search for other types of biomarkers beyond diagnostic ones, such as those that can identify patients who will respond to a given treatment.</div></div>","PeriodicalId":21321,"journal":{"name":"Revue neurologique","volume":null,"pages":null},"PeriodicalIF":2.8,"publicationDate":"2024-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142352995","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-11-01DOI: 10.1016/j.neurol.2024.08.002
Paraneoplastic neurological syndromes (PNS) are rare autoimmune disorders triggered by the presence of a cancer. The autoimmunity is herein directed against proteins expressed both in the tumor and in the nervous system, namely the onconeural antigens, against which are directed specific autoantibodies, each of them characterizing a neurological syndrome. The mechanisms of the immune tolerance breakdown in PNS leading to the production of specific autoantibodies directed against the nervous system and leading to the immune attack begins to be explained. Each syndrome is associated with a specific histo-molecular subtype of tumor suggesting a link between the PNS genesis and oncogenesis. The expression of the onconeural antigen by these tumors is insufficient to explain the immune tolerance breakdown. In some PNS tumors, alterations of the antigen have been identified: mutations, gene copy number variation and overexpression of transcript and protein. But in others PNS, no such molecular alterations of the onconeural antigens have been demonstrated. In these cases, other mechanisms of neoantigen generation that may be involved remain to be deciphered. Cancer outcomes of PNS tumors are also characterized by the high frequency of lymph node metastasis at diagnosis. At the primary tumor site, the antitumor immune reaction seems to be particularly intense and characterized by a prominence of B-cell and Ig-secreting plasma cells that may generate the autoantibody secretion. The immune control mechanisms leading to such organization of the immune attack are not known to date. Renewed research efforts are thus needed to better understand the mechanism of immune tolerance breakdown in each PNS and determine potential targets to meet the therapeutic challenges posed by these rare disorders.
{"title":"Mechanisms of immune tolerance breakdown in paraneoplastic neurological syndromes","authors":"","doi":"10.1016/j.neurol.2024.08.002","DOIUrl":"10.1016/j.neurol.2024.08.002","url":null,"abstract":"<div><div>Paraneoplastic neurological syndromes (PNS) are rare autoimmune disorders triggered by the presence of a cancer. The autoimmunity is herein directed against proteins expressed both in the tumor and in the nervous system, namely the onconeural antigens, against which are directed specific autoantibodies, each of them characterizing a neurological syndrome. The mechanisms of the immune tolerance breakdown in PNS leading to the production of specific autoantibodies directed against the nervous system and leading to the immune attack begins to be explained. Each syndrome is associated with a specific histo-molecular subtype of tumor suggesting a link between the PNS genesis and oncogenesis. The expression of the onconeural antigen by these tumors is insufficient to explain the immune tolerance breakdown. In some PNS tumors, alterations of the antigen have been identified: mutations, gene copy number variation and overexpression of transcript and protein. But in others PNS, no such molecular alterations of the onconeural antigens have been demonstrated. In these cases, other mechanisms of neoantigen generation that may be involved remain to be deciphered. Cancer outcomes of PNS tumors are also characterized by the high frequency of lymph node metastasis at diagnosis. At the primary tumor site, the antitumor immune reaction seems to be particularly intense and characterized by a prominence of B-cell and Ig-secreting plasma cells that may generate the autoantibody secretion. The immune control mechanisms leading to such organization of the immune attack are not known to date. Renewed research efforts are thus needed to better understand the mechanism of immune tolerance breakdown in each PNS and determine potential targets to meet the therapeutic challenges posed by these rare disorders.</div></div>","PeriodicalId":21321,"journal":{"name":"Revue neurologique","volume":null,"pages":null},"PeriodicalIF":2.8,"publicationDate":"2024-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142294304","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-11-01DOI: 10.1016/j.neurol.2024.08.004
In this mini-review, we focus on novelties in the field of neuromyelitis optica spectrum disorders (NMOSD) and myelin oligodendrocyte glycoprotein antibody associated disease (MOGAD). We first describe the proposed criteria for MOGAD and evaluate their impact and potential limitations, with a highlight on the subgroups of patients tested MOG-antibody positive only in the cerebrospinal fluid. We then propose a brief state of the art on the current knowledge on the so-call “double seronegative” NMOSD group, regarding nosology, clinical, biological and imaging features and the unmet need in this field. The last part is dedicating to the present and future of acute treatment in NMSOD and MOGAD.
