-
Handbook of Clinical Neurology 2024Paraneoplastic neurologic syndromes (PNS) represent a rare group of immune-mediated complications associated with an underlying tumor. Ectopic protein expression in... (Review)
Review
Paraneoplastic neurologic syndromes (PNS) represent a rare group of immune-mediated complications associated with an underlying tumor. Ectopic protein expression in neoplastic cells or an aberrant immune regulation in the course of hematooncologic diseases or thymomas trigger an autoimmune response that may affect any part of the central and/or peripheral nervous system. Recent advances in drug therapies as well as novel animal models and neuropathologic studies have led to further insights on the immune pathomechanisms of PNS. Although the syndromes share common paths in pathogenesis, they may differ in the disease course, prognosis, and therapy targets, depending on the localization and type of antibody epitope. Neuropathologic hallmarks of PNS associated with antibodies directed against intracellular epitopes are characterized by T cell-dominated inflammation, reactive gliosis including microglial nodules, and neuronal degeneration. By contrast, the neuropathology of cell surface antibody-mediated PNS strongly depends on the targeted antigen and varies from B cell/plasma cell-dominated inflammation and well-preserved neurons together with a reduced expression of the target antigen in anti-NMDAR encephalitis to irreversible Purkinje cell loss in anti-P/Q-type VGCC antibody-associated paraneoplastic cerebellar degeneration. The understanding of different pathomechanisms in PNS is important because they strongly correspond with therapy response and prognosis, and should guide treatment decisions.
Topics: Animals; Humans; Autoantibodies; Paraneoplastic Syndromes, Nervous System; Nervous System Diseases; Neoplasms; Inflammation
PubMed: 38494287
DOI: 10.1016/B978-0-12-823912-4.00027-X -
Cell Reports Aug 2023Neuroblastoma is a lethal childhood solid tumor of developing peripheral nerves. Two percent of children with neuroblastoma develop opsoclonus myoclonus ataxia syndrome...
Neuroblastoma is a lethal childhood solid tumor of developing peripheral nerves. Two percent of children with neuroblastoma develop opsoclonus myoclonus ataxia syndrome (OMAS), a paraneoplastic disease characterized by cerebellar and brainstem-directed autoimmunity but typically with outstanding cancer-related outcomes. We compared tumor transcriptomes and tumor-infiltrating T and B cell repertoires from 38 OMAS subjects with neuroblastoma to 26 non-OMAS-associated neuroblastomas. We found greater B and T cell infiltration in OMAS-associated tumors compared to controls and showed that both were polyclonal expansions. Tertiary lymphoid structures (TLSs) were enriched in OMAS-associated tumors. We identified significant enrichment of the major histocompatibility complex (MHC) class II allele HLA-DOB01:01 in OMAS patients. OMAS severity scores were associated with the expression of several candidate autoimmune genes. We propose a model in which polyclonal auto-reactive B lymphocytes act as antigen-presenting cells and drive TLS formation, thereby supporting both sustained polyclonal T cell-mediated anti-tumor immunity and paraneoplastic OMAS neuropathology.
Topics: Child; Humans; Autoimmunity; Neuroblastoma; Opsoclonus-Myoclonus Syndrome; Autoantibodies; Genes, MHC Class II; Ataxia
PubMed: 37537844
DOI: 10.1016/j.celrep.2023.112879 -
The American Journal of Medicine Feb 2024
Topics: Humans; Limbic Encephalitis; Autoantibodies; Magnetic Resonance Imaging
PubMed: 37875218
DOI: 10.1016/j.amjmed.2023.10.010 -
Biochemical Pharmacology Dec 2023Myasthenia gravis (MG) is a type of autoimmune disease caused by the blockage of neuromuscular junction transmission owing to the attack of autoantibodies on... (Review)
Review
Myasthenia gravis (MG) is a type of autoimmune disease caused by the blockage of neuromuscular junction transmission owing to the attack of autoantibodies on transmission-related proteins. Related antibodies, such as anti-AChR, anti-MuSK and anti-LRP4 antibodies, can be detected in most patients with MG. Although traditional therapies can control most symptoms, several challenges remain to be addressed, necessitating the development of more effective and safe treatment strategies for MG. With the in-depth exploration on the mechanism and immune targets of MG, effective therapies, especially therapies using biologicals, have been reported recently. Given the important roles of immune cells, cytokines and intercellular interactions in the pathological process of MG, B-cell targeted therapy, T-cell targeted therapy, proteasome inhibitors targeting plasma cell, complement inhibitors, FcRn inhibitors have been developed for the treatment of MG. Although these novel therapies exert good therapeutic effects, they may weaken the immunity and increase the risk of infection in MG patients. This review elaborates on the pathogenesis of MG and discusses the advantages and disadvantages of the strategies of traditional treatment and biologicals. In addition, this review emphasises that combined therapy may have better therapeutic effects and reducing the risk of side effects of treatments, which has great prospects for the treatment of MG. With the deepening of research on immunotherapy targets in MG, novel opportunities and challenges in the treatment of MG will be introduced.
