Autoantibodies to Synaptic Receptors and Neuronal Cell Surface Proteins in Autoimmune Diseases of the Central Nervous System
TL;DR: The process of discovery of these diseases is traced, describing the triggers and symptoms related to each autoantigen, and the structural and functional alterations caused by the autoantibodies are reviewed with special emphasis in those (NMDA receptor, amphiphysin) that have been modeled in animals.
Abstract: Investigations in the last 10 years have revealed a new category of neurological diseases mediated by antibodies against cell surface and synaptic proteins. There are currently 16 such diseases all...
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TL;DR: The category of autoimmune encephalitides constitutes disorders with relatively distinct characteristics such as psychosis, seizures, abnormal movements, coma, and dysautonomia that can be successfully treated.
Abstract: Antibody-Mediated Encephalitis The category of autoimmune encephalitides constitutes disorders with relatively distinct characteristics such as psychosis, seizures, abnormal movements, coma, and dysautonomia. Specific autoantibodies can be identified, and the disorders can be successfully treated.
697 citations
Cites background from "Autoantibodies to Synaptic Receptor..."
...On the basis of experimental models with cultured neurons, the presence of antibodies in the brain may lead to neuronal dysfunction through various mechanisms, including functional blocking of the target antigen (GABA type B receptor [GABABR] antibodies, Panel D), receptor cross-linking and internalization (NMDAR antibodies, Panel E), and disruption of protein–protein interactions (leucine-rich, glioma-inactivated 1 [LGI1]), potentially affecting the function of the voltage-gated potassium channels and leading to a decrease in the levels of AMPAR (Panel F).(1) These mechanisms are influenced by the type of antibodies; for example, IgG1 antibodies frequently crosslink and internalize the target antigen, but IgG4 antibodies are less effective in cross-linking the target and more often alter protein–protein interactions....
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TL;DR: Animal models have started to reveal the complexity of the underlying pathogenic mechanisms and will lead to novel treatments beyond immunotherapy, and future studies should aim at identifying prognostic biomarkers and treatments that accelerate recovery.
Abstract: The identification of anti-NMDA receptor (NMDAR) encephalitis about 12 years ago made it possible to recognise that some patients with rapidly progressive psychiatric symptoms or cognitive impairment, seizures, abnormal movements, or coma of unknown cause, had an autoimmune disease. In this disease, autoantibodies serve as a diagnostic marker and alter NMDAR-related synaptic transmission. At symptom onset, distinguishing the disease from a primary psychiatric disorder is challenging. The severity of symptoms often requires intensive care. Other than clinical assessment, no specific prognostic biomarkers exist. The disease is more prevalent in women (with a female to male ratio of around 8:2) and about 37% of patients are younger than 18 years at presentation of the disease. Tumours, usually ovarian teratoma, and herpes simplex encephalitis are known triggers of NMDAR autoimmunity. About 80% of patients improve with immunotherapy and, if needed, tumour removal, but the recovery is slow. Animal models have started to reveal the complexity of the underlying pathogenic mechanisms and will lead to novel treatments beyond immunotherapy. Future studies should aim at identifying prognostic biomarkers and treatments that accelerate recovery.
418 citations
TL;DR: In this review, the agents used for first- and second-line immunotherapy are discussed and recent attempts at finding new treatment options are introduced.
Abstract: Autoimmune encephalitis is one of the most rapidly growing research topics in neurology. Along with discoveries of novel antibodies associated with the disease, clinical experience and outcomes with diverse immunotherapeutic agents in the treatment of autoimmune encephalitis are accumulating. Retrospective observations indicate that early aggressive treatment is associated with better functional outcomes and fewer relapses. Immune response to first-line immunotherapeutic agents (corticosteroids, intravenous immunoglobulin, plasma exchange, and immunoadsorption) is fair, but approximately half or more of patients are administered second-line immunotherapy (rituximab and cyclophosphamide). A small but significant proportion of patients are refractory to all first- and second-line therapies and require further treatment. Although several investigations have shown promising alternatives, the low absolute number of patients involved necessitates more evidence to establish further treatment strategies. In this review, the agents used for first- and second-line immunotherapy are discussed and recent attempts at finding new treatment options are introduced.
