RESUMEN
Research into antibody-mediated disease, in response to immune dysfunction or to tumour development, has rapidly expanded in recent years. Antibodies binding to neuroreceptors can cause psychiatric features, including psychosis, in a minority of patients as well as neurological features. The responsiveness of some of these cases to immunotherapy supports the hypothesis that antibody-associated mechanisms play a role in the pathogenesis of psychotic diseases. The purpose of this chapter is to review autoantibodies that are most likely to be relevant for patients with psychotic symptoms. Herein, we describe receptor structure and mechanism of action, clinical and psychiatric features for the growing number of neuronal surface antibodies, including those to the N-methyl-D-aspartate (NMDA) receptor. The identification of a subgroup of patients with psychiatric features having antibody-mediated disease highlights the importance of considering the diagnosis, particularly in those patients presenting with a first episode of psychosis.
Asunto(s)
Autoanticuerpos , Trastornos Psicóticos , Humanos , Neuronas/inmunología , Trastornos Psicóticos/inmunología , Receptores de N-Metil-D-Aspartato/inmunologíaRESUMEN
BACKGROUND: The clinical significance of anti-neuronal antibodies in patients with psychiatric disorders, but without encephalitis, remains unknown. In patients admitted to acute psychiatric inpatient care we aimed to identify clinical features distinguishing anti-neuronal antibody positive patients from matched controls. RESULTS: Patients who were serum-positive to N-methyl D-aspartate receptor (NMDAR) (n = 21), contactin-associated protein 2 (CASPR2) (n = 14) and/or glutamic acid decarboxylase 65 (GAD65) (n = 9) antibodies (cases) were age and sex matched (1:2) with serum-negative patients from the same cohort (controls). The prevalence and severity of psychiatric symptoms frequently encountered in NMDAR, CASPR2 and GAD65 antibody associated disorders were compared in cases and controls. NMDAR, CASPR2 and GAD65 antibody positive patients did not differ in their clinical presentation from matched serum negative controls. CONCLUSION: In this cohort, patients with and without NMDAR, CASPR2 and GAD65 antibodies admitted to acute psychiatric inpatient care had similar psychiatric phenotypes. This does not exclude their clinical relevance in subgroups of patients, and studies further investigating the clinical significance of anti-neuronal antibodies in patients with psychiatric symptomatology are needed.
Asunto(s)
Autoanticuerpos/sangre , Glutamato Descarboxilasa/inmunología , Proteínas de la Membrana/inmunología , Trastornos Mentales/inmunología , Proteínas del Tejido Nervioso/inmunología , Receptores de N-Metil-D-Aspartato/inmunología , Enfermedad Aguda , Adulto , Estudios de Casos y Controles , Femenino , Hospitalización , Humanos , Masculino , Trastornos Mentales/sangre , Trastornos Mentales/epidemiología , Trastornos Mentales/terapia , Persona de Mediana Edad , Prevalencia , Escalas de Valoración Psiquiátrica , Estudios Retrospectivos , Índice de Severidad de la EnfermedadRESUMEN
Omega-3 and omega-6 polyunsaturated fatty acids (PUFAs), such as α-linolenic and linoleic acids, are essential fatty acids in mammals, because they cannot be synthesized de novo. However, fat-1 transgenic mice can synthesize omega-3 PUFAs from omega-6 PUFAs without dietary supplementation of omega-3, leading to abundant omega-3 PUFA accumulation in various tissues. In this study, we used fat-1 transgenic mice to investigate the role of omega-3 PUFAs in response to inflammatory pain. A high omega-3 PUFA tissue content attenuated formalin-induced pain sensitivity, microglial activation, inducible nitric oxide synthase expression, and the phosphorylation of NR2B, a subunit of the N-methyl-d-aspartate (NMDA) receptor. Our findings suggest that elevated omega-3 PUFA levels inhibit NMDA receptor activity in the spinal dorsal horn and modulate inflammatory pain transmission by regulating signal transmission at the spinal dorsal horn, leading to the attenuation of chemically induced inflammatory pain.
