Viral encephalitis: a practical review on diagnostic approach and treatment / Encefalite viral: uma revisão prática sobre abordagem diagnóstica e tratamento

Abstract Objectives To review the diagnostic criteria for encephalitis and encephalopathy of presumed infectious etiology, as well as the diagnostic workup for viral encephalitis and its treatment approaches. The authors also intended to summarize relevant information on specific viruses frequently found in Brazil. Source of data Literature search on Pubmed/MEDLINE using the following keywords: "viral", "encephalitis", "child", or "adolescents", filtering for articles on humans and in English. Summary of data Viral encephalitis is the most common cause of encephalitis and is responsible for high rates of morbidity, permanent neurologic sequelae, and according to the virus, may have high mortality rates. The most common etiologies are herpesviruses 1 and 2 (HSV-1 and HSV-2), non-polio enterovirus, and arboviruses (in Brazil, dengue, Zika, and chikungunya). Other relevant etiologies are seasonal influenza, cytomegalovirus (CMV), Epstein-Barr virus (EBV), human herpesvirus 6 (HHV-6), and the re-emergent measles. Conclusion Clinical data, laboratory results, and neuroimaging findings support the diagnosis of encephalitis and the specific viral etiology. To increase the likelihood of etiologic confirmation, it is important to know the best approach to collecting samples and to choose the best identification technique for each virus. The differential diagnosis of viral encephalitis includes other infections and immune-mediated inflammatory central nervous system disorders.

Resumo Objetivos Revisar os critérios diagnósticos para encefalite e encefalopatia de etiologia infecciosa presumida, assim como a investigação diagnóstica para encefalite viral e suas abordagens terapêuticas. Além disso, pretendemos resumir tópicos relevantes sobre os vírus específicos frequentemente encontrados no Brasil. Fonte de dados Pesquisa bibliográfica feita nos bancos de dados Pubmed/Medline utilizando as seguintes palavras-chave: "viral", "encephalitis", "child" ou "adolescents", limitando os artigos a estudos em humanos e escritos em inglês. Resumo dos dados A encefalite viral é a causa mais comum de encefalite e é responsável por altas taxas de morbidade, sequelas neurológicas permanentes e, de acordo com o vírus, altas taxas de mortalidade. As etiologias mais comuns são herpes vírus 1 e 2 (HSV-1 e HSV-2), enterovírus não pólio e arbovírus (no Brasil, Dengue, Zika e Chikungunya). Outras etiologias relevantes são a influenza sazonal, o citomegalovírus (CMV), o vírus Epstein-Barr (EBV), o herpes vírus humano 6 (HHV-6) e o sarampo reemergente. Conclusão Dados clínicos, resultados laboratoriais e de neuroimagem apoiam o diagnóstico de encefalite e a etiologia viral específica. Para aumentar a probabilidade de confirmação etiológica, é importante conhecer a melhor abordagem para coletar amostras e escolher a melhor técnica de identificação para cada vírus. O diagnóstico diferencial de encefalite viral inclui outras infecções e distúrbios inflamatórios do sistema nervoso central imunomediados.

Neuron-specific enolase as biomarker for possible neuronal damage in dogs with distemper vírus / Enolase neuronal específica como um possível biomarcador para lesão neuronal em cães com cinomose

Neuron-specific enolase (NSE) is a biomarker of neuronal cell lysis, which demonstrates stability in extracellular fluids such as blood and cerebrospinal fluid. To the authors knowledge there is no research information comparing the use of NSE in dogs with and without encephalitis, putting in evidence the importance of that biomarker to detect neuronal damage in dogs. The objective was to compare the serum NSE levels in dogs with and without encephalitis, and to determine the serum NSE levels in normal dogs. Thirty eight dogs were evaluated, 19 dogs with encephalitis (EG Group) and 19 dogs without encephalitis (CG Group). The criteria for inclusion in the EG Group were presence of neurological signs in more than one part of the CNS (multifocal syndrome) and positive molecular diagnosis for canine distemper virus; for the CG Group were an age between 1 to 7 years and be clinically normal; NSE were measured in serum using an ELISA assay, and the results were compared. In the EG Group the NSE values were higher with significant difference (P=0.0053) when compared with the CG Group. NSE is a biomarker that can be measured in serum samples of dogs to monitor neuronal lesions in encephalitis.(AU)

