Exotic and emerging viral encephalitides

PURPOSE OF REVIEW: The exotic and emerging viral encephalitides are caused by animal or human viruses and characterised by sudden unexpected outbreaks of neurological disease, usually in tropical and sub-tropical regions, but sometimes spreading to temperate areas. Although a wide range of viruses come within this label, as this review highlights, there are common research questions as to the origin and spread of the viruses, the contribution of viral and host factors to the clinical presentations and outcome, and the possibilities for treatment and vaccination. RECENT FINDINGS: During 2002, North America experienced the largest ever outbreak of West Nile encephalitis; a poliomyelitis-like flaccid paralysis due to West Nile virus was recognised, and transfusion-related infections were documented. Globally, Japanese encephalitis virus is the most important emerging viral encephalitis; interferon alpha was not effective against Japanese encephalitis in a double-blind placebo-controlled trial, but new chimeric vaccines are in development. Recent work suggests Japanese encephalitis virus originated in the Indonesia-Malaysia region, and spread from there. The origin of Nipah virus, which caused an encephalitis outbreak in Malaysia in 1998, is not known, but flying foxes have been identified as a natural host. Enterovirus 71 continues to cause large outbreaks of hand foot and mouth disease across Asia, associated with neurological and systemic complications; recent work has focused on the pathogenesis of these complications. SUMMARY: Disease surveillance remains important for the early recognition and containment of encephalitis outbreaks. Detailed clinical and laboratory studies will help answer the key questions, but there is a need to ensure the results translate to real benefits for the communities affected by these diseases.     

Improvement of advanced postvaccinal demyelinating encephalitis due to plasmapheresis

We report a case of acute demyelinating encephalitis that occurred after viral vaccination against hepatitis A-, hepatitis B-, and poliovirus and vaccination against bacterial toxins of diphtheria and tetanus. After different diagnosis had been excluded, we diagnosed postvaccinal demyelinating encephalitis and started treatment with high dose intravenous methylprednisolone, followed by peroral application in decreasing dosages for three weeks. A few days after the treatment with methylprednisolone had been finished, the patient’s medical condition deteriorated again. Thus, we initiated plasma exchange at an advanced state of illness, which led to significant continuous improvement. The role of plasma exchange is discussed controversially, in particular the issue of timing. We report a case that shows improvement due to plasmapheresis several weeks after symptom onset.     

A medical overview of encephalitis

Encephalitis is uncommon but is a neurological emergency which must be considered in a patient presenting with altered consciousness. Encephalitis is a diffuse inflammatory process of the brain parenchyma associated with evidence of brain dysfunction. The presentation of encephalitis can be acute or chronic. The aetiology of encephalitis can be broadly divided into two major subtypes. (1) Infection-related encephalitis which is a direct consequence of pathogenic viral, bacterial or parasitic agents. Herpes simplex virus (HSV) and varicella-zoster virus (VZV) are the most common cause of acute infectious encephalitis. (2) Autoimmune-mediated encephalitis which is mediated by an aberrant immune response. This can be triggered by a recent viral infection or vaccination. An example of this would be acute disseminated encephalitis (ADEM). This article will focus on the medical management of acute encephalitis. This will involve an extensive overview of the literature reviewing the diagnosis, investigation and treatment of acute viral encephalitis, ADEM and acute haemorrhagic leukoencephalopathy (AHLE). Encephalitis can also present chronically, and some of the different types of chronic encephalitis will be discussed.     

Expression of the interferon-induced MxA protein in viral encephalitis

MxA protein accumulates cytoplasmically in response to interferon stimulation, and mediates resistance against several viruses. In order to test whether MxA may serve as a diagnostic tool for viral infections of the central nervous system (CNS), we performed MxA immunohistochemistry on biopsies and autopsies of 57 patients with neurological disorders of known viral and nonviral aetiology. MxA was detectable in all HIV patients with proven opportunistic viral encephalitis, in all patients suffering from isolated viral encephalitis, in one of three HIV patients with cerebral toxoplasmosis, and in one case of micronodular encephalitis. No MxA was detectable in HIV patients with isolated HIV encephalitis or HIV infection accompanied by an opportunistic nonviral disorder. We were unable to show MxA expression in a variety of nonviral inflammatory and noninflammatory disorders of the CNS. Several cases of Rasmussen's encephalitis and multiple sclerosis tested negative, arguing against their possible viral aetiology. Two-colour immunohistochemistry identified macrophages and activated microglia as MxA expressing cells. In all studied cases MxA expression was accompanied by a marked T-cell infiltrate. Therefore, the detection of MxA-protein is a sensitive adjuvant marker for those cases of viral encephalitis which are accompanied by pronounced lymphocytic infiltrates.     

