Ovarian teratoma associated Anti-N-methyl-D-aspartate receptor encephalitis: a difficult diagnosis with a favorable prognosis

Anti-N-methyl-D-aspartate receptor (anti-NMDAR) encephalitis is a recently described auto-immune and paraneoplastic encephalitis with prominent neuropsychiatric manifestations affecting young adults with ovarian teratoma. The availability of a novel assay to measure these antibodies might suggest an etiology for this potentially life-threatening disease, which if early recognized can be treated promptly with surgery with chances of a good clinical outcome. Reported prognostic indicators for a good outcome depend on the presence of a tumor, prompt treatment and no admission to an intensive care unit. However, due to the rarity and unawareness of this disease, the diagnosis may be delayed as primary psychiatric disorders, and infective encephalitis is taken more into consideration and ruled out first. Here we report a case of anti-NMDAR encephalitis in a 22-year-old female prompted by an ovarian teratoma with a gradual and complete resolution of symptoms after surgical excision of the teratoma and immunomodulating therapies.

Non-inflammatory cerebrospinal fluid delays the diagnosis and start of immunotherapy in anti-NMDAR encephalitis / La ausencia de hallazgos de inflamación en líquido cefalorraquídeo retrasa el inicio de inmunoterapia en la encefalitis anti-NMDAR

ABSTRACT Anti-N-methyl-D-aspartate receptor (anti-NMDAR) encephalitis is a form of autoimmune encephalopathy that presents with a wide variety of symptoms, including neuropsychiatric manifestations. The authors' aim for this study was to analyze the results of paraclinical studies of patients with a diagnosis of anti-NMDAR encephalitis and the association between symptom onset and diagnosis, and start of immunotherapy. Retrospective data of 29 patients with anti-NMDAR encephalitis were gathered and analyzed. Abnormal EEG was found in 27 patients (93.1%), whereas MRI was abnormal in 19 patients (65.5%). In contrast, an inflammatory pattern on CSF analysis was found in only 13 patients (44.8%). The absence of pleocytosis or increased proteins in the CSF was associated with a longer time from symptom onset to diagnosis and treatment (p = 0.003). The authors conclude that noninflammatory CSF may delay the correct diagnosis and start of immunotherapy in anti-NMDAR encephalitis. In the presence of suggestive clinical features, extensive studies including EEG are recommended.

RESUMEN La encefalitis por receptor anti-N-metil-D-aspartato (anti-NMDAR) es una encefalopatía autoinmune con una amplia variedad de síntomas, incluyendo manifestaciones neuropsiquiátricas. Nuestro objetivo en este estudio fue analizar los resultados paraclínicos de pacientes diagnosticados con encefalitis anti-NMDAR y la asociación entre inicio de sintomatología, el diagnóstico y el inicio de inmunoterapia. Encontramos un EEG anormal en 27 pacientes (93.1%), así como IRM anormal en 19 de ellos (65.5%). En contraste, el análisis de LCR mostró un patrón inflamatorio en tan solo 13 pacientes (44.8%). La ausencia de pleocitosis o proteínas incrementadas en el LCR se asoció con un mayor tiempo desde el inicio de la sintomatología hasta el inicio del tratamiento (p=0.003). Concluimos que el LCR no inflamatorio puede retrasar el diagnóstico correcto y el inicio de tratamiento en encefalitis anti-NMDAR, por lo que se recomienda la realización de estudios exhaustivos, incluyendo EEG, ante la presencia de indicadores clínicos sugerentes del padecimiento.

Encefalitis por anticuerpos contra receptor NMDA. A propósito de un caso / Encephalitis by antibodies against NMDA receptor. About a case

