Tratamiento y evolución de la encefalitis inmunomediada en edad pediátrica, serie de casos / Treatment and outcome of immune-mediated encephalitis in children, a case series

Introducción: La encefalitis por anticuerpos contra el receptor N-metil.D.aspartato (NMDA-R) es un trastorno inflamatorio del sistema nervioso central (SNC) en el cual autoanticuerpos dirigidos hacia la subunidad NR1 del receptor N-metil-D aspartato (NMDA) desarrollan un conjunto de síntomas neuropsiquiátricos, convulsiones y movimientos anormales. El tratamiento recomendado incluye metilprednisolona (MP) y gamaglobulina (IVIg), y/o recambio plasmático terapéutico (RPT); y en caso de no respuesta: rituximab (RTX) y/o ciclofosfamida (CFM). Objetivos: Analizar características clínicas, bioquímicas, electroencefalograma (EEG), resonancia magnética (RM) cerebral, tratamientos recibidos y resultados observados en una serie de pacientes con encefalitis autoinmune (EA) probable o confirmada. Materiales y métodos: Analizamos las historias clínicas de pacientes menores a 17 años que cumplían criterios diagnósticos de Graus (2016) para EA probable, con seguimiento mayor a 6 meses, internados en el Hospital Garrahan entre 2008 y 2023. El diagnóstico se definió por la identificación de anticuerpos anti-NMDAR (N-metil D-aspartato) en líquido cefalorraquídeo (LCR) por ensayo basado en células - cell bassed assay (CBA). Resultados: Reunieron criterios de EA probable 94 pacientes con una edad media de 89.5 meses, 51% mujeres. Se dividieron en dos grupos: seropositivos y seronegativos de acuerdo al resultado del biomarcador. Seropositivos 45/94. El síntoma inicial más frecuente fue: convulsiones. El 28% requirió ingreso a Unidad de Cuidados Intensivos (UCI). 4 pacientes seropositivos y 1 seronegativo tuvieron encefalitis por el virus del herpes simple (Om) previamente. En una paciente seronegativa se diagnosticó teratoma ovárico. Hallazgos de estudios complementarios: LCR patológico en el 29%, RM cerebral en el 52%, EEG en el 74%. El tratamiento de primera línea más empleado fue MP + IVIg. El 46% de los pacientes presentó recuperación completa. Entre los pacientes que recibieron RTX, el 65% tuvo una recuperación completa. Ningún paciente que recibió RTX presentó recaída. Conclusión: Ante la sospecha de EA se debe considerar el inicio temprano de inmunoterapia para favorecer la rápida recuperación funcional. Se recomienda el uso temprano de RTX en los casos con presentación grave o respuesta subóptima al tratamiento de primera línea para beneficiar la respuesta clínica y reducir el riesgo de recaída (AU)

Introduction: Encephalitis due to antibodies against the N-methyl-D-aspartate receptor (NMDA-R) is an inflammatory disorder of the central nervous system (CNS) in which autoantibodies directed against the NR1 subunit of the N-methyl-D-aspartate (NMDA) receptor develop a set of neuropsychiatric symptoms, seizures, and abnormal movements. The recommended treatment includes methylprednisolone (MP) and intravenous immunoglobulin (IVIg), and/or therapeutic plasma exchange (TPE); and in case of non-response: rituximab (RTX) and/or cyclophosphamide (CFM). Objectives: To analyze clinical, biochemical, electroencephalogram (EEG), magnetic resonance imaging (MRI) of the brain, treatments received, and outcomes observed in a series of patients with probable or confirmed autoimmune encephalitis (AE). Materials and methods: We analyzed the medical records of patients under 17 years of age who met Graus' diagnostic criteria (2016) for probable AE, with follow-up of more than 6 months, hospitalized at Hospital Garrahan between 2008 and 2023. Diagnosis was defined by the identification of anti-NMDAR antibodies (N-methyl D-aspartate) in cerebrospinal fluid (CSF) by cell-based assay (CBA). Results: Ninety-four patients met criteria for probable AE with a mean age of 89.5 months, 51% female. They were divided into two groups: seropositive and seronegative according to the biomarker result. Seropositive 45/94. The most frequent initial symptom was seizures. Twenty-eight percent required admission to the Intensive Care Unit (ICU). Four seropositive patients and one seronegative patient had previously had herpes simplex encephalitis (Om). Ovarian teratoma was diagnosed in one seronegative patient. Findings of complementary studies: Pathological CSF in 29%, brain MRI in 52%, EEG in 74%. The most commonly used first-line treatment was MP + IVIg. Forty-six percent of patients experienced complete recovery. Among patients who received RTX, 65% had complete recovery. No patient who received RTX experienced relapse. Conclusion: In the suspicion of AE, early initiation of immunotherapy should be considered to promote rapid functional recovery. Early use of RTX is recommended in cases with severe presentation or suboptimal response to first-line treatment to benefit clinical response and reduce the risk of relapse (AU)

Autoimmune encephalitis in a resource-limited public health setting: a case series analysis / Encefalite autoimune em um hospital universitário público: análise de uma série de casos

Abstract Background Autoimmune encephalitis (AE) consists of a group of acquired diseases that affect the central nervous system. A myriad of phenotypes may be present at the onset. Due to the heterogeneity of clinical presentations, it is difficult to achieve uniformity for the diagnostic and therapeutic processes and follow-up strategies. Objective To describe a series of patients diagnosed with AE in a resource-limited public hospital in southern Brazil and to analyze therapeutics and outcomes. Methods We retrospectively reviewed the electronic medical records of patients diagnosed with AE at the Hospital de Clínicas de Porto Alegre from 2014 to 2022. Data collected included clinical presentation, neuroimaging, cerebrospinal fluid testings, electroencephalogram, autoantibodies, treatments, outcomes, follow-up time, degree of neurological impairment, and mortality. Results Data from 17 patients were retrieved. Eleven cases were classified as definite AE and 6 as possible AE. Autoantibodies were identified in 9 patients. Timing for diagnosis was impacted by the high costs associated with autoantibody testing. Most patients became functionally dependent (82.4%) and most survivors remained with autoimmune-associated epilepsy (75%). Five patients died during hospitalization, and one after a 26-month of follow-up. Conclusion In this resource-limited hospital, patients with AE had a worse clinical outcome than that previously described in the literature. Development of epilepsy during follow-up and mortality were greater, whilst functional outcome was inferior. Autoantibody testing was initially denied in most patients, which impacted the definitive diagnosis and the use of second-line therapies.