A case of clinically mild encephalitis with a reversible splenial lesion (MERS) after mumps vaccination

We describe for the first time an 8-year-old male patient who demonstrated clinically mild encephalitis with a reversible splenial lesion after mumps vaccination. He suffered from transient hallucinations, nuchal rigidity, and inappropriate antidiuretic hormone secretion syndrome. On the 5th day of admission, his head MRI showed symmetrical high-signal-intensity lesions on T2, FLAIR, and diffusion-weighted images in the splenium of the corpus callosum and in the periventricular white matter, while an apparent diffusion coefficient map showed reduced diffusion. The images were not enhanced by gadolinium. Follow-up MRI on the 16th day of admission revealed none of these abnormalities. His serum IgM and IgG antibodies against the mumps virus were positive according to an enzyme immunoassay. Mumps Torii vaccine strain was isolated from the patient’s cerebrospinal fluid. Previous reports demonstrated that transient delirious behavior, the syndrome of inappropriate antidiuretic hormone secretion, and good prognosis were the main clinical features of mild encephalitis with a reversible splenial lesion. This case shows that mild encephalitis with a reversible splenial lesion could occur after mumps vaccination.     

Clinical, immunological and therapeutic aspects of autoimmune encephalitis

Autoimmune encephalitis is a heterogeneous group of disorders probably resulting from a reaction of the immune system against antigens of the central nervous system. Historically, the autoimmune hypothesis was based on the neuropathological discovery of an immune cellular infiltrate in the brain parenchyma and around the cerebral blood vessels, resembling a form of viral encephalitis without any detectable viral antigens. These syndromes can be divided into forms with prevalent grey matter involvement, forms with prevalent white matter damage and forms in which the target of the immune process is the vessels. In this paper, we review recent knowledge about the syndromes belonging to the first group. This group encompasses syndromes in which there is neuronal loss and antibodies directed against antigens expressed in the neurons (anti-neuronal antibodies) are frequently detected in the sera or cerebrospinal fluid. These antibodies are not necessarily the cause of neurological impairment but are important markers for these syndromes. It is essential to acquire knowledge on these disorders since they are an important cause of rapidly progressive cognitive decline and behavioural problems which may remain underrecognized, but often improve with immunomodulatory therapies.     

Viral encephalitis: Neuropsychiatric and neurobehavioral aspects

Viral encephalitis, a condition in which a virus infects the brain and produces an inflammatory response, affects approximately 20,000 individuals per year in the United States. The viral encephalidities include sporadic and epidemic acute viral encephalidities and subacute and chronic/progressive viral encephalitis or encephalomyelitis. In people who survive these conditions, postencephalitic impairments of elemental neurologic, cognitive, emotional, and behavioral function are common. This article will provide a brief overview of the diagnosis and acute management of acute viral infections of the central nervous system. The neurologic and neuropsychiatric features, neuropathologies, and treatments of two of the more common types of acute viral encephalitis in North America— herpes simplex encephalitis and West Nile encephalitis—will be reviewed. The current and future role of psychiatrists and neuropsychiatrists in the care and study of individuals with these conditions will be discussed.     

Clinical relevance of polymerase chain reaction (PCR) assays and antigen-driven immunoblots for the diagnosis of neurological infectious diseases

Polymerase chain reaction assays are a powerful tool for detecting the presence of infectious genomes in the cerebrospinal fluid. Positive results always mean a current or pending infection of the central nervous system. Subacute (>7 days) or chronic infections induce an intrathecal humoral immune response and the appearance of oligoclonal IgG antibodies directed against the causal infectious agent. This local synthesis may be observed even in cases of severe systemic immunodeficiency. The use of polymerase chain reactions in combination with the detection of a specific intrathecal immune response should represent the most reliable strategy for the diagnosis of viral and chronic infections of the central nervous system. The authors describe their experience, using this approach, in herpetic encephalitis, acute and recurrent herpetic meningitis, varicella zoster-induced neurological diseases, cytomegalovirus encephalitis, progressive multifocal leukoencephalitis and tuberculous meningitis.     

Japanese encephalitis in a French traveler to Nepal

Japanese encephalitis is frequent in Asia, with a severe prognosis, but rare in travelers. Culex mosquitoes transmit Japanese encephalitis virus. Risk factors are destination, duration of stay, summer and fall seasons, outdoor activities, and type of accommodation. We report the case of a French traveler to Nepal with neutralization-based serological confirmed Japanese encephalitis. He presented classical clinical (viral syndrome before an encephalitis status with behavioral disorder, global hypotonia, mutism, movement disorders, seizure, and coma), radiological (lesions of thalami, cortico-spinal tracts, and brainstem) and biological features (lymphocytic meningitis). Nowadays, the presence of Japanese encephalitis virus in Nepal, including mountain areas, is established but Japanese encephalitis remains rare in travelers returning from this area and neurologist physicians need to become familiar with this. We recommend vaccination for travelers spending a long period of time in Nepal and having at-risk outdoor activities.     