Enolase neuronal específica (NSE) é um biomarcador de lise de neurônios, que demonstra estabilidade em fluidos extracelulares como sangue e líquido cerebrospinal. Para o conhecimento dos autores, não há informações de pesquisa que comparem o uso de NSE em cães com e sem encefalite, evidenciando a importância desse biomarcador para detectar danos neuronais em cães. O objetivo foi comparar os níveis séricos de NSE em cães com e sem encefalites, e determinar os níveis séricos de NSE em cães saudáveis. Trinta e oito cães foram avaliados, 19 cães com encefalites (Grupo EG) e 19 cães sem encefalite (Grupo CG). O critério para inclusão no Grupo EG foi presença de sinais neurológicos em mais de uma estrutura do SNC (síndrome multifocal) e positividade no diagnóstico molecular para o vírus da cinomose canina; para o Grupo CG foi idade entre 1 e 7 anos e ser clinicamente normal; NSE foram mensuradas em amostras séricas usando o método de ELISA, e os resultados comparados. No Grupo EG os valores de NSE foram altos com diferença significativa (P=0.0053) quando comparado com o Grupo CG. NSE é um biomarcador que pode ser mensurado em amostras séricas de cães para monitorar lesões neuronais em encefalites.(AU)

Encefalopatía por virus herpes 6 como complicación de exantema súbito / Encephalopathy due to human herpesvirus 6 infection as exanthema subitum complication

La principal manifestación clínica del herpesvirus 6 es el exantema súbito (también conocido como roséola o sexta enfermedad) y el síndrome febril. Las manifestaciones en el sistema nervioso central no son infrecuentes en la infección por herpesvirus 6, y su fisiopatología no está esclarecida, pero precisan diagnóstico y tratamiento temprano para evitar secuelas potencialmente graves. Se presenta el caso de una niña inmunocompetente de 2 años con cuadro de encefalitis como complicación de infección por herpesvirus 6. Se destaca la importancia del diagnóstico oportuno a fin de instaurar un adecuado tratamiento y seguimiento para evitar complicaciones secundarias a la afectación del sistema nervioso central.

The main clinical manifestation of human herpesvirus 6 is exanthema subitum (also known as roseola infantum) and febrile syndrome. Central nervous system manifestations are not unusual in herpesvirus 6 infection, and even though the pathophysiology is not clear, they need to be early diagnosed and treated in order to avoid potentially serious damage. We present the case of an immunocompetent 2-year-old girl with encephalitis as a complication of herpesvirus 6 infection. We want to emphasize the significance of an early diagnosis and treatment in order to prevent further complications due to the central nervous system extension.

Viral encephalitis / Encefalites virais

While systemic viral infections are exceptionally common, symptomatic viral infections of the brain parenchyma itself are very rare, but a serious neurologic condition. It is estimated that viral encephalitis occurs at a rate of 1.4 cases per 100.000 inhabitants. Geography is a major determinant of encephalitis caused by vector-borne pathogens. A diagnosis of viral encephalitis could be a challenge to the clinician, since almost 70% of viral encephalitis cases are left without an etiologic agent identified. In this review, the most common viral encephalitis will be discussed, with focus on ecology, diagnosis, and clinical management.

Embora as infecções virais sistêmicas sejam muito comuns, as infecções virais sintomáticas do parênquima cerebral são raras, mas potencialmente graves. Estima-se que a encefalite viral ocorra em 1,4 casos por 100.000 habitantes anualmente. A localização geográfica é um fator determinante a ser levado em consideração frente aos patógenos transmitidos por vetores. O diagnóstico clínico das encefalites virais pode ser um desafio para o clínico, visto que quase 70% dos casos de encefalite viral ficam sem a identificação do agente viral. Nesta revisão, as encefalites virais mais comuns serão discutidas, com interesse especial sobre os aspectos da ecologia, do diagnóstico e do seu manejo clínico.

Encefalitis virales en la infancia / [Viral encephalitis in children].