Resumo Antecedentes A encefalite autoimune (EA) consiste em um grupo de doenças adquiridas que afetam o sistema nervoso central. Objetivo Descrever uma série de pacientes diagnosticados com EA em um contexto de atenção terciária à saúde com recursos limitados e analisar a terapêutica e os resultados. Métodos Revisamos retrospectivamente os prontuários eletrônicos de pacientes diagnosticados com EA no Hospital de Clínicas de Porto Alegre de 2014 a 2022. Os dados coletados incluíram apresentação clínica, neuroimagem, exames de líquido cefalorraquidiano, eletroencefalograma, autoanticorpos, tratamentos, resultados, tempo de acompanhamento, grau de comprometimento neurológico e mortalidade. Resultados Dados de 17 pacientes foram coletados. Onze casos foram classificados como EA definitivo e seis como EA possível. Autoanticorpos foram identificados em nove pacientes. O tempo para o diagnóstico foi afetado pelos altos custos associados ao teste de autoanticorpos. A maioria dos pacientes tornou-se funcionalmente dependente (82,4%), e a maioria dos sobreviventes permaneceu com epilepsia autoimune associada (75%). Cinco pacientes faleceram durante a internação, e um após 26 meses de seguimento. Conclusão No hospital em questão, os pacientes com EA tiveram um desfecho clínico pior do que o previamente descrito na literatura. O desenvolvimento de epilepsia durante o acompanhamento e a mortalidade foram maiores, enquanto o desfecho funcional foi inferior. Os testes de autoanticorpos foram inicialmente negados para a maioria dos pacientes, o que impactou o diagnóstico definitivo e o uso de terapias de segunda linha.

Review of dengue, zika and chikungunya infections in nervous system in endemic areas / Revisão da infecção por dengue, zika e chikungunya no sistema nervoso em áreas endêmicas

Abstract Dengue, zika, and chikungunya are arboviruses of great epidemiological relevance worldwide. The emergence and re-emergence of viral infections transmitted by mosquitoes constitute a serious human public health problem. The neurological manifestations caused by these viruses have a high potential for death or sequelae. The complications that occur in the nervous system associated with arboviruses can be a challenge for diagnosis and treatment. In endemic areas, suspected cases should include acute encephalitis, myelitis, encephalomyelitis, polyradiculoneuritis, and/or other syndromes of the central or peripheral nervous system, in the absence of a known explanation. The confirmation diagnosis is based on viral (isolation or RT-PCR) or antigens detection in tissues, blood, cerebrospinal fluid, or other body fluids, increase in IgG antibody titers between paired serum samples, specific IgM antibody in cerebrospinal fluid and serological conversion to IgM between paired serum samples (non-reactive in the acute phase and reactive in the convalescent). The cerebrospinal fluid examination can demonstrate: 1. etiological agent; 2. inflammatory reaction or protein-cytological dissociation depending on the neurological condition; 3. specific IgM, 4. intrathecal synthesis of specific IgG (dengue and chikungunya); 5. exclusion of other infectious agents. The treatment of neurological complications aims to improve the symptoms, while the vaccine represents the great hope for the control and prevention of neuroinvasive arboviruses. This narrative review summarizes the updated epidemiology, general features, neuropathogenesis, and neurological manifestations associated with dengue, zika, and chikungunya infection.

Resumo Dengue, zika e chikungunya são arboviroses de grande relevância epidemiológica em todo o mundo. A emergência e reemergência dessas infecções virais transmitidas por mosquitos constituem um grave problema de saúde pública humana. As manifestações neurológicas causadas por esses vírus têm alto potencial de morte ou sequelas. As complicações que ocorrem no sistema nervoso associadas às arboviroses podem representar um desafio diagnóstico e de tratamento. Em áreas endêmicas, casos suspeitos devem incluir encefalite, mielite, encefalomielite, polirradiculoneurite e/ou outras síndromes do sistema nervoso central ou periférico, na ausência de explicação conhecida. Caso confirmado de arbovirose neuroinvasivo é baseado na detecção viral (isolamento ou RT-PCR) ou de antígenos em tecidos, sangue, líquido cefalorraquidiano ou outros fluidos corporais, aumento dos títulos de anticorpos IgG entre amostras de soro pareadas, anticorpo IgM específico no líquido cefalorraquidiano e conversão sorológica para IgM entre amostras de soro pareadas. O exame do líquido cefalorraquidiano pode demonstrar: 1. agente etiológico; 2. reação inflamatória ou dissociação proteico-citológica, dependendo do quadro neurológico; 3. valor absoluto de IgM específica; 4. síntese intratecal de anticorpos IgG específicos (dengue e chikungunya); 5. exclusão de outros agentes infecciosos. O tratamento das complicações neurológicas visa melhorar os sintomas, enquanto a vacina representa a grande esperança para o controle e a prevenção das arboviroses neuroinvasivas. Esta revisão narrativa resume a atualização da epidemiologia, características gerais, neuropatogênese e manifestações neurológicas associadas à infecção pelos vírus da dengue, zika e chikungunya.

