Antibody-mediated neuropsychiatric disorders
2021; Elsevier BV; Volume: 149; Issue: 1 Linguagem: Inglês
10.1016/j.jaci.2021.11.008
ISSN1097-6825
Autores Tópico(s)Genetics and Neurodevelopmental Disorders
ResumoThe first diseases of the central nervous system mediated by antibodies against neuronal cell surface proteins were identified about 20 years ago.1Buckley C. Oger J. Clover L. Tüzün E. Carpenter K. Jackson M. et al.Potassium channel antibodies in two patients with reversible limbic encephalitis.Ann Neurol. 2001; 50: 73-78Crossref PubMed Scopus (385) Google Scholar,2Dalmau J. Tüzün E. Wu H.Y. Masjuan J. Rossi J.E. Voloschin A. et al.Paraneoplastic anti-N-methyl-D-aspartate receptor encephalitis associated with ovarian teratoma.Ann Neurol. 2007; 61: 25-36Crossref PubMed Scopus (1841) Google Scholar Currently, 19 such diseases, named autoimmune encephalitis (AE), have been described (Table I).3Dalmau J. Geis C. Graus F. Autoantibodies to synaptic receptors and neuronal cell surface proteins in autoimmune diseases of the central nervous system.Physiol Rev. 2017; 97: 839-887Crossref PubMed Scopus (3) Google Scholar Some of these disorders have provided entirely new syndromes, whereas others have revealed the physiopathological mechanisms of diseases that had been considered idiopathic or not even thought to be immune-mediated. For example, the encephalitis associated with antibodies to the GluN1 subunit of the N-methyl-d-aspartate receptor (NMDAR) is now readily suspected on clinical grounds but before its discovery in 2007, the syndrome and the pattern of temporal progression of symptoms were unknown.2Dalmau J. Tüzün E. Wu H.Y. Masjuan J. Rossi J.E. Voloschin A. et al.Paraneoplastic anti-N-methyl-D-aspartate receptor encephalitis associated with ovarian teratoma.Ann Neurol. 2007; 61: 25-36Crossref PubMed Scopus (1841) Google Scholar However, a complication of herpes simplex encephalitis named choreoathetosis post–herpes simplex encephalitis had been known for many years, but the underlying mechanism and appropriate treatment were unclear until it was found to be antibody-mediated.4Armangue T. Spatola M. Vlagea A. Mattozzi S. Cárceles-Cordon M. Martinez-Heras E. et al.Frequency, symptoms, risk factors, and outcomes of autoimmune encephalitis after herpes simplex encephalitis: a prospective observational study and retrospective analysis.Lancet Neurol. 2018; 17: 760-772Abstract Full Text Full Text PDF PubMed Scopus (273) Google ScholarTable IAE: Syndromes and tumor associationAntibody, main IgG classMain syndromeFrequency of tumor association, and main types of tumorsCommentsNMDAR,IgG1Anti-NMDAR encephalitis: psychosis, seizures, orofacial and limb dyskinesias, dystonic postures, decreased level of consciousness, hypoventilation, autonomic dysfunctionVaries with age and sex∗The association with teratoma is sex and age dependent. Although young adult females frequently have an ovarian teratoma, the presence of a tumor is uncommon in children or young adult males.; 56% of women 18-45 y old have an ovarian teratoma∼35% younger than 18 yCan occur after herpes simplex or Japanese B encephalitis. Unclear HLA association with B∗The association with teratoma is sex and age dependent. Although young adult females frequently have an ovarian teratoma, the presence of a tumor is uncommon in children or young adult males.07:02, DRB1∗The association with teratoma is sex and age dependent. Although young adult females frequently have an ovarian teratoma, the presence of a tumor is uncommon in children or young adult males.16:02AMPAR,IgG1Limbic encephalitis∼60% (SCLC, thymoma, breast)Long-term prognosis depends on tumor controlGluK2R,IgG1Encephalitis with cerebellar ataxia, cerebellitisLimited information: 1 of 7 patients had Hodgkin lymphomaCan occur in childrenThe cerebellitis can result in fourth ventricle obstruction and hydrocephalusGABAaR,IgG1Encephalitis with frequent seizures and status epilepticus27% (thymoma)∼30% are children80% of patients develop highly suggestive cortical and subcortical brain MRI FLAIR abnormalitiesCan occur after herpes