Introducción: En la encefalitis por anticuerpos contra receptores N-Metil-D-Aspartato (NMDA) se genera una disfunción neuronal del ácido gamma-aminobutírico (GABA), con desregulación del glutamato y la dopamina. Los teratomas y las infecciones virales se presumen causales de la respuesta autoinmunitaria. La clínica evoluciona por etapas con un pródromo similar a una infección viral con posteriores manifestaciones psiquiátricas y convulsiones, seguidas de disfunción motora, cognitiva y autonómica. El diagnóstico se basa en la clínica y la presencia de anticuerpos del receptor NMDA. El tratamiento incluye inmunoterapia y eventual eliminación del tumor. La enfermedad puede ser letal o provocar daño irreversible en regiones corticales. Objetivo: Destacar la importancia del diagnóstico precoz en los casos de encefalitis autoinmune para una mayor efectividad de los tratamientos postulados. Reporte de caso: Paciente femenina de 13 años de edad, con diagnóstico de diabetes tipo I; presenta dolor y pérdida de fuerza con movimientos involuntarios en miembro superior izquierdo con dificultad en la deambulación, más episodio convulsivo tónico clónico generalizado seguido de manifestaciones neuropsiquiátricas. Se sospecha encefalitis autoinmune, se dosan anticuerpos anti ácido glutámico descarboxilasa (GAD) y anti NMDA, con resultados positivos. Recibe corticoterapia, inmunoglobulina endovenosa, rituximab y plasmaferesis. Presenta escasa mejoría clínica, con persistencia de síntomas secuelares psiquiátricos y neurológicos. Discusión: Es importante sospechar esta entidad aunque las manifestaciones clínicas iniciales sugieran otras etiologías. El tratamiento inmunosupresor agresivo no debería demorarse aun cuando no se haya confirmado la positividad de los anticuerpos NMDA. El buen pronóstico depende del inicio precoz del tratamiento.

Introduction: The encephalitis by antibodies against NMDA receptors, a neuronal dysfunction of gamma-aminobutyric acid (GABA) is generated, with deregulation of glutamate and dopamine. Teratomas and viral infections are presumed to be the cause to the autoimmune response. The clinic evolves in stages with a prodrome similar to a viral infection with subsequent psychiatric manifestations and seizure, followed by motor, cognitive and autonomic dysfunction. Diagnosis is based on clinical symptoms and the presence of NMDA receptor antibodies. The treatment includes immunotherapy and, eventually, elimination of the tumor. The disease can be lethal or cause irreversible damage in cortical regions. Objective: Highlight the importance of early diagnosis in cases of autoimmune encephalitis for greater effectiveness of postulated treatments. Case report.:13 year old female patient diagnosed with type I diabetes; presents pain, loss of strength and involuntary movements of the upper left limb and ambulation difficulties, associeted with a generalized tonic-clonic seizure episode followed by neuropsychiatric manifestations. Autoinmune encefalitis was suspected so antiglutamic acid decarboxylase (GAD) and anti-NMDA antibodies were dosed, which throw a positive result. The patient receives corticotherapy, intravenous immunoglobulin, rituximab and plasmapheresis. Presenting little clinical improvement, with persistence of psychiatric and neurological sequelae symptoms. Discussion: It is important to suspect this entity although the initial clinical manifestations suggests other etiologies. Aggressive immunosuppressive therapy should not be delayed even when the positivity of NMDA antibodies has not been confirmed. The good prognosis depends on the early start of the treatment.

Encefalitis subaguda por anticuerpos anti receptor de N-metil-D-aspartato: Serie de 13 casos pediátricos / Subacute anti-N-methyl-D-aspartate receptor encephalitis: A serie of 13 paediatric cases

Introducción: La encefalitis subaguda por anticuerpos anti-receptor N-metil-Daspartato (NMDA) es un cuadro autoinmune reconocido el año 2007 como entidad clínica y descrito primero en mujeres jóvenes con teratoma ovárico. El año 2009 se describe primera serie pediátrica no relacionada con tumores. Objetivo: Mostrar características clínicas, tratamiento y pronóstico de 13 pacientes con encefalitis por anticuerpos anti receptor NMDA en Chile. Pacientes y método: Se describen 13 niños, 9 varones, de edades comprendidas entre 1-16 años, estudiados entre 2009-2016 en 7 hospitales y diagnosticados entre 2009-2016. Los pacientes fueron estudiados con resonancia magnética cerebral, electroencefalograma y estudio de líquido cefalorraquídeo, citoquímico, bandas oligoclonales y panel viral (anticuerpos y PCR). Todos fueron estudiados para detección de anticuerpos anti receptor NMDA en suero y líquido cefalorraquídeo (LCR) y pesquisa de tumores por imágenes. Resultados: Trece de 13 niños iniciaron la enfermedad con síntomas psiquiátricos y 11/13 tuvieron crisis epilépticas. Posteriormente todos presentaron agitación psicomotora, distonías y discinesias bucolinguales; 11/13 pérdida de lenguaje y 6/13 trastornos autonómicos. Todos ellos tuvieron anticuerpos anti receptor NMDA positivo. El LCR fue normal en 12/13 niños, hubo bandas oligoclonales positivas en 6/10 pacientes, la resonancia cerebral fue normal en todos los niños, el EEG estuvo alterado en 12/13 niños y la SPECT resultó anormal en 6/6 niños. Doce de 13 niños recibieron metilprednisolona en bolos 30 mg/kg/3-5 días y 6 recibieron inmunoglobulina 2 g/kg. Doce de 13 niños se recuperaron de 2 a 4 meses después de iniciada la enfermedad. Un niño tuvo recidiva un año después y se recuperó rápidamente. Conclusiones: La encefalitis subaguda por anticuerpos anti-receptor NMDA debe sospecharse en niños con alteraciones psiquiátricas y movimientos anormales. Los estudios funcionales (EEG y SPECT) son valiosos para apoyar el diagnóstico. La detección precoz de esta encefalitis permite la recuperación más rápida de los pacientes.