Manifestaciones neurológicas asociadas a infección por virus chikungunya en una población pediátrica hospitalaria

Introducción: La infección por Chikungunya se presenta fiebre y afectación cutánea. Las manifestaciones neurológicas, incluyen encefalopatías principalmente encefalitis; afectación periférica como mielitis, o una combinación de éstas. Objetivo: Describir la frecuencia y las manifestaciones neurológicas asociadas a infección por virus Chikungunya en el periodo enero-marzo 2023 en una población pediátrica. Materiales y Métodos: Estudio descriptivo retrospectivo de corte transversal de serie de casos Ingresaron menores de 18 años con manifestaciones neurológicas y resultados positivos PCR RT a virus Chikungunya que acudieron a un Hospital Público en enero-marzo del 2023. Las variables: demográficas, tiempo de evolución, síntomas, diagnósticos neurológicos, estudio de líquido cefalorraquídeo, electroencefalograma, estudios imagenológicos, tratamiento, ingreso a Unidad de Cuidados Intensivos, disfunción orgánica, mortalidad. Los datos se analizaron en SPSS utilizando estadística descriptiva. El protocolo fue aprobado por el comité de ética. Resultados: Ingresaron 24 pacientes, con edad de 10.0 ±1 meses. El 58.7% de sexo masculino. Como síntoma neurológico, el 54.1% tuvo convulsión. Los diagnósticos neurológicos, el 83.3% fue Encefalitis. Los pacientes con diagnóstico de Encefalitis, 75% fueron menores de 3 meses, 50% con líquido cefalorraquídeo patológico, 45% se realizó Electroencefalografía, 50% recibió inmunoglobulinas. El 50% ingresaron a Unidad de Cuidados Intensivos. Pediátricos. El 60% presentó disfunción orgánica. La mortalidad fue del 4.2%. Conclusión: El diagnóstico neurológico más frecuente fue la encefalitis, predominó en lactantes menores de 3 meses. Los síntomas neurológicos fueron: crisis convulsivas e irritabilidad. Más de la mitad presentaron disfunción orgánica, se registró la mortalidad de un paciente.

Introduction: Chikungunya infection present clinically with fever and skin involvement. Neurological manifestations include encephalopathies, mainly encephalitis and meningoencephalitis; peripheral involvement such as myelitis, Guillain Barré Syndrome; or a combination of these such as encephaloneuromyelopathy. Objective: To describe the frequency and neurological manifestations associated with Chikungunya virus infection during the January-March 2023 time period in a pediatric population. Materials and Methods: This was a descriptive, retrospective and cross-sectional study of a case series. Minors under 18 years of age were admitted with neurological manifestations and positive RT-PCR results for Chikungunya virus who presented to a Public Hospital in January-March 2023. The variables were: demographics, reason for hospitalization, symptoms, neurological diagnoses, cerebrospinal fluid study, electroencephalogram, imaging studies, treatment, admission to the Intensive Care Unit, organic dysfunction and mortality. Data were analyzed in SPSS using descriptive statistics. The protocol was approved by the Ethics Committee. Results: 24 patients were admitted, aged 10.0 ±16 months. 58.7% were male. As a neurological symptom, 54.1% had a seizure. Among the neurological diagnoses, 83.3% were encephalitis. Among the patients diagnosed with encephalitis, 75% were younger than 3 months, 50% had pathological cerebrospinal fluid, 45% underwent electroencephalography, and 50% received immunoglobulins. 50% were admitted to the Pediatric Intensive Care Unit. 60% presented organic dysfunction. Mortality was 4.2%. Conclusions: The most frequent neurological diagnosis was encephalitis, it predominated in infants under 3 months. The neurological symptoms were: seizures and irritability. More than half presented organic dysfunction, one patient expired.

Encefalitis autoinmune seronegativa asociada a síndrome de Sjögren primario / Autoimmune seronegative encephalitis associated to primary Sjögren's disease

La encefalitis autoinmune es un trastorno inmunomediado que compromete distintos territorios del parénquima cerebral, involucrando frecuentemente la materia gris profunda o la corteza, con o sin compromiso de la materia blanca, meninges o médula espinal. Se asocia frecuentemente con enfermedades autoinmunes o paraneoplásicas, y constituye un reto diagnóstico. Reportamos el caso de una mujer de 55 años con antecedente de síndrome de Sjögren que consultó a Emergencias por cefalea y confusión. El líquido cefalorraquídeo (LCR) presentaba leucocitosis con neutrofilia. En la resonancia magnética nuclear (RMN) cerebral se evidenciaron múltiples imágenes de comportamiento restrictivo, de señal hiperintensa en T2 y FLAIR, a predominio córtico-subcortical a nivel occipital bilateral, hemisferio cerebeloso derecho y parietal derecho. Se descartaron infecciones y neoplasias. El panel de anticuerpos para encefalitis autoinmune aquaporina-4 y anti-MOG en LCR fue negativo. Recibió metilprednisolona endovenosa con mejoría progresiva de los síntomas.

Autoimmune encephalitis is an immune-mediated disorder that affects different areas of the brain parenchyma, often involving deep gray matter or the cortex, with or without involvement of white matter, meninges, or spinal cord. It is frequently associated with autoimmune or paraneoplastic diseases and is a diagnostic challenge. We report the case of a 55-year-old woman with history of Sjögren's syndrome who presented to the emergency department with headache and episodes of confusion. Cerebrospinal fluid (CSF) analysis showed leukocytosis with neutrophilia. Brain MRI revealed multiple restricted diffusion lesions with hyperintense signal on T2 and FLAIR sequences, predominantly in the bilateral occipital region, right cerebellar hemisphere, and right parietal region. Infections and neoplasms were ruled out. The panel of antibodies for autoimmune encephalitis, including Aquaporin-4 and anti-MOG in CSF, was negative. She received intravenous methylprednisolone, leading to symptom improvement.

Encefalitis autoinmune posherpética. Caso clínico pediátrico / Autoimmune post-herpes simplex encephalitis. A pediatric clinical case report

La encefalitis por virus herpes simple (VHS) es una causa frecuente de encefalitis grave y potencialmente fatal. La encefalitis autoinmune posherpética (EAPH) afecta a un porcentaje de los pacientes que han presentado encefalitis herpética (EH) y se caracteriza por la aparición de nuevos síntomas neurológico/psiquiátricos, y/o por el empeoramiento de los déficits adquiridos durante la infección viral dentro de un lapso temporal predecible. Se produce por un mecanismo no relacionado con el VHS, sino por fenómenos autoinmunes, y es susceptible de tratamiento con inmunomoduladores. Se presenta el caso de un varón de 5 años de edad con EAPH que requirió tratamiento inmunomodulador, de primera y segunda línea, con buena evolución y remisión de los síntomas.