Topics: Humans; Receptor Protein-Tyrosine Kinases; Myasthenia Gravis; Neuromuscular Junction; Autoantibodies; Immunotherapy
PubMed: 37865142
DOI: 10.1016/j.bcp.2023.115872 -
JAMA Feb 2024
Topics: Humans; Myasthenia Gravis
PubMed: 38153702
DOI: 10.1001/jama.2023.16872 -
Current Opinion in Neurology Oct 2023This review highlights recent knowledge on the diagnosis and treatment of immune checkpoint inhibitor-induced neurological side effects (irNAE) focussing on the... (Review)
Review
PURPOSE OF REVIEW
This review highlights recent knowledge on the diagnosis and treatment of immune checkpoint inhibitor-induced neurological side effects (irNAE) focussing on the neuromuscular system.
RECENT FINDINGS
irNAEs mainly resemble sporadic neuromuscular autoimmune diseases and paraneoplastic neurological syndromes. However, neurological symptoms may be unspecific (muscle weakness, fatigue) in the oncological setting and carry the risk of misdiagnosis and delayed therapeutic intervention. The role of disease-specific neuromuscular autoantibodies in the diagnosis is controversial as preexisting autoantibodies may otherwise be present before immune checkpoint inhibitor (ICI) treatment without clinical symptoms and may not develop in case of irNAE manifestation. A new necrotising form of myositis (irMyositis) has been described presenting with facial weakness and ptosis mimicking myasthenia gravis. It comes along with a high rate of severe myocarditis accounting for a triad overlap syndrome (myasthenia/myositis/myocarditis). The role of modern biologicals in the treatment of irNAEs has to be determined.
SUMMARY
irNAEs are rare but carry the risk of permanent morbidity and mortality. Early suspicion and diagnosis are key to prevent neurological sequelae. Beyond interruption of ICI administration, treatment corresponds to sporadic autoimmune diseases. The myasthenia/myositis/myocarditis overlap syndrome deserves special attention as it carries the highest risk of mortality. The role of neurotoxic pretreatment regimens, preexisting subclinical neurological autoimmune diseases and the risk of ICI-re-challenge after irNAEs has to be further investigated.
Topics: Humans; Immune Checkpoint Inhibitors; Myocarditis; Drug-Related Side Effects and Adverse Reactions; Peripheral Nervous System; Myasthenia Gravis; Myositis; Autoantibodies
PubMed: 37639489
DOI: 10.1097/WCO.0000000000001188 -
Handbook of Clinical Neurology 2024Neuroendocrine neoplasms (NENs) are a heterogeneous group of tumors arising from the transformation of neuroendocrine cells in several organs, most notably the... (Review)
Review
Neuroendocrine neoplasms (NENs) are a heterogeneous group of tumors arising from the transformation of neuroendocrine cells in several organs, most notably the gastro-entero-pancreatic system and respiratory tract. The classification was recently revised in the 5th Edition of the WHO Classification of Endocrine and Neuroendocrine Tumors. NENs can rarely spread to the central or peripheral nervous systems. Neurologic involvement is determined by the rare development of paraneoplastic syndromes, which are remote effects of cancer. Mechanisms depend on immunologic response to a tumor, leading to the immune attack on the nervous system or the production of biologically active ("functioning") substances, which can determine humoral (endocrine) effects with neurologic manifestations. Paraneoplastic neurologic syndromes (PNS) are immunologically mediated and frequently detected in small cell lung cancer but rarely seen in other forms of NEN. PNS and Merkel cell carcinoma is increasingly reported, especially with Lambert Eaton myasthenic syndrome. Endocrine manifestations are found in a wide spectrum of NENs. They can develop at any stage of the diseases and determine neurologic manifestations. Patient outcomes are influenced by tumor prognosis, neurologic complications, and the severity of endocrine effects.