{"title":"What's new in NMOSD and MOGAD?","authors":"","doi":"10.1016/j.neurol.2024.08.004","DOIUrl":"10.1016/j.neurol.2024.08.004","url":null,"abstract":"<div><div>In this mini-review, we focus on novelties in the field of neuromyelitis optica spectrum disorders (NMOSD) and myelin oligodendrocyte glycoprotein antibody associated disease (MOGAD). We first describe the proposed criteria for MOGAD and evaluate their impact and potential limitations, with a highlight on the subgroups of patients tested MOG-antibody positive only in the cerebrospinal fluid. We then propose a brief state of the art on the current knowledge on the so-call “double seronegative” NMOSD group, regarding nosology, clinical, biological and imaging features and the unmet need in this field. The last part is dedicating to the present and future of acute treatment in NMSOD and MOGAD.</div></div>","PeriodicalId":21321,"journal":{"name":"Revue neurologique","volume":null,"pages":null},"PeriodicalIF":2.8,"publicationDate":"2024-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142294308","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-11-01DOI: 10.1016/j.neurol.2024.10.004
{"title":"History and novelties in autoimmune encephalitis and paraneoplastic neurological syndromes","authors":"","doi":"10.1016/j.neurol.2024.10.004","DOIUrl":"10.1016/j.neurol.2024.10.004","url":null,"abstract":"","PeriodicalId":21321,"journal":{"name":"Revue neurologique","volume":null,"pages":null},"PeriodicalIF":2.8,"publicationDate":"2024-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142554670","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-11-01DOI: 10.1016/j.neurol.2024.07.005
Chimeric antigen receptor T-cell (CAR T-cell) therapies have emerged as a promising treatment modality for several malignancies, particularly haematological malignancies, by inducing robust antitumour responses. However, CAR T-cell therapies are associated with a spectrum of adverse events, including neurological complications. We here provide a review of neurological adverse events observed in patients undergoing CAR T-cell therapy, focusing on their incidence, clinical manifestations, underlying mechanisms and potential management strategies.
嵌合抗原受体 T 细胞（CAR T 细胞）疗法通过诱导强大的抗肿瘤反应，已成为治疗多种恶性肿瘤（尤其是血液系统恶性肿瘤）的一种前景广阔的治疗模式。然而，CAR T 细胞疗法与一系列不良事件有关，包括神经系统并发症。我们在此综述了在接受 CAR T 细胞疗法的患者中观察到的神经系统不良事件，重点关注其发生率、临床表现、潜在机制和潜在管理策略。
{"title":"CAR T-cell-associated neurotoxicity: A comprehensive review","authors":"","doi":"10.1016/j.neurol.2024.07.005","DOIUrl":"10.1016/j.neurol.2024.07.005","url":null,"abstract":"<div><div>Chimeric antigen receptor T-cell (CAR T-cell) therapies have emerged as a promising treatment modality for several malignancies, particularly haematological malignancies, by inducing robust antitumour responses. However, CAR T-cell therapies are associated with a spectrum of adverse events, including neurological complications. We here provide a review of neurological adverse events observed in patients undergoing CAR T-cell therapy, focusing on their incidence, clinical manifestations, underlying mechanisms and potential management strategies.</div></div>","PeriodicalId":21321,"journal":{"name":"Revue neurologique","volume":null,"pages":null},"PeriodicalIF":2.8,"publicationDate":"2024-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142256855","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-11-01DOI: 10.1016/j.neurol.2024.08.009
Antibody-associated autoimmune neurological diseases are a group of disorders with various immune effector mechanisms that result in significant differences in disease course and prognosis. Paraneoplastic or idiopathic autoimmune encephalitis associated with antibodies against intracellular antigens are mostly characterized by a T-cell-dominated inflammation with neuronal loss, astrogliosis, and microglial nodules. In anti-Yo paraneoplastic cerebellar degeneration CD8+/granzymeB+ T cells were demonstrated in close apposition to neurons along with a nuclear upregulation of the activator of transcription 1, suggesting an important role of interferon-gamma in disease pathogenesis. Early and late disease stages may show different lesion types. For example, tissue samples from patients with temporal lobe epilepsy associated with antiglutamic acid decarboxylase 65 antibodies in early disease stages show numerous infiltrating T cells targeting hippocampal neurons and high numbers of B cells and plasma cells, while in chronic stages inflammation gets less and is followed by hippocampal sclerosis. Similarly, antiglial fibrillary acidic protein meningoencephalomyelitis may show loss of astrocytes only in the very early lesions, whereas in subacute and chronic stages astrocytes can get replenished most likely due to their high regeneration potential. In contrast, neuropathology of autoimmune neurological diseases mediated by surface antibodies is mostly characterized by a dysfunction of neurons in the absence of immune-mediated neuronal damage. The interaction of surface antibodies with their target antigen and the resulting downstream mechanisms are variable and can range from an internalization of the receptor in well-preserved neurons in anti-N-methyl-D-aspartate receptor encephalitis to an irreversible internalization and blocking of the receptor that may be associated with an accumulation of phosphorylated tau in specific brain regions in anti-IgLON5 disease. Interestingly, anti-IgLON5 patients with short disease duration were shown to present prominent deposition of IgG4 in the neuropil and on neuronal membranes in the absence of neuronal tau deposits, suggesting that the immune mechanisms precede neurodegeneration. Knowledge about pathomechanisms and patterns of tissue damage in different disease stages of antibody-associated autoimmune diseases will help to identify novel biomarkers and can give important clues for possible therapeutic interventions.