Herpes simplex virus (HSV) encephalitis is a common cause of severe and potentially fatal encephalitis. Autoimmune post-herpes simplex encephalitis (AIPHSE) affects a percentage of patients who developed herpes simplex encephalitis (HSE) and is characterized by the onset of new neurological/psychiatric symptoms and/or worsening of deficits acquired during the herpes infection within a predictable time frame. It is caused by a mechanism not related to HSV, but by autoimmune conditions, and is susceptible to treatment with immunomodulators. Here we describe the case of a 5-year-old boy with AIPHSE who required first- and second-line immunomodulatory treatment, with an adequate course and remission of symptoms.

Encefalitis asociada a infección por SARS-CoV-2

El virus SARS-CoV-2 produce una enfermedad conocida como COVID-19 y puede producir complicaciones neurológicas como la encefalitis, la cual consiste en la inflamación a nivel del parénquima cerebral. Su pronto diagnóstico es crucial para poder asegurar la supervivencia de los individuos, ya que puede llevar al paciente al ingreso en unidad de cuidados intensivos. El tratamiento consiste en el soporte vital, la disminución de la inflamación y de la presión intracraneal, aunque estas medidas en ocasiones no son suficientes debido a que posee una alta tasa de mortalidad. Objetivo. Identificar las principales características clínicas de la encefalitis asociada a la infección por SARS-CoV-2. Metodología. Se realizó una revisión sistemática bajo la metodología PRISMA, utilizando diversos motores de búsqueda como PubMed, ScienceDirect, Web of Science y Scopus de los últimos cinco años en idioma inglés y español. Resultados. Se encontraron 63 artículos identificados en las bases de datos: PubMed; 18, Scielo con un total de 3, Sciencedirect con 3 y Google Scholar; 39. De estos artículos encontrados, 15 artículos estaban duplicados, 13 artículos eliminados por título y resumen, esto realizado luego de tomar en cuenta criterios de exclusión y relevancia del artículo mismo, se eliminaron 25 artículos luego de analizar el texto completo, obteniendo finalmente 10 artículos a emplear dentro del presente estudio. Conclusión. Se concluyó que el SARS-CoV-2 tiene repercusión a nivel del sistema nervioso central, dando como resultado la presencia de patologías como encefalitis, la cual tiene una baja incidencia entre los pacientes, pero una mortalidad para nada despreciable.

The SARS-CoV-2 virus produces a disease known as COVID-19 and can produce neurological complications such as encephalitis, which consists of inflammation at the level of the brain parenchyma. Early diagnosis is crucial to ensure the survival of individuals, as it can lead to admission to the intensive care unit. Treatment consists of life support, reduction of inflammation and intracranial pressure, although these measures are sometimes not sufficient due to a high mortality rate. Objective. To identify the main clinical features of encephalitis associated with SARS-CoV-2 infection. Methodology. A systematic review was carried out under the PRISMA methodology, using different search engines such as PubMed, ScienceDirect, Web of Science and Scopus from the last five years in English and Spanish. Results. We found 63 articles identified in the databases: PubMed; 18, Scielo with a total of 3, Sciencedirect with 3 and Google Scholar; 39. Of these articles found, 15 articles were duplicates, 13 articles eliminated by title and abstract, this done after taking into account exclusion criteria and relevance of the article itself, 25 articles were eliminated after analyzing the full text, finally obtaining 10 articles to be used within the present study. Conclusion. It was concluded that SARS-CoV-2 has repercussions at the level of the central nervous system, resulting in the presence of pathologies such as encephalitis, which has a low incidence among patients, but not negligible mortality.

O vírus SARS-CoV-2 causas uma doença conhecida como COVID-19 e pode levar a complicações neurológicas, como a encefalite, que consiste em uma inflamação no nível do parênquima cerebral. O diagnóstico precoce é fundamental para garantir a sobrevivência dos indivíduos, pois pode levar à internação na unidade de terapia intensiva. O tratamento consiste em suporte à vida, redução da inflamação e redução da pressão intracraniana, embora essas medidas às vezes não sejam suficientes devido à alta taxa de mortalidade. Objetivo. Identificar as principais características clínicas da encefalite associada à infecção pelo SARS-CoV-2. Metodologia. Foi realizada uma revisão sistemática de acordo com a metodologia PRISMA, usando vários mecanismos de busca, como PubMed, ScienceDirect, Web of Science e Scopus, dos últimos cinco anos, em inglês e espanhol. Resultados. Sessenta e três artigos foram identificados nos seguintes bancos de dados: PubMed; 18, Scielo com um total de 3, Sciencedirect com 3 e Google Scholar; 39. Desses artigos encontrados, 15 eram duplicatas, 13 artigos foram eliminados pelo título e resumo, o que foi feito após levar em conta os critérios de exclusão e a relevância do artigo em si, 25 artigos foram eliminados após a análise do texto completo, obtendo-se finalmente 10 artigos a serem usados no presente estudo. Conclusões. Concluiu-se que o SARS-CoV-2 tem repercussões em nível do sistema nervoso central, resultando na presença de patologias como a encefalite, que tem baixa incidência entre os pacientes, mas mortalidade não desprezível.

Secuelas cognitivas en encefalitis inmunomediadas: cohorte de pacientes en Argentina / Cognitive sequelae in immunomediated encephalitis: cohort of patients in Argentina

