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Background: This study investigated the efficacy of the integrated blood purification mode of early haemoperfusion (HP) combined with continuous venovenous haemodiafiltration (CVVHDF) in children with severe viral encephalitis, and evaluated the correlation of cerebrospinal fluid (CSF) neopterin (NPT) levels with prognosis., Methods: The records of children with viral encephalitis who received blood purification treatment in the authors' hospital from September 2019 to February 2022 were retrospectively analysed. According to the blood purification treatment mode, they were divided into the experimental group (HP + CVVHDF, 18 cases), control group A (CVVHDF only, 14 cases), and control group B (16 children with mild viral encephalitis who did not receive blood purification treatment). The correlation between the clinical features, severity of the disease and the extent of lesions on brain magnetic resonance imaging (MRI) and the CSF NPT levels was analysed., Results: The experimental group and control group A were comparable with respect to age, gender and hospital course (P > 0.05). There was no significant difference in speech and swallowing functions between the two groups after treatment (P > 0.05) and no significant difference in 7 and 14-day mortality (P > 0.05). The CSF NPT levels in the experimental group before treatment were significantly higher compared with control group B (P < 0.05). The extent of brain MRI lesions correlated positively with CSF NPT levels (P < 0.05). In the experimental group (14 cases), the serum NPT levels decreased after treatment, whereas the CSF NPT levels increased after treatment, and the differences were statistically significant (P < 0.05). Dysphagia and motor dysfunction correlated positively with CSF NPT levels (P < 0.05)., Conclusion: Early HP combined with CVVHDF in the treatment of severe viral encephalitis in children may be a better approach than CVVHDF only for improving prognosis. Higher CSF NPT levels indicated the likelihood of a more severe brain injury and a greater possibility of residual neurological dysfunction., (© 2023. The Author(s).)

Viral diseases of the central nervous system (CNS) represent a major global health concern. Difficulties in treating these diseases are caused mainly by the biological tissues and barriers, which hinder the transport of drugs into the CNS. To counter this, a nanobody-mediated virus-targeting drug delivery platform (SWCNTs-P-A-Nb) is constructed for CNS viral disease therapy. Viral encephalopathy and retinopathy (VER), caused by nervous necrosis virus (NNV), is employed as a disease model. SWCNTs-P-A-Nb is successfully constructed by employing single-walled carbon nanotubes, amantadine, and NNV-specific nanobody (NNV-Nb) as the nanocarrier, anti-NNV drug, and targeting ligand, respectively. Results showed that SWCNTs-P-A-Nb has a good NNV-targeting ability in vitro and in vivo , improving the specific distribution of amantadine in NNV-infected sites under the guidance of NNV-Nb. SWCNTs-P-F-A-Nb can pass through the muscle and gill and be excreted by the kidney. SWCNTs-P-A-Nb can transport amantadine in a fast manner and prolong the action time, improving the anti-NNV activity of amantadine. Results so far have indicated that the nanobody-mediated NNV-targeting drug delivery platform is an effective method for VER therapy, providing new ideas and technologies for control of the CNS viral diseases. IMPORTANCE CNS viral diseases have resulted in many deadly epidemics throughout history and continue to pose one of the greatest threats to public health. Drug therapy remains challenging due to the complex structure and relative impermeability of the biological tissues and barriers. Therefore, development in the intelligent drug delivery platform is highly desired for CNS viral disease therapy. In the study, a nanobody-mediated virus-targeting drug delivery platform is constructed to explore the potential application of targeted therapy in CNS viral diseases. Our findings hold great promise for the application of targeted drug delivery in CNS viral disease therapy.

Viral encephalitis is a devastating disease with high mortality, and survivors often suffer from severe neurological complications. Microglia are innate immune cells of the central nervous system (CNS) parenchyma whose turnover is reliant on local proliferation. Microglia express a diverse range of proteins, which allows them to continuously sense the environment and quickly react to changes. Under inflammatory conditions such as CNS viral infection, microglia promote innate and adaptive immune responses to protect the host. However, during viral infection, a dysregulated microglia-T-cell interplay may result in altered phagocytosis of neuronal synapses by microglia that causes neurocognitive impairment. In this review, we summarize the current knowledge on the role of microglia in viral encephalitis, propose questions to be answered in the future and suggest possible therapeutic targets.

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., (Copyright © 2020 Sociedade Brasileira de Pediatria. Published by Elsevier Editora Ltda. All rights reserved.)