simplex encephalitisGABAbR,IgG1Limbic encephalitis with early and prominent seizures∼50% (SCLC)—mGluR1,IgG1Cerebellar ataxia3 of 26 (11%); 2 Hodgkin lymphoma, 1 T-cell lymphoma and prostate adenocarcinoma—mGluR2,IgG1Gait instability, ataxiaLimited information: 1 of 2 cases rhabdomyosarcoma, and the other, small cell neuroendocrine cancer—mGluR5,IgG1Encephalitis with limbic and extralimbic involvement6/11 (Hodgkin lymphoma)Can occur in childrenD2R, unknownBasal ganglia encephalitis, dystonia, tremor, parkinsonism, chorea, psychiatric disturbances0%Usually in childrenCan occur after herpes simplex encephalitisGlyR,IgG1PERM∼20% (thymoma, B-cell lymphoma, breast cancer)—LGI1IgG4, IgG1Limbic encephalitis, faciobrachial dystonic seizures, frequent hyponatremia<10% (thymoma)Association with DRB1∗The association with teratoma is sex and age dependent. Although young adult females frequently have an ovarian teratoma, the presence of a tumor is uncommon in children or young adult males.07:01, DQA1∗The association with teratoma is sex and age dependent. Although young adult females frequently have an ovarian teratoma, the presence of a tumor is uncommon in children or young adult males.02:01, and DQB1∗The association with teratoma is sex and age dependent. Although young adult females frequently have an ovarian teratoma, the presence of a tumor is uncommon in children or young adult males.02:02CASPR2IgG4, IgG1Limbic encephalitis, Morvan syndrome, neuromyotonia∼20% of all cases have thymoma. Thymoma is more frequent in patients with Morvan syndrome (∼40%)Association with DRB1∗The association with teratoma is sex and age dependent. Although young adult females frequently have an ovarian teratoma, the presence of a tumor is uncommon in children or young adult males.11:01DPPX,IgG4, IgG1Encephalitis with CNS hyperexcitability, hyperekplexia. PERM-like features. Often preceded by diarrhea and important loss of weight 90% Hodgkin lymphoma—P/Q type VGCC, IgG1Cerebellar degeneration with or without LEMSFrequent association with SCLC: >80% if associated with cerebellar syndrome; about 50% if associated with LEMS—Amphiphysin,IgG1Stiff-person syndrome, encephalomyelitis>80% SCLC, breast cancer—AMPAR, α-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid; CASPR2, contactin-associated protein-like 2; CNS, central nervous system; D2R, dopamine 2 receptor; DNER, Delta/notch-like epidermal growth factor–related receptor; DPPX, dipeptidyl-peptidase-like protein-6; GABAaR, gamma-aminobutyric acid A receptor; GABAbR, gamma-aminobutyric acid B receptor; GluK2R, glutamate ionotropic kainate 2 receptor; GlyR, glycine receptor; IgLON5, Ig-like domain–containing protein 5; LEMS, Lambert-Eaton myasthenic syndrome; LGI1, leucine-rich, glioma inactivated 1; mGluR, metabotropic glutamate receptor; OSA, obstructive sleep apnea; PERM, progressive encephalomyelitis with rigidity and myoclonus; REM, rapid eye movement (sleep); NREM, nonrapid eye movement (sleep); SCLC, small-cell lung cancer; SEZ6L2, seizure-related 6 homolog like 2; VGCC, voltage-gated calcium channel.∗ The association with teratoma is sex and age dependent. Although young adult females frequently have an ovarian teratoma, the presence of a tumor is uncommon in children or young adult males. Open table in a new tab AMPAR, α-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid; CASPR2, contactin-associated protein-like 2; CNS, central nervous system; D2R, dopamine 2 receptor; DNER, Delta/notch-like epidermal growth factor–related receptor; DPPX, dipeptidyl-peptidase-like protein-6; GABAaR, gamma-aminobutyric acid A receptor; GABAbR, gamma-aminobutyric acid B receptor; GluK2R, glutamate ionotropic kainate 2 receptor; GlyR, glycine receptor; IgLON5, Ig-like domain–containing protein 5; LEMS, Lambert-Eaton myasthenic syndrome; LGI1, leucine-rich, glioma inactivated 1; mGluR, metabotropic glutamate receptor; OSA, obstructive sleep apnea; PERM, progressive encephalomyelitis with rigidity and myoclonus; REM, rapid eye movement (sleep); NREM, nonrapid eye movement (sleep); SCLC, small-cell lung cancer; SEZ6L2, seizure-related 