Resumen Introducción: Las encefalitis inmunomediadas son un desorden neurológico de origen autoinmune. Actual mente es escasa la descripción de las secuelas cognitivas crónicas. El objetivo del presente trabajo fue caracterizar la secuela cognitiva de diferentes tipos de encefalitis inmunomediadas en una cohorte de un centro único de Argentina. Métodos: Estudio prospectivo, observacional, trans versal, de pacientes en seguimiento en un hospital de la Ciudad de Buenos Aires, con diagnóstico de encefalitis inmunomediada probable y definitiva. Se evaluaron variables epidemiológicas, clínicas, paraclínicas y tra tamiento. Se determinó la secuela cognitiva a través de una evaluación neurocognitiva realizada a partir del año de la presentación clínica. Resultados: Fueron incluidos 15 pacientes, todos con resultado disminuido en al menos un test. La memoria fue el dominio más afectado. Aquellos que se encon traban bajo tratamiento inmunosupresor al momento de evaluarse presentaron menores resultados en el aprendizaje seriado (media -2.94; desvío estándar 1.54) versus los que se encontraban sin tratamiento (media -1.18; desvío estándar 1.40; p = 0.05) y en la prueba de reconocimiento (media -10.34; desvío estándar 8.02) ver sus sin tratamiento (media -1.39; desvío estándar 2.21; p = 0.003). Los pacientes con estatus epiléptico tuvieron resultados deficitarios en la prueba de reconocimiento (media -7.2; desvío estándar 7.91) en comparación a los que no lo tenían (media -1.47; desvío estándar 2.34; p = 0.05). Conclusión: Nuestros resultados demuestran que, a pesar del curso monofásico de la enfermedad, todos los pacientes presentan daño cognitivo persistente más allá del año del inicio del cuadro. Estudios prospectivos de mayor envergadura serían necesarios para confirmar nuestros hallazgos.

Abstract Introduction: Autoimmune encephalitis represents a group of immune-mediated neurological disorders. At present, the description of the chronic cognitive sequela is scarce. The objective of this study was to characterize the cognitive after effects of different types of autoimmune encephalitis in a cohort from a single center in Argentina. Methods: Prospective, observational, cross-sectional study of patients under follow-up at a hospital in Buenos Aires city, with a diagnosis of probable and definitive immune-mediated encephalitis. Epidemiological, clini cal, paraclinical and treatment related variables were evaluated. Cognitive sequela was determined through a neurocognitive evaluation performed at least a year after the clinical presentation. Results: Fifteen patients were included. All had di minished results in at least one test. Memory was the most affected domain. Patients who were under im munosuppressive treatment at the time of evaluation presented lower results in serial learning (mean -2.94; standard deviation 1.54) versus those who weren't under treatment (mean -1.18; standard deviation 1.40; p = 0.05). The same pattern was observed on the recognition test of treatment group (mean -10.34; standard deviation 8.02) versus treatment-free group (mean -1.39; standard deviation 2.21; p =0.003). Patients with status epilepticus had poorer results in the recognition test (mean -7.2; standard deviation 7.91) compared to those without it (mean -1.47; standard deviation 2.34; p = 0.05). Conclusion: Our results show that, despite the mo nophasic course of this disease, all patients had persis tent cognitive damage beyond the year of onset. Larger prospective studies are required to confirm our findings.

Autoimmune encephalitis related to nivolumab followed by tumor regression / Encefalitis autoinmune relacionada con nivolumab se guida de regresión tumoral

Abstract Immune checkpoints inhibitors have shown a re markable improvement in overall survival of stage IV renal cell carcinoma patients. Nevertheless, there is a wide range of immune-related adverse events (IRAE) that arise from these revolutionary treatments. Autoim mune encephalitis is a rare but severe central nervous system IRAE in these cancer patients. The severities of these IRAEs preclude patients from continuing im munotherapy treatment. Few cases of autoimmune encephalitis with immunotherapy have been described in the literature and optimal clinical management of these events as well as patient's immune-mediated response after treatment suspension is still unclear. Here, we report a case of a 67 years-old woman with stage IV renal cell carcinoma under treatment with nivolumab who developed autoimmune encephalitis. After high doses of corticosteroids patient's condition improved significantly with full recovery after 5 days of treatment. Even though nivolumab was not reinstalled, a persistent response of her oncologic disease was evi denced. We expect that this case can contribute to the existing literature of both subjects, the management of autoimmune encephalitis as grade IV immune related adverse event and the responses of immune checkpoint inhibitors after IRAE.

Resumen Los inhibidores de puntos de control inmunológico han mostrado una importante mejoría en la supervi vencia global de los pacientes con carcinoma de riñón estadio IV. Sin embargo, existe una amplia variedad de efectos adversos inmunomediados que surgen a partir de estos tratamientos revolucionarios. La encefalitis au toinmune es un infrecuente pero grave efecto adverso inmunomediado del sistema nervioso central en estos pacientes. La gravedad de este cuadro impide que los pa cientes continúen con el tratamiento de inmunoterapia. Se han descrito pocos casos de encefalitis autoinmune con inmunoterapia en la literatura y aún no está claro el manejo clínico óptimo de estos eventos, ni cómo continua la respuesta inmunomediada después de la suspensión del tratamiento. Presentamos el caso de una mujer de 67 años con carcinoma de células renales estadio IV que desarrolló encefalitis autoinmune durante el tratamiento con nivolumab. La paciente mejoró significativamente luego del inicio del tratamiento con altas dosis de cor ticoides, con una recuperación completa después de 5 días del mismo. Si bien el nivolumab no se reinició, se evidenció una respuesta persistente de su enfermedad oncológica. Esperamos que este caso pueda contribuir a la literatura existente de ambos temas, el manejo de la encefalitis autoinmune como efecto adverso inmunome diado grado IV y las respuestas que se obtienen con la inmunoterapia luego de estos efectos adversos.

Encefalitis aguda por dengue durante el embarazo

El dengue es un problema de salud pública. La mayoría de los pacientes desarrollan signos clínicos que van desde enfermedad leve hasta síndrome hemorrágico. Las manifestaciones neurológicas inusuales son raras y cada vez existen más pruebas de neurotropismo. La encefalitis por dengue es el resultado del trastorno multisistémico que ocurre en la infección grave y durante el embarazo puede ser difícil de diagnosticar. Además, es importante considerarla como diagnóstico diferencial en pacientes en zonas endémicas en pacientes con enfermedad febril aguda y síntomas neurológicos. El manejo de la encefalitis por dengue durante el embarazo es un desafío y es necesario realizar todas las pruebas posibles para decidir el manejo óptimo y preciso para evitar complicaciones maternas. Se presenta un caso de encefalitis aguda por dengue durante el embarazo.