Viral encephalitis is a severe illness that produces inflammation of the brain. CNS viral infections frequently occur as a complication of systemic viral infections. Over 100 viruses are implicated as causative agents, including herpes simplex virus type I which is the most common agent implied in non-epidemic encephalitis in all population groups in the world, and is responsible for the most severe cases in all ages. Many viruses, for which there are vaccines, may also cause encephalitis: measles, mumps, polio, rabies, rubella, and chickenpox. The virus causes an inflammation of the brain tissue, which may progress to destruction of nerve cells, cause bleeding and brain damage, leading to severe encephalitis, such as hemorrhagic or necrotizing encephalitis, with a worse prognosis, producing serious sequelae or death. The clinical evolution includes the presence of headache, fever and altered consciousness rapidly progressive. The outcome of viral encephalitis is variable, some cases are mild, with full recovery, but there are serious cases that can cause severe sequel in the brain. To diagnose this illness as soon as possible is essential, through laboratory tests (biochemistry, virus PCR, culture) and neuroimaging (CT, MRI) and above all, the establishment of early treatment to prevent the development of the process and possible complications. The prognosis worsens if the initiation of treatment is delayed.

Infecciones del sistema nervioso central por enterovirus en niños atendidos en un hospital de Lima, Perú / Enteroviral central nervous system infections in children treated at a hospital in Lima, Peru

Objetivos. Determinar la frecuencia y las características clínicas de las infecciones del sistema nervioso central por enterovirus en niños atendidos en el Hospital Nacional Cayetano Heredia de Lima, Perú. Materiales y métodos. Se realizó un estudio prospectivo y descriptivo desde abril 2008 hasta marzo 2010. Se enrolaron pacientes de un mes a 14 años con diagnóstico clínico de encefalitis o meningitis asépticas. Se investigó la presencia de enterovirus, virus herpes simple 1 (VHS-1), virus herpes simple 2 (VHS-2) y virus varicela-zoster (VZV) mediante reacción en cadena de polimerasa (PCR). Resultados. Se enrolaron 97 pacientes de los cuales 69 por ciento presentaron encefalitis aguda y 31 por ciento meningitis aguda. Se identificó enterovirus en 52,6 por ciento del total de infecciones agudas no bacterianas del sistema nervioso central; encontrándose en 83,3 por ciento de las meningitis y en 38,8 por ciento de las encefalitis. No hubo casos de infección por VHS-1, VHS-2 ni VZV. Las infecciones por enterovirus alcanzaron el 82,9 por ciento en los meses cálidos de noviembre a enero y el 28,6 por ciento en los meses fríos de mayo a julio. Conclusiones. Los enterovirus fueron los principales agentes etiológicos en las encefalitis y meningitis asépticas agudas en pacientes pediátricos de Lima, Perú. Los enterovirus tienen un comportamiento epidemiológico estacional con un claro aumento del número de casos en los meses de verano. Resulta útil tener disponible un método de diagnóstico rápido, como una ayuda para el manejo de las infecciones agudas del sistema nervioso.

Objectives. To determine the frequency and clinical features of central nervous system infections caused by enterovirus in children treated at the Hospital Nacional Cayetano Heredia in Lima, Peru. Materials and methods. A prospective, descriptive study was performed from April 2008 to March 2010. Patients aged 1 month - 14 years with clinical diagnosis of encephalitis or aseptic meningitis were included. We investigated the presence of enterovirus, herpes simplex virus 1 (HSV-1), herpes simplex virus 2 (HSV-2) and varicella-zoster virus (VZV) by polymerase chain reaction (PCR). Results. 97 patients were included, out of which 69 percent had acute encephalitis and 31 percent acute meningitis. Enteroviruses were identified in 52,6 percent of all acute non-bacterial central nervous system infections; corresponding to 83,3 percent of meningitis and 38,8 percent of encephalitis. There were no cases of infection due to HSV-1, HSV-2 or VZV. Enterovirus infections reached 82,9 percent in the warm months (November-January) and 28,6 percent in the colder months (May-July). Conclusions. Enteroviruses are the principal etiologic agents in acute aseptic meningitis and encephalitis in pediatric patients in Lima, Peru. Enteroviruses have a seasonal epidemiological pattern with a clear increase in the number of cases during the summer months. It is useful to have this rapid diagnostic method available as an aid in the management of acute central nervous system infections.