164 citations
TL;DR: An overview of paraneoplastic neurological syndromes, the associations of these conditions with ICI therapy and recommendations for the prevention and management of ICI-associated PNSs are provided.
Abstract: Paraneoplastic neurological syndromes (PNSs) comprise a group of disorders that can affect any part of the nervous system in patients with cancer and frequently result from autoimmune responses triggered by the ectopic expression of neuronal proteins in cancer cells. These disorders are rare, although the introduction of immune-checkpoint inhibitors (ICIs) into cancer treatment algorithms has renewed interest in PNSs. ICIs are associated with a considerably increased incidence of immunological toxicities compared with traditional anticancer therapies, including neurological immune-related adverse effects (nirAEs) that can manifest as PNSs. Theoretically, the use of ICIs might increase the risk of PNSs, in particular, in patients with the types of cancer that are most frequently associated with these disorders (such as small-cell lung cancer), emphasizing the importance of their prompt diagnosis and treatment to prevent irreversible neurological deficits. To facilitate the recognition of these disorders in the context of immune-checkpoint inhibition, we provide an overview of PNSs, including the main syndromes, types of neuronal autoantibodies and associated immunological mechanisms. We also review the scenarios in which nirAEs fulfil the criteria for PNSs and examine their frequency and clinical presentations. Finally, we provide recommendations for the prevention and management of PNSs that can occur during ICI therapy. Immunotherapy with immune-checkpoint inhibitors (ICIs) is a new pillar in the treatment of cancer but can a have range of immune-related adverse effects, including some rare neurological toxicities that constitute paraneoplastic neurological syndromes (PNSs). In this Review, the authors provide an overview of PNSs, the associations of these conditions with ICI therapy and recommendations for the prevention and management of ICI-associated PNSs.
159 citations
Journal Article•
TL;DR: In this paper, the authors describe a large cohort of contactin-associated protein 2 (Caspr2) patients with this disorder and provide a framework for patient recognition, which is important because it is treatable.
Abstract: Objective: We describe a large cohort of contactin-associated protein 2 (Caspr2) patients with this disorder and provide a framework for patient recognition.
Background: Caspr2 is a membrane protein closely related to the voltage-gated potassium channel (VGKC). The clinical spectrum of Caspr2 antibodies is diverse and poorly known. Recognition of this disorder is important because it is treatable.
Methods: Clinical information and patients’ serum and CSF samples were assessed at two neuroimmunology centers in Barcelona or Rotterdam. Antibody studies were investigated using previously reported brain immunohistochemistry and cell-based assays. Clinical information was obtained by the authors or provided by treating physicians after patients’informed consent.Results: Thirty-eight patients were included, 89[percnt] were male. The median age at symptom onset was 66 years. The nadir of the disease was reached at a median of 4 months, but in 30[percnt] of the patients was reached after 1 year. The most frequent syndromes included Morvan’s syndrome (29[percnt]), limbic encephalitis (LE) with additional symptoms (26[percnt]) or LE (16[percnt]). Seventy-seven percent of the patients had ≥3 of the following symptoms: encephalopathy, cerebellar symptoms, peripheral nervous hyperexcitability, autonomic dysfunction, insomnia, neuropathic pain and weight loss. The presence of an underlying tumor (usually thymoma) occurred in 19[percnt] of the patients. IgG4 subclass antibodies were present in 94[percnt] of the patients. Full or partial response to treatment occurred in 93[percnt] of the patients; overall, 73[percnt] had a favorable outcome. Relapses occurred in 25[percnt] of the patients.