Dengue is a public health problem. Most patients develop clinical signs ranging from mild illness to hemorrhagic syndrome. Unusual neurological manifestations are rare and there is increasing evidence of neurotropism by the virus. Dengue encephalitis is the result of the multisystem disorder that occurs in severe infection and during pregnancy can be difficult to diagnose. In addition, it is important to consider it as a differential diagnosis in patients in endemic areas in patients with acute febrile illness and neurological symptoms. The management of dengue encephalitis during pregnancy is a challenge and it is necessary to perform all possible tests to decide the optimal and accurate management to avoid maternal complications. A case of acute dengue encephalitis during pregnancy is presented.

Epilepsia secundaria a encefalitis por el virus de Epstein Barr / Epilepsy secondary to encephalitis due to Epstein Barr virus

Presentación del caso. Se trata de una mujer de 44 años de edad, con historia de cefalea occipital, lenguaje incoherente y pensamiento confuso. Inicialmente presentaba diez puntos en la escala de Glasgow y una hemiparesia izquierda. La tomografía computarizada de cráneo, reportó edema cerebral con lesión hipodensa talámica derecha y deterioro neurológico progresivo.El electroencefalograma evidenció desaceleración unilateral hemisférica derecha. El estudio del líquido cefalorraquídeo describió hiperproteinorraquia y un recuento a predominio linfocitario de 450 células con glucorraquia conservada, sin presencia de bacterias. Intervención terapéutica. se manejó con soporte ventilatorio invasivo y con tratamiento antibiótico y antiviral a dosis meníngeas, además de anticonvulsivantes. Los hallazgos tomográficos de control reportaron una hidrocefalia; se colocó una derivación ventricular tipo Becker. La serología IgM resultó positiva para virus de Epstein Barr y se identificó el genoma viral en el líquido cefalorraquídeo, a través de la prueba de reacción en cadena de polimerasa. La tomografía cerebral de control, evidenció la persistencia de la ventriculomegalia y de edema cerebral, lo que generó el diagnóstico de una encefalitis de etiología viral complicada con epilepsia secundaria por una lesión estructural desmielinizante del hemisferio cerebral derecho. Evolución clínica. La intervención terapéutica con inmunoglobulina intravenosa generó una mejoría del estado general. Fue posible retirar la derivación ventricular y la ventilación pulmonar diez y 19 días después del ingreso, respectivamente. La paciente se encuentra actualmente en fisioterapia con persistencia de hemiparesia izquierda, alteraciones de la marcha, disartria y episodios convulsivos controlados durante los últimos seis meses

Case presentation. This case is about a 44 years old woman with a history of occipital headache, incoherent speech and confused thinking. She initially presented ten points on the Glasgow scale and left hemiparesis. Cranial CT scan reported cerebral edema with right thalamic hypodense lesion and progressive neurological deterioration. The electroencephalogram showed unilateral right hemispheric deceleration. The cerebrospinal fluid study showed hyperproteinuria and a predominantly lymphocyte count of 450 cells with preserved glycorrhachia, without the presence of bacteria. Treatment.was managed with invasive ventilatory support and antibiotic and antiviral treatment at meningeal doses, in addition to anticonvulsants. Control tomographic findings showed hydrocephalus; a Becker type ventricular shunt was placed. IgM serology was positive for Epstein Barr virus and the viral genome was identified in the cerebrospinal fluid by polymerase chain reaction test. The control brain tomography showed persistent ventriculomegaly and cerebral edema, which led to the diagnosis of encephalitis of viral etiology complicated by epilepsy secondary to a demyelinating structural lesion of the right cerebral hemisphere. Outcome. Therapeutic intervention with intravenous immunoglobulin was performed with improvement of the general condition, it was possible to remove the ventricular shunt and pulmonary ventilation ten and 19 days after admission, respectively. The patient is currently in physical therapy with persistence of left hemiparesis, gait disturbances, dysarthria, and controlled convulsive episodes during the last six months.

DIAGNOSTIC DILEMMA IN TYPHOID ENCEPHALOPATHY

Using the immune system to its advantage, Salmonella Typhi initially invades the gut followed by the reticuloendothelial system and finally the nervous system, involvement of which usually occurs around the second week of fever. In developing countries, delayed diagnosis is predominantly due to hesitation in seeking treatment. Our subject presented with fever since one week, altered mentation, headache and neck pain; she was diagnosed with enteric fever. Although her neurological abnormality could be a complication of the infection, it appeared when she became afebrile- hence we evaluated her for autoimmune conditions. Positive results hinted at autoimmune encephalitis triggered by the infection; further studies were inconclusive. Association of enteric fever with autoimmune encephalitis has not been reported. Three months later, presence of antinuclear antibodies (ANA) was rechecked- a negative report led to a retrospective diagnosis of transient ANA positivity in a nonautoimmune inflammatory disease, the case in point being enteric fever.

The relationship between MMP-2 rs243865, MMP-9 rs398242 and CXCL-12 rs1801157 gene polymorphisms with Japanese encephalitis disease and disease outcome in North Indian population

Background & objectives: Japanese encephalitis virus (JEV) is one of the most important causes of acute and uncontrolled inflammatory disease in Asia. Matrix metalloproteinases (MMPs) and chemokines play a detrimental role in the host response to JE disease, aetiology, and disease outcome. Evidently, MMPs are widely circulated in the brain and regulate various process including microglial activation, inflammation, blood-brain barrier disruption as well as affects central nervous system (CNS). The present study was to assess the association of single nucleotide polymorphisms of MMP-2, MMP-9 and chemokine (CXCL-12/SDF1-3’) in the north Indian population. Methods: We performed case-control study comprising of 125 patients and 125 healthy controls in north Indian population. Genomic DNA was extracted from whole blood and gene polymorphism have been determined by PCR-RFLP method. Results: MMP-2, MMP-9 and CXCL-12 gene was not significantly associated with JE disease, but homozygous (T/T) genotype of MMP-2 was statically associated with disease outcome (p=0.05, OR=0.110). A/G and G/G genotype of CXCL-12 was significantly associated with severity of disease. (p=0.032, OR=5.500, p=0.037, OR= 9.167). The serum level of MMP-2 was observed significantly increased in JE patients with homozygous (T/T) genotype whereas increased MMP-9 level was associated with heterozygous genotype. Interpretation & conclusion: MMP-2, MMP-9 and CXCL-12 gene polymorphism were not associated with JE susceptibility, but MMP-2 may be contributed to disease protection. CXCL-12 was associated with disease severity. In our concern this is the first report from northern India.