6 homolog like 2; VGCC, voltage-gated calcium channel. Most AEs share the following properties: (1) the clinical phenotypes are often similar to those obtained by pharmacological or genetic alterations of the antigens targeted by the antibodies, (2) the syndromes although severe and life-threatening are often reversible, (3) the antibodies react with extracellular epitopes of the cognate antigens, which are usually proteins or receptors involved in synaptic transmission and plasticity, and (4) the antibodies directly alter the structure or function of the corresponding receptor or synaptic protein targets. AEs clinically manifest with a wide range of symptoms that vary according to the type of antibody, and may include psychiatric and behavioral alterations, memory deficits, rapidly progressive cognitive decline, seizures, abnormal movements, sleep disorders (one that is so distinctive it led to the discovery of anti-IgLON5 disease), and autonomic dysfunction (Table I). For some AEs, the associated syndrome, paraclinical findings (magnetic resonance imaging or electoencephalogram), and triggers of the immune response are highly characteristic of the underlying immune response, but for others, there is a substantial overlap of symptoms that make the diagnosis less clinically obvious.5Graus F. Titulaer M.J. Balu R. Benseler S. Bien C.G. Cellucci T. et al.A clinical approach to diagnosis of autoimmune encephalitis.Lancet Neurol. 2016; 15: 391-404Abstract Full Text Full Text PDF PubMed Scopus (1872) Google Scholar Several AEs may occur with or without tumor association. The type and frequency of tumor association vary according to the type of AE; some AEs almost never associate with tumors (Table I). It is believed that the ectopic tumor expression of neuronal proteins initiates an immune response that is misdirected against the same protein expressed in the brain (Fig 1). In other instances, the tumor itself is responsible for an immune dysregulation that favors autoimmunity, such as in the case of thymomas (usually cortical epithelial) or some lymphomas. Enhanced antitumor immune responses by immune checkpoint inhibitors to treat cancer rarely cause AE. In the absence of a tumor, the immunologic trigger is usually unknown. Some AEs associate with specific HLA haplotypes, but to date the clinical implications are unclear (Table I). In rare instances, viral encephalitis such as herpes simplex or Japanese B encephalitis is able to trigger AE; it has been postulated that antigen release by infected neurons undergoing degeneration contributes to triggering the immune response (Fig 1). Accordingly, some of these patients develop concurrent autoantibodies against several neuronal proteins (eg, NMDAR and dopamine 2 receptor). These patients are neuronal antibody-negative during the viral encephalitis, and become antibody positive a few weeks later, preceding the development of AE.4Armangue T. Spatola M. Vlagea A. Mattozzi S. Cárceles-Cordon M. Martinez-Heras E. et al.Frequency, symptoms, risk factors, and outcomes of autoimmune encephalitis after herpes simplex encephalitis: a prospective observational study and retrospective analysis.Lancet Neurol. 2018; 17: 760-772Abstract Full Text Full Text PDF PubMed Scopus (273) Google Scholar AEs are the second most frequent cause of encephalitis after viral etiologies. The annual incidence of all types of encephalitis is approximately 13 per 100,000 persons, of which approximately 30% are AEs.6Venkatesan A. Michael B.D. Probasco J.C. Geocadin R.G. Solomon T. Acute encephalitis in immunocompetent adults.Lancet. 