Conclusions: Caspr2 antibodies associate with a treatable disorder that predominantly affects elderly men. The resulting syndrome may vary among patients, but usually includes a set of well-established symptoms. The recognition of this spectrum of symptoms and the consideration of a protracted clinical course are essential for the early diagnosis of this disorder. Prompt immunotherapy and tumor therapy (if needed) often result in improvement.
Disclosure: Dr. Sonderen has nothing to disclose. Dr. Arino has nothing to disclose. Dr. Petit-Pedrol has nothing to disclose. Dr. Leypoldt has received personal compensation for activities with Grifols as a speaker. Dr. Kortvelyessy has nothing to disclose. Dr. Lancaster has nothing to disclose. Dr. Wirtz has nothing to disclose. Dr. Schreurs has nothing to disclose. Dr. Sillevis Smitt has nothing to disclose. Dr. Graus has nothing to disclose. Dr. Dalmau has received personal compensation in an editorial capacity from the board of Up-To-Date. Dr. Dalmau has received royalty payments from Memorial Sloan-Kettering Cancer Center. Dr. Dalmau has received research support from Euroimmun. Dr. Titulaer has nothing to disclose.
157 citations
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TL;DR: The cloning of cDNAs encoding glutamate receptor subunits, which occurred mainly between 1989 and 1992, stimulated the development of ionotropic glutamate receptors in the brain.
Abstract: The ionotropic glutamate receptors are ligand-gated ion channels that mediate the vast majority of excitatory neurotransmission in the brain. The cloning of cDNAs encoding glutamate receptor subunits, which occurred mainly between 1989 and 1992 ([Hollmann and Heinemann, 1994][1]), stimulated this
4,112 citations
TL;DR: Pharmacological and biochemical criteria can be used to separate those dopamine receptors which are linked to the enzyme adenylyl cyclase and those which are not.
Abstract: Pharmacological and biochemical criteria can be used to separate those dopamine receptors which are linked to the enzyme adenylyl cyclase and those which are not.
3,746 citations
TL;DR: These data indicate that N-methyl-D-aspartate antagonists produce a broad range of symptoms, behaviors, and cognitive deficits that resemble aspects of endogenous psychoses, particularly schizophrenia and dissociative states.
Abstract: Background: To characterize further behavioral, cognitive, neuroendocrine, and physiological effects of subanesthetic doses of ketamine hydrochloride in healthy human subjects. Ketamine, a phencyclidine hydrochloride derivative, is a dissociative anesthetic and a noncompetitive antagonist of the N -methyl-D-aspartate subtype of excitatory amino acid receptor. Methods: Nineteen healthy subjects recruited by advertisements from the community participated in this randomized, double-blind, placebo-controlled study. Subjects completed three test days involving the 40-minute intravenous administration of placebo, ketamine hydrochloride (0.1 mg/kg), or ketamine hydrochloride (0.5 mg/kg). Behaviors associated with the positive and negative symptoms of schizophrenia were assessed by using the Brief Psychiatric Rating Scale. Changes in perception and behaviors associated with dissociative states were assessed by the Perceptual Aberration Subscale of the Wisconsin Psychosis Proneness Scale and the Clinician-Administered Dissociative States Scale. Cognitive function was assessed by using the (1) Mini-Mental State Examination; (2) tests sensitive to frontal cortical dysfunction, including a continuous performance vigilance task, a verbal fluency task, and the Wisconsin Card Sorting Test; and (3) tests of immediate and delayed recall. Plasma levels of cortisol, prolactin, homovanillic acid, and 3-methoxy-4-hydroxyphenethyleneglycol were measured. Results: Ketamine (1) produced behaviors similar to the positive and negative symptoms of schizophrenia; (2) elicited alterations in perception; (3) impaired performance on tests of vigilance, verbal fluency, and the Wisconsin Card Sorting Test; (4) evoked symptoms similar to dissociative states; and (5) preferentially disrupted delayed word recall, sparing immediate recall and postdistraction recall. Ketamine had no significant effect on the Mini-Mental State Examination at the doses studied. Ketamine also had no effect on plasma 3-methoxy-4hydroxyphenethyleneglycol levels, although it blunted a test day decline in plasma homovanillic acid levels at the higher dose. It also dose dependently increased plasma cortisol and prolactin levels. Ketamine produced small dose-dependent increases in blood pressure. Conclusions: These data indicate that N -methyl-Daspartate antagonists produce a broad range of symptoms, behaviors, and cognitive deficits that resemble aspects of endogenous psychoses, particularly schizophrenia and dissociative states.