Introduction: Subacute anti-NMDA receptor encephalitis was recognised in 2007 as a clinical entity, and was first described in young women with ovarian teratoma. The first paediatric series unrelated with tumours was reported in 2009. Objective: To present the clinical features, treatment, and prognosis of 13 patients with anti-NMDA receptor encephalitis in Chile. Patients and method: A description is presented of 13 children, 9 males, aged between 1 and 16 years, diagnosed between 2009 and 2016 in 7 hospitals. All patients were evaluated with cerebral magnetic resonance and electroencephalogram. Cytochemical, oligoclonal bands and virus studies (PCR and antibodies) were performed in cerebrospinal fluid. All patients were evaluated in search of anti NMDA receptor in serum and cerebrospinal fluid. Tumor imaging studies were performed in all children. Results: All children began the disease with psychiatric symptoms, and 11/13 had seizures. All of them subsequently presented with psychomotor agitation, dystonia, and bucolingual dyskinesias, with 11/13 loss of language and 6/13 autonomic disorders. All of them (13/13) had positive anti-NMDA receptor antibodies. CSF was normal in 12/13 children, positive oligoclonal bands in 6/10 patients, normal brain resonance in 13/13 children, EEG changes in 11/13 children, and abnormal SPECT in 6/6 children. A methylprednisolone bolus of 30 mg/kg was given for 3-5 days to 12/13 children, and 6 received immunoglobulin 2 g/kg. The large majority (12/13) of children recovered 1-4 months after disease onset. One child had a recurrence one year later, and recovered quickly. Conclusions: Subacute encephalitis due to NMDA anti-receptor antibodies should be suspected in children with psychiatric disorders and abnormal movements. Functional studies, such as EEG and SPECT are valuable diagnostic support. Early detection of this encephalitis leads to a faster recovery of patients.

Encefalitis por anticuerpos antirreceptor N-metil-D-aspartato / Anti N-methyl-D-aspartate receptor encephalitis

Resumen:La encefalitis por anticuerpos antirreceptor N-metil-D-Aspartato pertenece a un grupo de enfermedades que inicialmente se llamaban encefalitis límbicas, hoy conocidas como encefalitis autoinmunes. Se caracterizan por estar frecuentemente asociadas a algún tumor, responder a la inmunoterapia y provocar daños cerebrales variables que se manifiestan como cuadros clínicos polimorfos (desde la disfunción límbica hasta una encefalopatía multifocal o difusa). Algunos pacientes con condiciones psiquiátricas agudas podrían tener en realidad una encefalitis autoinmune, sin embargo, no es tan fácil sospecharlo con las manifestaciones iniciales. Su incidencia exacta no se conoce, pero cada vez hay más reportes de casos. Sus características clínicas están bien descritas y evolucionan en cinco fases. El diagnóstico definitivo se hace al obtener la confirmación serológica de los anticuerpos, pero hay algunas pruebas que pueden orientar la sospecha diagnóstica. El tratamiento se basa en esteroides y otros inmunosupresores.

Abstract:Anti NMDA-receptor encephalitis belongs to a group of diseases originally called limbic encephalitis, nowadays known as autoimmune encephalitis. These encephalitis are characterized by a frequent association with a tumor, a good response to immunotherapy, and by causing a broad range of brain injuries which manifest in polymorphous clinical pictures (from limbic dysfunction to multifocal or diffuse encephalopathy). Some patients diagnosed with acute psychiatry conditions may have instead autoimmune encephalitis. Nevertheless, it is not easy to discern one from the other in the initial stages. Its exact incidence is unknown, but there are increasingly more case reports. Its clinical characteristics are well described and evolve in five stages or phases. The final diagnosis is made when antibodies serologic confirmation is obtained, but some other tests may help guide the diagnosis. The treatment is based on steroids and other immunosuppressants.