抗体相关自身免疫性神经疾病是一组具有不同免疫效应机制的疾病，这些机制导致了疾病过程和预后的显著差异。与细胞内抗原抗体相关的副肿瘤性或特发性自身免疫性脑炎大多以 T 细胞为主的炎症为特征，伴有神经元缺失、星形胶质细胞增生和小胶质细胞结节。在抗-Yo 副肿瘤性小脑变性中，CD8+/granzymeB+ T 细胞与神经元紧密结合，转录激活因子 1 核上调，这表明干扰素-γ 在疾病发病机制中起着重要作用。疾病的早期和晚期可能表现出不同的病变类型。例如，与抗谷氨酸脱羧酶 65 抗体相关的颞叶癫痫患者的组织样本在疾病早期阶段显示出大量以海马神经元为目标的浸润性 T 细胞以及大量 B 细胞和浆细胞，而在慢性阶段炎症会减轻，随后出现海马硬化。同样，抗胶质纤维酸性蛋白脑膜脑脊髓炎只有在病变早期才会出现星形胶质细胞丢失，而在亚急性和慢性阶段，星形胶质细胞很可能因其再生潜力大而得到补充。相比之下，由表面抗体介导的自身免疫性神经系统疾病的神经病理学特征主要是神经元功能障碍，而没有免疫介导的神经元损伤。表面抗体与其靶抗原的相互作用以及由此产生的下游机制是多变的，从抗N-甲基-D-天冬氨酸受体脑炎中保存完好的神经元的受体内化，到抗IgLON5疾病中不可逆的受体内化和阻断，这可能与磷酸化tau在特定脑区的积累有关。有趣的是，病程较短的抗IgLON5患者的神经髓鞘和神经元膜上有明显的IgG4沉积，而神经元tau沉积却不存在，这表明免疫机制先于神经变性。对抗体相关自身免疫性疾病不同疾病阶段的病理机制和组织损伤模式的了解将有助于确定新的生物标记物，并为可能的治疗干预提供重要线索。
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Pub Date : 2024-11-01DOI: 10.1016/j.neurol.2024.08.006
Autoimmune encephalitis encompasses a spectrum of conditions characterized by distinct clinical features and magnetic resonance imaging (MRI) findings. Here, we review the literature on acute MRI changes in the most common autoimmune encephalitis variants. In N-methyl-D-aspartate (NMDA) receptor encephalitis, most patients have a normal MRI in the acute stage. When lesions are present in the acute stage, they are typically subtle and non-specific white matter lesions that do not correspond with the clinical syndrome. In some NMDA receptor encephalitis cases, these T2-hyperintense lesions may be indicative of an NMDA receptor encephalitis overlap syndrome with simultaneous co-existence of multiple sclerosis (MS), neuromyelitis optica spectrum disorder (NMOSD) or myelin oligodendrocyte glycoprotein antibody-associated disease (MOGAD). Encephalitis with leucine-rich glioma-inactivated 1 (LGI1)-, contactin-associated protein-like 2 (CASPR2)- or glutamic acid decarboxylase (GAD)- antibodies typically presents as limbic encephalitis (LE) with unilateral or bilateral T2/fluid attenuated inversion recovery (FLAIR) hyperintensities in the medial temporal lobe that can progress to hippocampal atrophy. Gamma aminobutyric acid-B (GABA-B) receptor encephalitis also often shows such medial temporal hyperintensities but may additionally involve cerebellar lesions and atrophy. Gamma aminobutyric acid-A (GABA-A) receptor encephalitis features multifocal, confluent lesions in cortical and subcortical areas, sometimes leading to generalized atrophy. MRI is unremarkable in most patients with immunoglobulin-like cell adhesion molecule 5 (IgLON5)-disease, while individual case reports identified T2/FLAIR hyperintense lesions, diffusion restriction and atrophy in the brainstem, hippocampus and cerebellum. These findings highlight the need for MRI studies in patients with suspected autoimmune encephalitis to capture disease-specific changes and to exclude alternative diagnoses. Ideally, MRI investigations should be performed using dedicated autoimmune encephalitis imaging protocols. Longitudinal MRI studies play an important role to evaluate potential relapses and to manage long-term complications. Advanced MRI techniques and current research into imaging biomarkers will help to enhance the diagnostic accuracy of MRI investigations and individual patient outcome prediction. This will eventually enable better treatment decisions with improved clinical outcomes.
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