Development of a recombinant vaccine against Japanese encephalitis

Japanese encephalitis (JE) is the major form of viral encephalitis in much of the South-East Asia, India, and China. The disease is caused by a mosquito-borne virus known as Japanese encephalitis virus (JEV). The virus spreads in the form of epidemics, although several endemic areas for JEV activity are known. In recent years, JEV has spread to newer geographic locations such as Australia and Pakistan, and thus has become an important emerging virus infection in these areas. A mouse brain-derived, formalin-inactivated vaccine is available for immunization against JE. Because the formalin-inactivated JEV vaccine has limitations in terms of safety, availability, and cost, attempts are being made to develop improved vaccine using the recombinant DNA technology. This article reviews various attempts in this direction and summarizes the latest developments such as the recombinant yellow fever virus- or the plasmid DNA-based JEV vaccine.     

The evolving epidemiology of viral encephalitis

PURPOSE OF REVIEW: The introduction of West Nile virus to North America illustrates the potential emergence of novel encephalitic agents in unexpected settings. There has been continued recognition of emerging neurotropic viruses in both the developed and developing world and novel modes of transmission of these agents. This review describes recent developments in the epidemiology of West Nile virus and several other emerging viral encephalitides in the developed and developing world and the emergence of novel mechanisms of transmitting viral encephalitis. RECENT FINDINGS: West Nile virus has continued to have a large public health impact in North America. Improvements in blood donor screening have decreased transfusion-associated transmission of the virus. Monkeypox, with associated encephalitis, occurred in the US. Chandipura virus, an infrequently recognized rhabdovirus, was attributed to large outbreaks of viral encephalitis; however, compelling evidence suggests that the relationship of illness and the virus are questionable. Recent cases of transfusion-associated and transplant-associated viral encephalitis, including West Nile virus, rabies virus, and lymphocytic choriomeningitis virus, were described. SUMMARY: Continued West Nile virus activity in North America reinforces the fact that viruses can emerge and thrive in new environments and unexpected settings and suggests the need for continued surveillance. Transfusion-associated and transplant-associated viral encephalitis may be an underrecognized risk of these procedures.     

Encephalitis in the 21 st century

As the 21st century begins, several outbreaks of encephalitis have been reported. An examination of these outbreaks brings into focus important epidemiological developments. Specifically, urbanization and encroachment on natural environments, the ease of world travel, and global trade can lead to spread of vectors and viruses from the developing world to the developed world. This review focuses on two recent epidemics of encephalitis: West Nile virus encephalitis in the eastern United States and Nipah virus encephalitis in Malaysia and Singapore. These examples demonstrate spread of a known viral agent from an endemic area to an area in which it had not previously been found and identification of a new viral agent. Infectious diseases in the developed world once considered "exotic" are now potential threats to all patients.     

Viral encephalitis: a clinician's guide

The management of patients with suspected viral encephalitis has been revolutionised in recent years with improved imaging and viral diagnostics, better antiviral and immunomodulatory therapies, and enhanced neurointensive care. Despite this, disasters in patient management are sadly not uncommon. While some patients are attacked with all known antimicrobials with little thought to investigation of the cause of their illness, for others there are prolonged and inappropriate delays before treatment is started. Although viral encephalitis is relatively rare, patients with suspected central nervous system (CNS) infections, who might have viral encephalitis, are not. In addition, the increasing number of immunocompromised patients who may have viral CNS infections, plus the spread of encephalitis caused by arthropod-borne viruses, present new challenges to clinicians. This article discusses the Liverpool approach to the investigation and treatment of adults with suspected viral encephalitis, and introduces the Liverpool algorithm for investigation and treatment of immunocompetent adults with suspected viral encephalitis (available at www.liv.ac.uk/braininfections).     

^18F-FDG PETCT在抗NMDA受体脑炎及病毒性脑炎诊断中的价值

抗N-甲基-D-天冬氨酸(NMDA)受体脑炎及病毒性脑炎的临床表现相似但治疗方法及预后不同,故早期鉴别至关重要。抗体检测及病原学检测存在延时、假阴性等不足,常规辅助检查缺乏特异性,鉴别价值有限。^18F脱氧葡萄糖(FDG)标记的正电子发射计算机断层显像(PETCT)检查对于抗NMDA受体脑炎早期代谢异常敏感性高,存在特征性的枕叶低代谢和额颞叶高代谢。病毒性脑炎行^18F-FDG PETCT检查研究病例数较少,不同病毒性脑炎的脑代谢表现不同,但均无特征性的枕叶代谢减退。本文现围绕NMDA受体脑炎及病毒性脑炎行^18F-FDG PETCT检查时的脑代谢特点综述如下。     

Japanese encephalitis revisited

Japanese encephalitis (JE) is a major public health problem in Southeast Asia with around 50,000 cases and 10,000 deaths per year affecting essentially children below 10 years of age. The JE virus has shown a tendency to extend to other geographic regions. JE may cause severe encephalitis and survivors are frequently left with serious neurological lesions. In the absence of an effective antiviral treatment, prevention constitutes the best defense against this disease. Besides the implementation of vector control, immunization by vaccination is available. Vector control is expensive and difficult to implement on a large scale, leaving vaccination as the best means for mass campaigns. Recent progress in the development of live attenuated vaccines has given hope of an effective vaccine, which is both easy to use and inexpensive for large scale programs.     