Imaging in adult patients with acute febrile encephalopathy: What is better computerized tomography or magnetic resonance imaging.

Context: Imaging techniques are commonly used by emergency physicians in a febrile comatose patient. Their utility requires judicious use of the available resources. In this study, we have compared the efficacy of cranial imaging techniques in adult patients with acute febrile encephalopathy. Materials and Methods: This prospective observational study enrolled 101 patients presenting to the emergency with fever of less than 15 days duration and altered sensorium. All the patients were subjected to routine investigations, detailed cerebrospinal fluid analysis, computerized tomograms (noncontrast followed by contrast enhanced), and magnetic resonance imaging of the brain. Final diagnosis was reached after considering the clinical, biochemical findings, imaging results, and response to therapy. The positive yield of radiological investigations was compared against the final diagnosis. Results: The patients were divided into three groups. Forty-eight had evidence of meningoencephalitis, 22 patients had pyogenic meningitis, and 20 were combined together in other group. In 12 patients, a definitive diagnosis could not be made. Only 37% patients were detected to have abnormal computerized tomograms and the most common abnormality was diffuse edema, which failed to point to an etiological diagnosis. Magnetic resonance imaging was abnormal in 62.75% cases and was able to suggest an etiological diagnosis in 100% cases of cerebral venous thrombosis, tubercular meningitis, 95% cases of meningoencephalitis, and 45% patients with meningitis. Conclusions: We can conclude that magnetic resonance imaging provides better information than computerized tomography in adult patients with acute febrile encephalopathy.

Novel Swine-Origin Influenza A (H1N1) Viral Encephalitis

The World Health Organization declared that a new strain of novel swine-origin influenza A (H1N1) virus was responsible for the pandemic infection in June 2009. We report a case of encephalitis diagnosed as the H1N1 virus infection. We describe a 17-year-old patient who had a seizure attack, diagnosed with a H1N1 virus infection via real time reverse-transcriptase polymerase chain reaction (RT-PCR). The H1N1 virus infection can be causative of the encephalitis, as with other influenza virus infections. Careful monitoring is essential for reducing complications.

Management of acute viral encephalitis in Brazil

The appropriate management of acute viral encephalitis is a challenge. Clinical picture includes general symptoms and a wide range of neurological signs. Etiological diagnosis cannot be performed only by clinical means and depends on neuroimaging studies and cerebrospinal fluid molecular analyses. It is recommended since some of these viruses are treatable and that the prognoses of these infections depend on the prompt administration of antiviral and/or immunomodulatory drugs. The management of acute viral encephalitis in Brazil has some peculiarities. First, the etiological distribution of the viral encephalitis may differ from what is found in other countries. Some viruses, such as dengue virus, are more common in Brazil than in developed countries while others, like West Nile virus, are not found here. Second, there are some regions in Brazil where neuroimaging and laboratorial methods are not available, and a clinical-based decision is the only therapeutic approach. As most of the guidelines in the literature are based on complimentary methods, it is relevant to establish an alternative approach compatible with the Brazilian health system reality. The goal of this study was to review the recent advances in the field of the acute viral encephalitis, to discuss the diagnosis and the treatment of the main etiologies of acute viral encephalitis found in Brazil, and to propose a viable guideline for the evaluation of the suspected acute viral encephalitis cases in the emergence room in Brazil.

Meningitis y encefalitis víricas en Uruguay. Relevamiento mediante técnicas de reacción en cadena de polimerasa aplicadas al líquido cefalorraquídeo de los grupos herpes, enterovirus y arbovirus como principalesagentes etiológicos: a propósito de 59 casos / Meningitis and viral encephalitis in Uruguay. Survey through polymerase chain reaction (PCR) on cerebrospinal fluid for herpesvirus, enterovirus and arbovirus as main etiological agents: 59 cases studied