2019; 393: 702-716Abstract Full Text Full Text PDF PubMed Scopus (45) Google Scholar Even though AEs are rare, they are disproportionally frequent in the differential diagnosis of patients in the emergency room or those admitted with neuropsychiatric disorders of unclear etiology. This is likely due to their broad spectrum of symptoms and that they affect patients of all ages. The functional interaction of AE-associated antibodies with the target neuronal antigens has been demonstrated in multiple studies using primary cultures of neurons or cells expressing the target antigen, and in animal models.3Dalmau J. Geis C. Graus F. Autoantibodies to synaptic receptors and neuronal cell surface proteins in autoimmune diseases of the central nervous system.Physiol Rev. 2017; 97: 839-887Crossref PubMed Scopus (3) Google Scholar In all these models, the antibody effects vary according to the immunoglobulin class. IgG1 class antibodies, which represent most of these diseases (eg, anti-NMDAR, α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid [AMPA] receptor, and gamma-aminobutyric acid [GABA] A receptor) cross-link and disrupt the cell-surface dynamics of the target protein and interacting partners, leading to antigen internalization.7Haselmann H. Mannara F. Werner C. Planagumà J. Miguez-Cabello F. Schmidl L. et al.Human autoantibodies against the AMPA receptor subunit GluA2 induce receptor reorganization and memory dysfunction.Neuron. 2018; 100: 91-105.e109Abstract Full Text Full Text PDF PubMed Scopus (65) Google Scholar Less frequently, IgG1 antibodies directly block the function of the target (eg, glycine receptor and GABA B receptor). Even though IgG1 can potentially fix complement, human pathological studies have shown that complement-mediated neuronal injury rarely occurs in AEs, probably due to the relative preservation of the blood-brain barrier. In a group of AE mediated by IgG4 class antibodies, the antibody pathogenicity is usually through disruption of protein-protein interactions (for more details on disease mechanisms, see Dalmau et al3Dalmau J. Geis C. Graus F. Autoantibodies to synaptic receptors and neuronal cell surface proteins in autoimmune diseases of the central nervous system.Physiol Rev. 2017; 97: 839-887Crossref PubMed Scopus (3) Google Scholar). In mouse models of cerebroventricular transfer of patients' antibodies, the antibodies caused similar molecular and electrophysiological alterations as those found in vitro, resulting in altered synaptic plasticity and symptoms (memory deficits, anhedonia, psychotic-like behavior) that evolve and resolve in parallel with the presence or clearance of the antibodies. Several animal models of active immunization with NMDAR have been also reported.8Wagnon I. Helie P. Bardou I. Regnauld C. Lesec L. Leprince J. et al.Autoimmune encephalitis mediated by B-cell response against N-methyl-d-aspartate receptor.Brain. 2020; 143: 2957-2972Crossref PubMed Scopus (17) Google Scholar An important contribution of these models is the demonstration of predominant B-cell or antibody-related mechanisms that support the neuropathological findings observed in human studies where neuronophagia or cytotoxic T-cell infiltrates are minimal or absent.9Bien C.G. Vincent A. Barnett M.H. Regnauld C. Lesec L. Leprince J. et al.Immunopathology of autoantibody-associated encephalitides: clues for pathogenesis.Brain. 2012; 135: 1622-1638Crossref PubMed Scopus (420) Google Scholar The current treatment approach to most AEs is immunotherapy and tumor removal (when it applies). The immunotherapy is aimed at reducing inflammatory infiltrates (corticosteroids), removing the antibodies (plasma exchange or intravenous immunoglobulins), and eliminating the antibody-producing cells (rituximab, cyclophosphamide, and others). About 80% of patients have substantial improvement or full recovery. However, the recovery process is usually slow (often >6-9 months), and some patients have clinical relapses or are left with variable cognitive or behavioral deficits. Overall, the AEs are a new category of synaptic disorders that since their identification have changed the landscape of neurology and psychiatry, revealing new syndromes and immunopathogenic mechanisms. There are however many unanswered questions. Future studies should aim to provide a better understanding of the triggers and specific pathogenic mechanisms of each AE. This will facilitate diagnosis and the development of syndrome-specific treatments to speed recovery and reduce residual deficits.
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