Asunto(s)
Ácidos Grasos Omega-3/administración & dosificación , Dolor/tratamiento farmacológico , Dolor/inmunología , Animales , Suplementos Dietéticos/análisis , Ácidos Grasos Omega-6/administración & dosificación , Humanos , Masculino , Ratones , Ratones Endogámicos C57BL , Ratones Transgénicos , N-Metilaspartato/metabolismo , Receptores de N-Metil-D-Aspartato/inmunología , Asta Dorsal de la Médula Espinal/efectos de los fármacos , Asta Dorsal de la Médula Espinal/inmunologíaRESUMEN
Autoimmune dementia and encephalopathies (ADE) are complex disorders that can cause immune-mediated cognitive deficits and have confusing nomenclature. Presentation varies from acute limbic encephalitis to subacute or chronic disorders of cognition mimicking neurodegenerative dementia. It may occur as a paraneoplastic phenomenon or an idiopathic autoimmune phenomenon. The presence of a personal/family history of autoimmunity, inflammatory spinal fluid, serologic evidence of autoimmunity (neural or nonorgan-specific), or mesial temporal magnetic resonance imaging abnormalities are clues to diagnosis. Bedside cognitive assessment and/or detailed neuropsychologic testing are useful. Neural-specific autoantibodies, mostly discovered in the past two decades, may bind antigens on the cell surface (e.g., N-methyl-d-aspartate receptor autoantibodies) and are likely to be pathogenic, with treatment aimed at antibody-depleting agents often with success, while antibodies binding intracellular antigens (e.g., antineuronal nuclear autoantibody type 1 (ANNA1 or anti-Hu)) are a marker of a T-cell-mediated process and treated with T-cell-depleting immunotherapies, with variable responses. Detection and treatment of cancer (when present) are essential. High-dose corticosteroids are the initial treatment in most patients and may serve as a diagnostic test when the diagnosis is uncertain. Repeat cognitive testing after immunotherapy helps document objective improvements. Maintenance immunotherapy is recommended in those at risk for relapse. Prognosis is variable, but paraneoplastic ADE with antibodies to intracellular antigens have a worse prognosis. The field is still developing and future studies should provide guidelines for diagnosis and treatments.
Asunto(s)
Enfermedades Autoinmunes del Sistema Nervioso , Demencia , Inmunoterapia/métodos , Receptores de N-Metil-D-Aspartato/inmunología , Anticuerpos Antineoplásicos/metabolismo , Autoanticuerpos/metabolismo , Enfermedades Autoinmunes del Sistema Nervioso/complicaciones , Enfermedades Autoinmunes del Sistema Nervioso/inmunología , Enfermedades Autoinmunes del Sistema Nervioso/terapia , Demencia/complicaciones , Demencia/inmunología , Demencia/terapia , Proteínas ELAV/inmunología , Proteínas ELAV/metabolismo , Humanos , Canales de Potasio con Entrada de Voltaje/inmunología , Canales de Potasio con Entrada de Voltaje/metabolismoRESUMEN
A confused and agitated 18-year-old woman presented to the emergency unit with orolingual movements, eye deviation, and a temperature of 38°C. The symptoms had begun 2 weeks prior to the admission when she developed a severe headache associated with pathologic laughing and intermittent episodes of upgaze deviation. A urine pregnancy test was positive and a transvaginal ultrasonography showed a 9-week-old fetus. An MRI of the brain was unremarkable and results of the CSF analysis were also unremarkable apart from a CSF pleocytosis (62 lymphocytes) and slightly elevated protein (55 mg/dL; normal range 0-45 mg/dL). Extensive microbiologic and serologic studies with CSF were all negative. She gradually lost consciousness, experienced respiratory failure, and was intubated. There were semirhythmic movements consisting of complex patterns of mouth opening, chewing, facial grimacing, synchronous flexion-extension, and supination-pronation limb movements, which persisted during the period of unresponsiveness. She also had generalized hyperreflexia, persistent hyperthermia, and a full bladder. Three EEGs showed diffuse slow waves with no epileptic discharges. A diagnosis of anti-NMDA receptor (NMDAR) encephalitis was made on clinical grounds and strongly positive serum NMDAR antibodies.