Introducción: en nuestro país no existen trabajos sistemáticos relativos a la incidencia de virus que provoquen encefalitis y meningitis. Sí existen trabajos realizados en las décadas de1960 y 1970 sobre seroprevalencia de arbovirus y poliovirus. Mediante la técnica de reacción en cadena de polimerasa (PCR) aplicada al líquidocefalorraquídeo (LCR) hoy es posible realizar en un breve lapso de tiempo un diagnóstico de certeza sobre diversos agentes virales responsables de estas neurovirosis. Material y métodos: se exploró la incidencia de virus de la familia herpes, enterovirus y grupoarbovirus mediante técnicas de PCR aplicadas al LCR en pacientes VIH negativos. Resultados: este trabajo presenta a 59 pacientes VIH negativos que padecieron encefalitis ymeningitis de presumible etiología viral. Estos agentes son los responsables de la mayor cantidad de meningitis y encefalitis que suceden en nuestro continente. Conclusiones: el diagnóstico virológico final es posible realizarlo en más de la mitad de los casos presentados, predominando virus de la familia herpes tanto en niños como en adultos, no siendo despreciable la incidencia de enterovirus. No se detectó en este trabajo la presencia de arbovirus.

Introduction: in our country there are no systematic studies on the incidence of virus as a cause of encephalitis and meningitis. However, some studies on the seroprevalence of arbovirus and poliovirus were carried out in the sixties and seventies. Today, the polymerasechain reaction (PCR) applied to cerebrospinal fluid technique allows us to obtain accurate diagnosis within a short time, on the different viral agents that cause these neuroviroses.Method: we explored the incidence of virus from the herpesvirus, enterovirus and arbovirus group through PCRtechniques applied to HIV negative patients. Results: this study included 59 HIV negative patients who suffered from encephalitis and meningitis of viral etiology. These agents are responsible for most of the cases of meningitis and encephalitis in our continent.Conclusions: the final viral diagnosis may be obtained in over half of the cases presented. The herpesvirus is themost frequent both in children and in adults, being it significant the incidence of enterovirus. No arbovirus wereidentified in this study.

Introdução: no nosso país não existem estudos sistemáticos relativos à incidência de vírus que provoquemencefalites e meningites. Existem trabalhos realizados nas décadas de 1960 e 1970 sobre a soroprevalência dearbovírus e de poliovirus. Utilizando a técnica de reação em cadeia da polimerase (PCR) no líquido cefalorraquidiano (LCR) é possível realizar, em pouco tempo, um diagnóstico de certeza sobre diversosagentes virais responsáveis por estas neuroviroses. Material e métodos: buscou-se determinar a incidênciade vírus das famílias herpes, enterovírus e grupo arbovírus pelas técnicas de PCR no LCR de pacientes VIH negativos.Resultados: este trabalho apresenta 59 pacientes VIH negativos que tiveram encefalite ou meningite com provável etiologia viral. Estes agentes são responsáveis pelo maior número de casos de meningite e encefalite nonosso continente. Conclusões: em mais da metade dos casos apresentadosfoi possível realizar o diagnóstico virológico final; registrou-se uma predominância dos vírus da família herpes tanto em crianças como em adultos sendo que a incidência de enterovírus não era desprezível. Não se detectou a presença de arbovirus.

Encefalitis aguda: Manifestaciones neuropsiquiátricas como expresión de infección por virus de influenza / Acute encephalitis: Neuropsychiatric manifestations as expression of influenza virus infection

El objetivo fue revisar la encefalitis en niños y adolescentes, su etiología, manifestaciones clínicas, fisiopatología, métodos diagnósticos y tratamiento, enfatizando las manifestaciones neuropsiquiátricas de la encefalitis durante una epidemia de influenza. La encefalitis se considera una inflamación del sistema nervioso central (SNC) que compromete el cerebro. Se manifiesta usualmente por cefaleas, fiebre y trastorno del estado de conciencia. Puede además manifestarse por convulsiones, cambios en la personalidad y manifestaciones obsesivas (síntomas neuropsiquiátricos). Las manifestaciones dependerán del tipo de virus y las células afectadas. La encefalitis puede ser causada por una gran variedad de agentes infecciosos incluyendo virus, bacterias, hongos y parásitos. Causas virales de encefalitis incluyen herpesvirus, arbovirus, rabia y enterovirus. Casos establecidos de bacterias incluyen Borrelia burgdorferi y rickettsia y el Mycoplasma neumoniae, al cual se atribuyen varios casos de encefalitis. Otros agentes como el hongo Coccidioides immitis e Histoplasma capsulatum pueden también generarla. Más de 100 agentes se han asociado a encefalitis. El diagnóstico de encefalitis constituye un reto para el clínico, y su etiología infecciosa usualmente se identifica entre el 40% al 70% de casos. El diagnóstico se hace con absoluta certeza sólo con una biopsia cerebral. La epidemiología depende de ciertos factores como la edad, la localización geográfica, la época del año, las condiciones climáticas y la inmunocompetencia del huésped. El tratamiento temprano puede disminuir el riesgo de muerte y las secuelas. Describimos cuatro pacientes con encefalitis y manifestaciones neuropsiquiátricas durante una epidemia de influenza, con el fin de alertar sobre esta asociación.