Tandem expression and purification of tick-borne encephalitis virus E protein Domain Ⅲ and preparation of its polyclonal antibody / 中国生物制品学杂志

@#Objective To express and purify the E protein Domain Ⅲ(ED Ⅲ) of tick-borne encephalitis virus(TBEV) in tandem and prepare the corresponding polyclonal antibody.Methods The TBEV RNA was extracted by Trizol method,and then reversely transcribed into cDNA,which was used as template to amplify ED Ⅲ gene fragment by PCR.Two ED Ⅲ gene fragments were ligated into fusion gene by the hydrophobic flexible polypeptide(G_4S)_3 using overlapping PCR,which was then linked to prokaryotic expression vector pET-28a(+) to construct the recombinant expression plasmid pET-28a-2ED Ⅲ.After sequencing,pET-28a-2ED Ⅲ was transformed into E.coli BL21(DE3) competent cells,induced by IPTG and purified by Ni~(2+) affinity chromatography.Female New Zealand white rabbits were immunized with the renatured recombinant protein to prepare polyclonal antibody.The antibody titer was detected by indirect ELISA and the specificity was identified by Western blot.The homology of ED Ⅲ amino acid sequence between TBEV and other flaviviruses was analyzed by DNAMAN software.Results The recombinant plasmid pET-28a-2ED Ⅲ was identified by sequencing,and the amplified sequence contained two genes consistent with the E sequence of TBEV "Senzhang" strain(JQ650523.1) included on GenBank,indicating that the recombinant plasmid was constructed correctly.The recombinant 2ED Ⅲ protein was expressed mainly in the form of inclusion bodies,with a relative molecular mass of about 21 000 and a purity of 97.5%.The titer of rabbit anti-2ED Ⅲ serum polyclonal antibody was 1:10~7,which reacted specifically with TBEV whole virus.DNAMAN software alignment showed that the homology of ED Ⅲ amino acid sequences between TBEV and Japanese encephalitis virus(JEV),yellow fever virus(YFV) and Dengue virus(DENY) was 36.56%,9.28% and 30.77%,respectively.Conclusion The TBEV envelope ED Ⅲ tandem recombinant expression plasmid pET-28a-2ED Ⅲ was successfully constructed.The expressed recombinant 2ED Ⅲ protein had good reactivity and immunogenicity,and the prepared polyclonal antibody had high titer.

Correlation of serum antibody titers with clinical features and prognosis of anti leucine-rich glioma inactivated 1 antibody encephalitis / 中华神经科杂志

Objective:To analyze the relationship between serum antibody titers, clinical characteristics, and prognosis in patients with encephalitis induced by anti leucine-rich glioma inactivated 1 (LGI1) antibody.Methods:Clinical data of 20 patients diagnosed with encephalitis in the Department of Neurology, First Hospital of Shanxi Medical University from February 2015 to February 2021 were collected and retrospectively analyzed. Patients were divided into 2 groups based on their serum anti LGI1 antibody titers, namely the high titer group (1∶100, 1∶320) and the low titer group (1∶10, 1∶32). The clinical characteristics, laboratory test results, and prognosis of the 2 groups of patients were compared. Relusts The age of the 20 patients with anti LGI1 antibody encephalitis ranged from 27 to 69 (53.5±11.2) years, with a male to female ratio of 1∶1. There were 9 patients in the low titer group and 11 patients in the high titer group. There was no statistically significant difference in the types and quantities of clinical symptoms between the 2 groups. Patients in the high titer group were more prone to abnormal lesions on cranial magnetic resonance imaging (10/11 vs 3/9, P=0.014). There was no statistically significant difference between the 2 groups in the presence or absence of cerebrospinal fluid anti LGI1 antibodies (9/11 vs 4/9, P=0.160). During the follow-up, it was found that 1/20 patient died of pulmonary embolism, 7/20 of patients were able to recover to their predisease state, and 9/20 of patients had residual memory impairment. In the high titer group, 3/11 of patients experienced recurrence, while there was no recurrence in the low titer group. There was no statistically significant difference in the neurological prognosis between the 2 groups at 3 months of discharge and follow-up (the number of patients whose modified Rankin Scale score≤2: 10/10 vs 8/9, P=0.474). Conclusions:Patients with high serum anti LGI1 antibody titers are more likely to develop intracerebral lesions. Higher antibody titers may be associated with a higher risk of disease recurrence. There was no significant correlation between serum antibody titers and neurological outcomes.

Voltage-gated potassium channel-complex antibodies associated clinical syndromes with myasthenia gravis complicated with thymoma: analysis of 2 cases and literature review / 中华神经科杂志

Objective:To investigate the clinical characteristics and outcome of patients with voltage-gated potassium channel complex (VGKCc) antibody associated clinical syndromes complicated with myasthenia gravis (MG) with thymoma.Methods:The clinical history, examinations and follow-up prognosis of 2 cases of VGKCc antibodies associated clinical syndromes with MG complicated with thymoma in Qilu Hospital (Qingdao), Cheeloo College of Medicine,Shandong University in September 2020 and December 2020 were reviewed. Related literatures were summarized at the same time.Results:Case 1, a 64-year-old female clinically presented with cognitive impairment, psychosis, and epilepsy seizures, whose serum autoimmune antibody testing showed positive leucine-rich glioma-inhibited 1 (LGI1) antibody, was diagnosed as anti-LGI1 encephalitis,and had history of MG with thymoma. Her symptoms were improved by immunotherapy. Case 2, a 67-year-old male, was diagnosed as MG, and developed cognitive impairment, myokymia and autonomic dysfunction later. His serum autoimmune antibody testing showed positive contactin associated protein-like 2 antibody. Therefore, Morvan syndrome complicated with MG with thymoma was definitely diagnosed. After admission, the patient was improved with immunotherapy and thymoma resection.Conclusions:Patients with VGKCc antibody-associated clinical syndromes complicated with MG have the clinical characteristics of the two diseases simultaneously, and there is also crossover. Immunotherapy and treatment for thymoma are generally effective.