Asunto(s)
Anticuerpos/administración & dosificación , Malformaciones del Desarrollo Cortical/tratamiento farmacológico , Intercambio Materno-Fetal , Receptores de N-Metil-D-Aspartato/inmunología , Estimulación Acústica , Adolescente , Encéfalo/patología , Preescolar , Femenino , Humanos , Imagen por Resonancia Magnética , Malformaciones del Desarrollo Cortical/diagnóstico , Malformaciones del Desarrollo Cortical/fisiopatología , Embarazo , Complicaciones del Embarazo , Ultrasonografía PrenatalRESUMEN
We describe two cases of confirmed anti-NMDA receptor encephalitis; one patient initially presented with a clinical picture that resembled delirium and later appeared to present with a conversion reaction and the second patient presented with a first psychotic break followed by the clinical picture of neuroleptic malignant syndrome with catatonia. Neither patient had a previous history of psychiatric illness or recreational drug use. These cases illustrate the diagnostic and treatment challenges associated with this neuropsychiatric condition and underscore the role of psychosomatic medicine psychiatrists in diagnosing anti-NMDA receptor encephalitis.
Asunto(s)
Encefalitis Antirreceptor N-Metil-D-Aspartato/diagnóstico , Medicina Psicosomática/métodos , Receptores de N-Metil-D-Aspartato/inmunología , Encefalitis Antirreceptor N-Metil-D-Aspartato/líquido cefalorraquídeo , Encefalitis Antirreceptor N-Metil-D-Aspartato/complicaciones , Encefalitis Antirreceptor N-Metil-D-Aspartato/tratamiento farmacológico , Catatonia/diagnóstico , Catatonia/etiología , Delirio/diagnóstico , Delirio/etiología , Diagnóstico Diferencial , Electroencefalografía , Femenino , Humanos , Neuroimagen , Trastornos Psicóticos/diagnóstico , Trastornos Psicóticos/etiología , Convulsiones/diagnóstico , Convulsiones/etiología , Adulto JovenAsunto(s)
Anticuerpos Monoclonales de Origen Murino/uso terapéutico , Antirreumáticos/uso terapéutico , Arteterapia/métodos , Enfermedades Autoinmunes del Sistema Nervioso/inmunología , Enfermedades Autoinmunes del Sistema Nervioso/rehabilitación , Encefalitis/inmunología , Encefalitis/rehabilitación , Inmunización Pasiva , Metilprednisolona/uso terapéutico , Trastornos Neurocognitivos/inmunología , Trastornos Neurocognitivos/rehabilitación , Receptores de N-Metil-D-Aspartato/inmunología , Adolescente , Trastornos del Conocimiento/inmunología , Trastornos del Conocimiento/rehabilitación , Quimioterapia Combinada , Femenino , Humanos , Escala del Estado Mental , Escalas de Valoración Psiquiátrica , RituximabRESUMEN
This report concerns a 32-year old man with non-herpetic acute limbic encephalitis. He was admitted to our hospital because of high fever and consciousness disturbance. Cranial MRI revealed abnormal signal intensities in the bilateral mesial temporal lobes. On the second hospitalization day, he developed status epilepticus, which necessitated general anesthesia. Following administration of intravenous (IV) methylprednisolone pulse therapy (1 g/day, 3 days), his consciousness disturbance began to improve. Treatment with high-dose IV methylprednisolone was continued for about 2 weeks, but on the 7th day, he showed severe anterograde amnesia and retrograde amnesia regarding the preceding 5 or 6 years. Subsequently, however, his amnesic disorders improved markedly, and on the 46th day, memory dysfunction had disappeared. Autoantibodies against the glutamate receptor subunits epsilon2 and delta2 were detected in both the CSF and serum, but these antibodies in the CSF became normal during the clinical course. The voltage-gated potassium channel antibody was negative. This case report indicates that high-dose IV methylprednisolone therapy may be an affective treatment for non-herpetic acute limbic encephalitis, possibly associated with autoimmune mechanisms.