3,166 citations
TL;DR: In searching for T-cell gateways into and out of the meninges, functional lymphatic vessels lining the dural sinuses are discovered, which may call for a reassessment of basic assumptions in neuroimmunology and sheds new light on the aetiology of neuroinflammatory and neurodegenerative diseases associated with immune system dysfunction.
Abstract: One of the characteristics of the central nervous system is the lack of a classical lymphatic drainage system. Although it is now accepted that the central nervous system undergoes constant immune surveillance that takes place within the meningeal compartment, the mechanisms governing the entrance and exit of immune cells from the central nervous system remain poorly understood. In searching for T-cell gateways into and out of the meninges, we discovered functional lymphatic vessels lining the dural sinuses. These structures express all of the molecular hallmarks of lymphatic endothelial cells, are able to carry both fluid and immune cells from the cerebrospinal fluid, and are connected to the deep cervical lymph nodes. The unique location of these vessels may have impeded their discovery to date, thereby contributing to the long-held concept of the absence of lymphatic vasculature in the central nervous system. The discovery of the central nervous system lymphatic system may call for a reassessment of basic assumptions in neuroimmunology and sheds new light on the aetiology of neuroinflammatory and neurodegenerative diseases associated with immune system dysfunction.
2,897 citations
TL;DR: A well-defined set of clinical characteristics are associated with anti-NMDA-receptor encephalitis and the pathogenesis of the disorder seems to be mediated by antibodies.
Abstract: Summary Background A severe form of encephalitis associated with antibodies against NR1–NR2 heteromers of the NMDA receptor was recently identified. We aimed to analyse the clinical and immunological features of patients with the disorder and examine the effects of antibodies against NMDA receptors in neuronal cultures. Methods We describe the clinical characteristics of 100 patients with encephalitis and NR1–NR2 antibodies. HEK293 cells ectopically expressing single or assembled NR1–NR2 subunits were used to determine the epitope targeted by the antibodies. Antibody titres were measured with ELISA. The effect of antibodies on neuronal cultures was determined by quantitative analysis of NMDA-receptor clusters. Findings Median age of patients was 23 years (range 5–76 years); 91 were women. All patients presented with psychiatric symptoms or memory problems; 76 had seizures, 88 unresponsiveness (decreased conciousness), 86 dyskinesias, 69 autonomic instability, and 66 hypoventilation. 58 (59%) of 98 patients for whom results of oncological assessments were available had tumours, most commonly ovarian teratoma. Patients who received early tumour treatment (usually with immunotherapy) had better outcome (p=0·004) and fewer neurological relapses (p=0·009) than the rest of the patients. 75 patients recovered or had mild deficits and 25 had severe deficits or died. Improvement was associated with a decrease of serum antibody titres. The main epitope targeted by the antibodies is in the extracellular N-terminal domain of the NR1 subunit. Patients' antibodies decreased the numbers of cell-surface NMDA receptors and NMDA-receptor clusters in postsynaptic dendrites, an effect that could be reversed by antibody removal. Interpretation A well-defined set of clinical characteristics are associated with anti-NMDA-receptor encephalitis. The pathogenesis of the disorder seems to be mediated by antibodies. Funding National Institutes for Health, University of Pennsylvania Institute for Translational Medicine, Lankenau Institute for Medical Research, Foederer Foundation of the Children's Hospital of Philadelphia.
2,604 citations