Encefalitis aguda mediada por anticuerpos contra el receptor ionotrópico de glutamato activado por N-metil-D-aspartato (NMDAR): análisis de once casos pediátricos en Argentina (Premio Benito Yelín) / [Acute encephalitis anti-ionotropic glutamate receptor activated N-methyl-D-aspartate (NMDAR): analysis of eleven pediatric cases in Argentina (Benito Yelín Award)].

Encephalitis are an inflammatory processes of various origin, among which include autoimmune origin. The identification of antibodies against the N-methyl-D- aspartate, allowed clinical immunological characterization of an entity susceptible to immunomodulatory therapy. Originally described in young women associated with ovarian teratoma, is now a recognized entity in children even in the absence of detectable tumors. The aim of the study was conducted through review of medical records, was to describe the clinical, developmental and findings in further studies of eleven children with confirmed diagnosis of this entity through identification of specific antibodies. All debuted with psychiatric symptoms in nine associating seizures, and two extrapyramidal movements. In the evolution of language all had commitment nine severe autonomic symptoms, one with hypoventilation and requirements of ARM. Brain MRI was abnormal in three. Eight had voltage EEG asymmetry and / or amplitude, three of them had spikes. Six had CSF pleocytosis and three of seven positive oligoclonal bands. Five IgM serology for mycoplasma were positive. CPK increase occurred in conjunction with antisychotics in five. With immunomodulatory treatment, five had complete recovery three behavioral disorders / cognitive deficits and one severe. A patient’s clinical picture resolved without treatment. In any associated tumor was detected. We conclude that in front of a child with acute encephalopathy and clinical support this entity after infectious cause were ruled out, immunomodulatory therapy should be started early, avoid the use of antipsychotic drugs and search for possible hidden tumors.

Encefalite anti-receptor N-metil-D-aspartato na infância / Anti-N-methyl D-aspartate receptor encephalitis in childhood

OBJETIVO: Discutir o diagnóstico diferencial das encefalites além daquelas de etiologia infecciosa, e alertar os pediatras para a possibilidade do diagnóstico de encefalite anti-receptor N-metil-D-aspartato (rNMDA) na população pediátrica, destacando suas principais características clínicas. DESCRIÇÃO: Três pacientes apresentaram-se com uma síndrome neuropsiquiátrica inicial seguida de encefalopatia e transtornos de movimento. As características neuropsiquiátricas iniciais se desenvolveram ao longo de dias ou semanas, com mudanças comportamentais, ansiedade, confusão mental e regressão da fala. Em seguida, os pacientes evoluíram com distúrbios de movimento, caracterizados por coreoatetose ou distonia, acometendo a região orofacial e os membros. Após a exclusão das principais causas de encefalite, foram identificados anticorpos anti-rNMDA no soro e no líquido cefalorraquidiano. Não foram detectadas neoplasias durante a investigação etiológica. Os pacientes foram submetidos a imunossupressão, e dois deles tiveram uma recuperação neurológica completa. Um deles ainda apresenta uma postura distônica leve em um dos membros. COMENTÁRIOS: Os sinais clínicos de encefalite anti-rNMDA em crianças são semelhantes aos anteriormente descritos em adultos. Tumores geralmente não são detectados nessa idade. O diagnóstico de encefalite anti-rNMDA deve ser abordado após a exclusão de outras causas de encefalite na infância, como as de origem infecciosa. Pediatras devem estar atentos a essa condição autoimune passível de tratamento.

OBJECTIVE: To discuss the differential diagnosis of encephalitis beyond that of infectious etiology and to inform pediatricians about the possibility of anti-N-methyl-D-aspartate receptor (NMDAr) encephalitis in children by highlighting its most important clinical features. DESCRIPTION: Three patients presented with an initial neuropsychiatric syndrome followed by encephalopathy and movement disorder. The initial neuropsychiatric features which developed over days to weeks included a change in personality, anxiety, confusion, and speech regression. This was followed by a choreoathetoid or dystonic movement disorder affecting the orofacial region and the limbs. After the exclusion of the major causes of encephalitis, NMDAr antibodies were identified in serum and cerebrospinal fluid, and neoplasm screening did not detect any tumor. Patients were submitted to immunosuppression, and two of them had a full neurological recovery. One of them still presents a mild dystonic posture in a limb. COMMENTS: Clinical signs of anti-NMDAr encephalitis in children are similar to those previously described in adults. Tumors are not usually detected by this age. The diagnosis of anti-NMDAr encephalitis must be addressed only after the exclusion of infectious and other recognizable causes of encephalitis. Pediatricians should be aware of this treatable autoimmune condition.