Asunto(s)
Autoanticuerpos/análisis , Glucocorticoides/administración & dosificación , Encefalitis Límbica/tratamiento farmacológico , Encefalitis Límbica/inmunología , Metilprednisolona/administración & dosificación , Receptores de Glutamato/inmunología , Receptores de N-Metil-D-Aspartato/inmunología , Enfermedad Aguda , Adulto , Humanos , Masculino , Quimioterapia por PulsoRESUMEN
In this report, we present evidence of a small-scale modularity (<100 microm) at the border of layers 1 and 2 in neocortical areas. The modularity is best seen in tangential sections, with double-labeling immunohistochemistry to reveal overlapping or complementary relationships of different markers. The pattern is overall like a reticulum or mosaic but is described as a "honeycomb," in which the walls and hollows are composed of distinct afferent and dendritic systems. We demonstrate the main components of the honeycomb in rat visual cortex. These are as follows: (1) zinc-enriched, corticocortical terminations in the walls, and in the hollows, thalamocortical terminations (labeled by antibody against vesicular glutamate transporter 2 and by cytochrome oxidase); (2) parvalbumin-dense neuropil in the walls that partly colocalizes with elevated levels of glutamate receptors 2/3, NMDAR receptor 1, and calbindin; and (3) dendritic subpopulations preferentially situated within the walls (dendrites of layer 2 neurons) or hollows (dendrites of deeper neurons in layers 3 and 5). Because the micromodularity is restricted to layers 2 and 1b, without extending into layer 3, this may be another indication of a laminar-specific substructure at different spatial scales within cortical columns. The suggestion is that corticocortical and thalamocortical terminations constitute parallel circuits at the level of layer 2, where they are segregated in association with distinct dendritic systems. Results from parvalbumin staining show that the honeycomb mosaic is not limited to rat visual cortex but can be recognized at the layer 1-2 border in other areas and species.
Asunto(s)
Proteínas de Transporte de Membrana , Proteínas de Transporte Vesicular , Corteza Visual/citología , Animales , Biomarcadores/análisis , Proteínas Portadoras/análisis , Proteínas Portadoras/inmunología , Gatos , Corteza Cerebral/química , Corteza Cerebral/citología , Dendritas/química , Dendritas/ultraestructura , Complejo IV de Transporte de Electrones/análisis , Haplorrinos , Inmunohistoquímica , Masculino , Modelos Neurológicos , Neuronas/química , Neuronas/citología , Neurópilo/química , Neurópilo/citología , Parvalbúminas/análisis , Parvalbúminas/inmunología , Terminales Presinápticos/química , Ratas , Ratas Wistar , Receptores de N-Metil-D-Aspartato/análisis , Receptores de N-Metil-D-Aspartato/inmunología , Especificidad de la Especie , Proteína 2 de Transporte Vesicular de Glutamato , Corteza Visual/química , Zinc/análisisRESUMEN
N-methyl-D-aspartic acid (NMDA) receptors transiently transfected into mammalian HEK-293 cells were characterized with subunit-specific antibodies and electrophysiological recordings. Deactivation time course recorded in response to fast-glutamate pulses were studied in isolated and lifted cells, as well as in outside-out membrane patches excised from cells expressing recombinant NR1 subunits in combination with the NR2A, NR2B, NR2C, or NR2D NMDA receptor subunits. Transfected cells were preidentified by the fluorescence emitted from the coexpressed Aequorea victoria jellyfish Green Lantern protein. Currents generated by NR1/NR2A channels displayed double exponential deactivation time course being faster than that in NR1/NR2B or NR1/NR2C channels. However, a large decay variability was observed within each cotransfection, suggesting that mechanisms additional to subunit composition may also regulate deactivation time course. NR1/NR2D channels displayed