Advances in relapse risk factors of anti-N-methyl-D-aspartate receptor encephalitis / 中华神经科杂志

Anti-N-methyl-D-aspartate receptor (NMDAR) encephalitis is an autoimmune encephalitis mediated by anti-NMDAR antibody. Current studies have found that most patients with anti-NMDAR encephalitis have a good prognosis after immunotherapy and tumor therapy, but there are still 4.5%-36.4% patients with relapse. It is important to identify the risk factors for the prevention of relapse. This article aims to review the relapse risk factors of NMDAR encephalitis in order to provide help for the prevention of relapse.

A case report of anti-NMDAR encephalitis complicated with acute peripheral nerve damage / 中国综合临床

N-methyl-D-aspartate receptor (NMDAR) encephalitis in combination with acute peripheral nerve damage is rare. A young female patient with anti-NMDAR encephalitis was admitted to Qianfoshan Hospital in Shandong Province on October 23, 2022. The main manifestations were abnormal mental behavior, consciousness disorders, and flaccid paralysis. Electromyography indicated axonal damage to the upper and lower extremities. Patient was in critical condition and admitted to the ICU with tracheal intubation for central hypoventilation. A combination of critical polyneuropathy was considered. The prognosis was good after hormone shock, immunosuppressive therapy, surgical therapy, anti-infection, respiratory support and symptomatic support. The diagnosis of anti-NMDAR encephalitis with acute peripheral nerve damage is difficult. Immune factors need to be considered and paraneoplastic syndrome should be differentially diagnosed.

Abnormal topology of cortical thickness covariance network and altered functional connectivity in patients with anti-N-methyl-D-aspartate receptor encephalitis / 中华行为医学与脑科学杂志

Objective:To explore the changes in topological attributes of structural covariance network based on cortical thickness and the brain functional activities in patients with anti-N-methyl-D-aspartate receptor (NMDAR) encephalitis by graph theory and functional connectivity (FC) analyses, and to investigate whether these changes were correlated to cognitive impairment.Methods:A total of 33 patients with anti-NMDAR encephalitis from Department of Neurology of the First Affiliated Hospital of Guangxi Medical University(patient group) and 35 healthy controls(control group) with matched gender, age, and education were included from July 2018 to November 2021.All subjects received cognitive function assessments, structural and functional magnetic resonance imaging scans.Structural covariance networks were constructed in the two groups based on cortical thickness values and topological characteristics of networks were computed.A non-parametric permutation test which repeated 1 000 times was used to compare the characteristics of the networks between the two groups.Brain regions with abnormal topology were defined as region of interest(ROI), and FC values in global brain level were calculated.SPM 12 and RESTplus were used to identify the brain regions with significant differences in FC values between the two groups.Finally, Spearman correlation analysis between FC values of significant brain regions and cognitive scores were performed by SPSS 24.0.Results:The cognitive score of patients with anti-NMDAR encephalitis (27.0(23.5, 28.0)) was lower than that in control group(29.0(27.0, 30.0)) ( Z=-3.029, P=0.002). Graph theory analysis found that the patients showed significantly increased clustering coefficients ( P=0.004) and decreased global efficiency ( P=0.004) compared with healthy controls.Moreover, the nodal efficiency of left ventral posterior cingulate cortex (vPCC) and right dorsal posterior cingulate cortex (dPCC), as well as the nodal degree centrality of left vPCC and left polar planum of superior temporal gyrus (ppSTG) in patient group were significantly decreased ( P<0.05, FDR corrected) compared with control group.FC analysis showed the increased FC values between left vPCC and posterior cerebellum (MNI: x=6, y=-66, z=-21), as well as between left ppSTG and anterior cerebellum (MNI: x=6, y=-54, z=-12) (GRF corrected, voxel level P<0.001, cluster level P<0.05) in patient grooup.The FC values between left vPCC and posterior cerebellum were negatively correlated with the cognitive scores ( r=-0.403, P=0.020). Conclusion:Patients with anti-NMDAR encephalitis show abnormal topology of structural covariance network based on cortical thickness and altered FC values, some of which are correlated to cognition and may be the underlying neural mechanism of cognitive impairment in patients with anti-NMDAR encephalitis.

Cerebrospinal fluid inflammatory cytokine profiles of patients with neurotropic parasitic infections

@#The pathogenesis of chronic parasitic central nervous system (CNS) infections, including granulomatous amoebic meningoencephalitis (GAE), cerebral toxoplasmosis (CT), and neurocysticercosis (NCC), is primarily due to an inflammatory host reaction to the parasite. Inflammatory cytokines produced by invading T cells, monocytes, and CNS resident cells lead to neuroinflammation which underlie the immunopathology of these infections. Immune molecules, especially cytokines, can therefore emerge as potential biomarker(s) of CNS parasitic infections. In this study, cerebral spinal fluid (CSF) samples from suspected patients with parasitic infections were screened for pathogenic free-living amoebae by culture (n=2506) and PCR (n=275). Six proinflammatory cytokines in smear and culture-negative CSF samples from patients with GAE (n = 2), NCC (n = 7), and CT (n = 23) as well as control (n = 7) patients were measured using the Multiplex Suspension assay. None of the CSF samples tested was positive for neurotropic free-living amoebae by culture and only two samples showed Acanthamoeba 18S rRNA by PCR. Of the six cytokines measured, only IL-6 and IL-8 were significantly increased in all three infection groups compared to the control group. In addition, TNFa levels were higher in the GAE and NCC groups and IL-17 in the GAE group compared to controls. The levels of IL-1b and IFNg were very low in all the infection groups and the control group. There was a correlation between CSF cellularity and increased levels of IL-6, IL-8, and TNFa in 11 patients. Thus, quantifying inflammatory cytokine levels in CSF might help with understanding the level of neuroinflammation in patients with neurotropic parasitic diseases. Further studies with clinico-microbiological correlation in the form of reduction of cytokine levels with treatment and the correlation with neurological deficits are needed.