The aim is to review the encephalitis in infants and adolescents as well as its etiology, clinical manifestation, epidemiology, physiopathology, diagnostic methods and treatment, and the neuropsyquiatric signs appearing an influenza epidemy. Encephalitis is an inflammation of the central nervous system (CNS) which involves the brain. The clinical manifestations usually are: headache, fever and confusional stage. It could also be manifested as seizures, personality changes, or psiqyiatric symptoms. The clinical manifestations are related to the virus and the cell type affected in the brain. A meningitis or encephalopathy need to be ruled out. It could be present as an epidemic or isolated form, beeing this the most frequent form. It could be produced by a great variety of infections agents including virus, bacterias, fungal and parasitic. Viral causes are herpesvirus, arbovirus, rabies and enterovirus. Bacterias such as Borrelia burgdorferi, Rickettsia and Mycoplasma neumoniae. Some fungal causes are: Coccidioides immitis and Histoplasma capsulatum. More than 100 agents are related to encephalitis. The diagnosis of encephalitis is a challenge for the clinician and its infectious etiology is clear in only 40 to 70% of all cases. The diagnosis of encephalitis can be established with absolute certainty only by the microscopic examination of brain tissue. Epidemiology is related to age of the patients, geographic area, season, weather or the host immune system. Early intervention can reduce the mortality rate and sequels. We describe four patients with encephalitis and neuropsychiatric symptoms during an influenza epidemic.

Hemorrhagic encephalopathy in dengue shock syndrome: a case report

Dengue fever is the most important arboviral infection in the world, with an estimated 100 million cases per year and 2.5 billion people at risk. Encephalopathy is a rare complication of dengue virus infection and may occur as a consequence of intracranial hemorrhage, cerebral edema, hyponatremia, cerebral anoxia, fulminant hepatic failure with portosystemic encephalopathy, microcapillary hemorrhage or release of toxic products. We report a rare case of hemorrhagic encephalopathy in dengue shock syndrome caused by type 3 dengue virus.

Fatal dengue encephalitis.

Central nervous system involvement is not an uncommon manifestation of dengue virus infection, but encephalitis is a rare entity. We report the case of a 5-year-old girl with fever and convulsions. She developed coma and shock during the high fever stage without abnormal bleeding.Treatment was supportive and symptomatic. The shock was poorly controlled. High fever persisted for 7.5 days then she expired.Cerebrospinal fluid (CSF) and blood dengue-IgM antibody showed dengue infection.

Síndrome neuroléptico maligno / Neuroleptic malignant syndrome

El Síndrome Neuroléptico Maligno es una enfermedad rara pero con alta mortalidad, por lo cual es conveniente tenerla presente ante la aparición de un cuadro de hipertermia inducido por drogas. En ocasiones la presentación clínica suele ser indistinguible de una Hipertermia Maligna, si bien su mecanismo fisiopatológico es completamente diferente. Sus características clínicas comprenden hipertermia, rigidez muscular, elevación de la creatininfosfoquinasa (C.P.K.) además de mioglobinemia y mioglobinuria, como consecuencia de la rabdomiólisis. En esta recopilación mencionaremos su fisiopatología, etiología, criterios clínicos, su relación con Hipertermia maligna y los detalles de su tratamiento.

Complexidade do diagnostico diferencial em psiquiatria: relato de sindrome catatonita / The complexity of the differential diagnosis in psychiatry exemplified by a catatonic syndrome

Os autores relatam um caso de sindrome catatonica que evoluiu com afasia apos um provavel episodio infeccioso do sistema nervoso central (encefalite viral?), que nao foi confirmado por exames complementares...