Neurological complications of tick borne encephalitis: the experience of 89 patients studied and literature review

Tick borne encephalitis (TBE) is an acute febrile syndrome that can be complicated with neurological symptoms ranging from mild meningitis to severe encephalomyelitis. The causative agent is a virus belonging to the family of flaviviruses. We have collected a series of 89 patients and compared the clinical course with the main data of the literature of TBE. This review in addition describes the clinical manifestations associated with TBE infections, the main molecular-biological properties of these viruses, and the different factors that define the incidence and severity of disease who are frequently situated in the age group young/adult with a social harm and functional non-negligible. This review also contains diagnostic elements and neuropathological features typical of this infection and a brief summary of vaccination against TBE.     

Relapsing Anti-NMDAR Encephalitis after a gap of eight years in a girl from North-East India

It has been just 7 years since the discovery of anti-NMDAR encephalitis as distinct immune-mediated encephalitis and we have such cases being reported from our country. Herein, we describe a case of a 13-year-old girl who had relapsing encephalitis consisting of multiple types of difficult-to-control seizures, abnormal behavior, language disintegration, memory loss and abnormal movements eight years after the first clinical attack. In 2005, when she was 5 yearsold, anti-NMDAR encephalitis was not yet discovered and she was provisionally diagnosed as a case of viral encephalitis. During her second attack in 2013, antibodies against NMDAR were demonstrated by immunofluoresence in serum (1:10). This is the first report from our country of a case of relapsing anti-NMDAR encephalitis of such a long duration, successfully treated by immunotherapy.     

Coxsackie B antigen in the central nervous system of a patient with fatal acute encephalitis: immunohistochemical studies of formalin-fixed paraffin-embedded tissue

Summary A case of fatal acute encephalitis due to Coxsackie B₁ virus is described. Confirmation of Coxsackie B virus as the etiological agent of encephalitis was based on identification of the virus antigen in formalin-fixed paraffin-embedded tissue sections. In the past, the diagnosis was obtained by serological studies of peripheral blood and viral isolation. This is the first report in which indirect immunofluorescent and immunoper-oxidase methods using rabbit antiserum raised against Coxsackie B types 1–6 was utilized in determining the etiology of encephalitis. It must be emphasized that these methods can be used both on biopsy or autopsy specimens, even retrospectively.Presented in part at the sixty-third Annual Meeting of the American Association of Neuropathologists, Seattle, Washington, June 11–14, 1987     

Vaccinations for Neuroinfectious Disease: A Global Health Priority

Vaccines for neuroinfectious diseases are becoming an ever-increasing global health priority, as neurologic manifestations and sequelae from existing and emerging central nervous system infections account for significant worldwide morbidity and mortality. The prevention of neurotropic infections can be achieved through globally coordinated vaccination campaigns, which have successfully eradicated nonzoonotic agents such as the variola viruses and, hopefully soon, poliovirus. This review discusses vaccines that are currently available or under development for zoonotic flaviviruses and alphaviruses, including Japanese and tick-borne encephalitis, yellow fever, West Nile, dengue, Zika, encephalitic equine viruses, and chikungunya. Also discussed are nonzoonotic agents, including measles and human herpesviruses, as well as select bacterial, fungal, and protozoal pathogens. While therapeutic vaccines will be required to treat a multitude of ongoing infections of the nervous system, the ideal vaccination strategy is pre-exposure vaccination, with the ultimate goals of minimizing disease associated with zoonotic viruses and the total eradication of nonzoonotic agents.     

Encephalitis complicating smallpox vaccination

A smallpox vaccination program has been initiated. The vaccine is a live virus that was used in the last century. Postvaccinal encephalitis is a complication of this vaccine. The clinical presentation, course, neuroimaging findings, and spinal fluid abnormalities are similar to a disorder that physicians are familiar with, acute disseminated encephalomyelitis. This complication can be prevented with the administration of antivaccinia gamma globulin at the time of vaccination. Antivaccinia gamma globulin is not efficacious once this complication occurs. Intravenous methylprednisolone is the recommended therapy, although intravenous immunoglobulin and plasmapheresis should be investigated in the treatment of postvaccinal encephalitis.