Topics: Humans; Neuroendocrine Tumors; Paraneoplastic Syndromes; Lambert-Eaton Myasthenic Syndrome; Nervous System Diseases; Paraneoplastic Syndromes, Nervous System; Autoantibodies
PubMed: 38494292
DOI: 10.1016/B978-0-12-823912-4.00023-2 -
Autoimmunity Reviews Sep 2023A growing body of evidence underscores the relevance of functional autoantibodies in the development of various pathogenic conditions but also in the regulation of... (Review)
Review
A growing body of evidence underscores the relevance of functional autoantibodies in the development of various pathogenic conditions but also in the regulation of homeostasis. However, the definition of functional autoantibodies varies among studies and a comprehensive overview on this emerging topic is missing. Here, we do not only explain functional autoantibodies but also summarize the mechanisms underlying the effect of such autoantibodies including receptor activation or blockade, induction of receptor internalization, neutralization of ligands or other soluble extracellular antigens, and disruption of protein-protein interactions. In addition, in this review article we discuss potential triggers of production of functional autoantibodies, including infections, immune deficiency and tumor development. Finally, we describe the contribution of functional autoantibodies to autoimmune diseases including autoimmune thyroid diseases, myasthenia gravis, autoimmune pulmonary alveolar proteinosis, autoimmune autonomic ganglionopathy, pure red cell aplasia, autoimmune encephalitis, pemphigus, acquired thrombotic thrombocytopenic purpura, idiopathic dilated cardiomyopathy and systemic sclerosis, as well as non-autoimmune disorders such as allograft rejection, infectious diseases and asthma.
Topics: Humans; Autoantibodies; Autoimmune Diseases; Myasthenia Gravis; Pemphigus; Encephalitis; Pulmonary Alveolar Proteinosis
PubMed: 37352904
DOI: 10.1016/j.autrev.2023.103386 -
Neurology(R) Neuroimmunology &... Jan 2024Research on autoimmune and infectious encephalitis has made substantial progress in recent years in revealing the pathophysiology of these diseases, establishing robust...
Research on autoimmune and infectious encephalitis has made substantial progress in recent years in revealing the pathophysiology of these diseases, establishing robust diagnostic criteria, and developing promising treatment options, with a range of clinical trials currently underway. Outcome measures in studies on autoimmune and infectious encephalitis mainly relied on established and widely used tools such as the modified Rankin Scale (mRS). However, the mRS was developed to assess stroke outcome and has a strong focus on motor symptoms and the degree of dependence in daily activities. For example, approximately 80% of patients with anti-NMDA receptor encephalitis (i.e., the most common autoimmune encephalitis variant) achieve a good outcome 2 years after disease onset when evaluated using the mRS. In contrast to these findings, recent studies show that a majority of patients with anti-NMDA receptor encephalitis suffer from relevant and persistent cognitive impairment, despite mRS scores indicating good or very good recovery. This shows that the mRS fails to detect clinically relevant long-term symptoms in these patients. Indeed, persisting cognitive deficits with their detrimental effect on quality of life are specifically important in the frequently very young patients with encephalitis. More recently, encephalitis-specific scores have been developed, e.g., the CASE score for the clinical assessment of patients with autoimmune encephalitis. While this score is tailored to symptoms in autoimmune encephalitis, it has a strong focus on acute disease symptoms and is less well suited to capture long-term sequalae.
Topics: Humans; Anti-N-Methyl-D-Aspartate Receptor Encephalitis; Quality of Life; Hashimoto Disease; Infectious Encephalitis
PubMed: 38086067
DOI: 10.1212/NXI.0000000000200189 -
Journal of Clinical Neuromuscular... Dec 2023This update covers several articles on diagnosis and misdiagnosis of myasthenia gravis (MG), the role of complement in MG, and then an impressive number of recent...
This update covers several articles on diagnosis and misdiagnosis of myasthenia gravis (MG), the role of complement in MG, and then an impressive number of recent treatment trials. There is a negative study on any corticosteroid-sparing effect of intravenous immunoglobulin. A number of positive studies are reviewed. Open-label extension studies of phase 3 trials showed benefit regarding quality of life with efgartigimod and in functional measures with ravulizumab. The phase 3 RAISE trial of zilucoplan, a self-administered complement C5 inhibitor, is covered as well as the MyCarinG trial of rozanolixizumab. The notion of using fast-acting therapies early in the course of MG is addressed. The last sections center on MG and Lambert-Eaton myasthenic syndrome as a consequence of immune checkpoint inhibitor therapy.
Topics: Humans; Quality of Life; Neuromuscular Junction; Myasthenia Gravis; Lambert-Eaton Myasthenic Syndrome; Complement Inactivating Agents
PubMed: 37962198
DOI: 10.1097/CND.0000000000000456