slowly deactivating currents. Channel deactivation was fast and comparable among receptors obtained by cotransfecting five distinct spliced variants of the NR1 subunit, each with the NR2A subunit. Additionally, recovery from desensitization was slower for NR1/NR2B than for NR1/NR2A channels. The average deactivation time course of responses to brief L-glutamate applications in cells where NR1/NR2A/NR2B cDNAs were cotransfected at variable ratio was intermediate between those of the NR1/NR2A and NR1/NR2B channels. Although immunocytochemical evidence indicates that the majority of cells are cotransfected by all plasmids in triple transfection, our experimental condition did not allow for a tight control of the expression of NMDA receptor subunits. This produced the result that many cells were characterized by deactivation time course and haloperidol sensitivities of separate NR1/NR2A and NR1/NR2B subunit heteromers. We also speculate on the possible formation of channels resulting from the coassembly in the same receptor of NR1/NR2A/NR2B subunits from a minority of cells that gave responses to brief application of L-glutamate characterized by slow deactivation time course and decreased haloperidol sensitivity.
Asunto(s)
Ácido Cisteico/farmacología , Ácido Glutámico/farmacología , Receptores de N-Metil-D-Aspartato/fisiología , Proteínas Recombinantes de Fusión/fisiología , Anticuerpos Monoclonales/inmunología , Especificidad de Anticuerpos , Línea Celular , ADN Complementario/genética , Técnica del Anticuerpo Fluorescente Indirecta , Genes Reporteros , Haloperidol/farmacología , Humanos , Riñón , Potenciales de la Membrana/efectos de los fármacos , Técnicas de Placa-Clamp , Conformación Proteica , Multimerización de Proteína , Empalme del ARN , Receptores de N-Metil-D-Aspartato/química , Receptores de N-Metil-D-Aspartato/efectos de los fármacos , Receptores de N-Metil-D-Aspartato/genética , Receptores de N-Metil-D-Aspartato/inmunología , Proteínas Recombinantes de Fusión/química , Proteínas Recombinantes de Fusión/efectos de los fármacos , Proteínas Recombinantes de Fusión/inmunología , TransfecciónRESUMEN
A single, large dose of N-methyl-D-aspartate (NMDA) or quisqualic acid (QA) injected into the chick eye has been shown previously to destroy many retinal amacrine cells and to induce excessive ocular growth accompanied by myopia. The purpose of this study was to identify distinct populations of retinal cells, particularly those believed to be involved in regulating ocular growth, that are sensitive to NMDA or QA. Two pmol of NMDA or 0.2 micromol of QA were injected unilaterally into eyes of 7-day-old chicks, and retinas were prepared for observation 1, 3, or 7 days later. Retinal neurons were identified by using immunocytochemistry, and cells containing fragmented DNA were identified by 3'-nick-end labelling in frozen sections. NMDA and QA destroyed many amacrine cells, including those immunoreactive for vasoactive intestinal polypeptide, Met-enkephalin, and choline acetyltransferase, but they had little effect upon tyrosine hydroxylase-immunoreactive cells. Other cells affected by both QA and NMDA included those immunoreactive for glutamic acid decarboxylase, gamma-aminobutyric acid, parvalbumin, serotonin, and aminohydroxy methylisoxazole propionic acid (AMPA) receptor subunits GluR1 and GluR2/3. Cells largely unaffected by QA or NMDA included bipolar cells immunoreactive for protein kinase C (alpha and beta isoforms) and amacrine cells immunoreactive for glucagon. DNA fragmentation was detected maximally in many amacrine cells and in some bipolar cells 1 day after exposure to QA or NMDA. We propose that excitotoxicity caused by QA and NMDA induces apoptosis in specific populations of amacrine cells and that these actions are responsible for the ocular growth-specific effects of QA and NMDA reported elsewhere.