We report the case of a patient who presented with viral encephalitis and a pulmonary infection complicated with bilateral acute retinal necrosis after direct contact with diseased swine. Next-generation sequencing of the cerebrospinal fluid and vitreous humor detected pseudorabies virus (PRV) simultaneously. Intravenous acyclovir and dexamethasone treatment improved the symptoms of encephalitis, and vitrectomy surgery with silicone oil tamponade was used to treat the retinal detachment. This case implies that PRV can infect humans; thus, self-protection is imperative when there is contact with animals., (Copyright © 2019 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Notwithstanding the availability of effective vaccines, 40 - 60 thousand rabies cases in humans are reported every year. Almost always the disease is fatal because therapeutic treatment of lyssavirus encephalitis has not been developed. Since 1970 the number of reports on rare cases of convalescence including those using experimental treatment protocols has been gradually increasing 20 cases of convalescence, "partial" convalescence or long-term survival of humans (1970-2015) were selected as they were complaint with laboratory criteria of active lyssavirus infection. Children and teenagers were predominant in the analyzed group (85%). The cases were irregularly spread between the continents: Asia - 6 cases, North America - 6 cases, Africa - 2 cases and Europe - 1 case. India and the USA were on the top of the list of countries by the number of described cases. More than 60% humans were infected from dogs, three cases got infection from bats and 2 cases were allegedly associated with an unknown lyssavirus and an unidentified infection source. 70% cases were vaccinated and 10% cases were treated with gamma globulin before the disease onset. Serological tests for detection of antibodies to lyssaviruses in cerebrospinal fluid of infected humans were typically used for diagnostic laboratory verification. Less than 30% IFA and PCR positives were obtained. Lyssaviruses were never detected. Only 4 convalescent patients were treated using experimental protocols. 80% cases demonstrated severe neurological consequences, four (may be more) patients died afterwards within the period from two months to four years. Different perspectives on prospects of Milwaukee protocol use and other therapeutic techniques are given., Competing Interests: The authors declare no conflict of interest.

Rabies encephalitis is a fulminant, almost universally fatal infection involving the central nervous system. A unique treatment protocol, including anti-exicitotoxic therapy and induced coma was credited with the survival of a vaccinated teenager with bat rabies encephalitis in 2005. However, multiple efforts to replicate this expensive and intense protocol have not been successful. In this article, we report the failure of the protocol in Indian patients with canine-acquired rabies and elucidate the potential explanations for the failure of the protocol in our patients.

Objectives: To describe the characteristics of an outbreak of brainstem encephalitis and encephalomyelitis related to enterovirus (EV) infection in Catalonia (Spain), a setting in which these manifestations were uncommon., Methods: Clinical and microbiological data were analysed from patients with neurological symptoms associated with EV detection admitted to a reference paediatric hospital between April and June 2016., Results: Fifty-seven patients were included. Median age was 27.7 months (p25-p75 17.1-37.6). Forty-one (72%) were diagnosed with brainstem encephalitis, seven (12%) with aseptic meningitis, six (11%) with encephalitis, and three (5%) with encephalomyelitis (two out of three with cardiopulmonary failure). Fever, lethargy, and myoclonic jerks were the most common symptoms. Age younger than 12 months, higher white-blood-cell count, and higher procalcitonin levels were associated with cardiopulmonary failure. Using a PAN-EV real-time PCR, EV was detected in faeces and/or nasopharyngeal aspirate in all the patients, but it was found in cerebrospinal fluid only in patients with aseptic meningitis. EV was genotyped in 47 out of 57 and EV-A71 was identified in 40 out of 47, being the only EV type found in patients with brainstem symptoms. Most of the detected EV-A71 strains were subgenogroup C1. Intravenous immunoglobulins were used in 34 patients. Eight cases (14%) were admitted to the intensive care unit. All the patients but three, those with encephalomyelitis, showed a good clinical course and had no significant sequelae. No deaths occurred., Conclusions: The 2016 outbreak of brainstem encephalitis in Catalonia was associated with EV-A71 subgenogroup C1. Despite the clinical manifestations of serious disease, a favourable outcome was observed in the majority of patients., (Copyright © 2017 European Society of Clinical Microbiology and Infectious Diseases. Published by Elsevier Ltd. All rights reserved.)

Background: Encephalitis is a syndrome of neurological dysfunction due to inflammation of the brain parenchyma, caused by an infection or an exaggerated host immune response, or both. Attenuation of brain inflammation through modulation of the immune response could improve patient outcomes. Biological agents such as immunoglobulin that have both anti-inflammatory and immunomodulatory properties may therefore be useful as adjunctive therapies for people with encephalitis., Objectives: To assess the efficacy and safety of intravenous immunoglobulin (IVIG) as add-on treatment for children with encephalitis., Search Methods: The Cochrane Multiple Sclerosis and Rare Diseases of the CNS group's Information Specialist searched the following databases up to 30 September 2016: CENTRAL, MEDLINE, Embase, CINAHL, ClinicalTrials.gov, and the WHO ICTRP Search Portal. In addition, two review authors searched Science Citation Index Expanded (SCI-EXPANDED) & Conference Proceedings Citation Index - Science (CPCI-S) (Web of Science Core Collection, Thomson Reuters) (1945 to January 2016), Global Health Library (Virtual Health Library), and Database of Abstracts of Reviews of Effects (DARE)., Selection Criteria: Randomised controlled trials (RCTs) comparing IVIG in addition to standard care versus standard care alone or placebo., Data Collection and Analysis: Two review authors independently selected articles for inclusion, extracted relevant data, and assessed quality of trials. We resolved disagreements by discussion among the review authors. Where possible, we contacted authors of included studies for additional information. We presented results as risk ratios (RR) or mean differences (MD) with 95% confidence intervals (CI)., Main Results: The search identified three RCTs with 138 participants. All three trials included only children with viral encephalitis, one of these included only children with Japanese encephalitis, a specific form of viral encephalitis. Only the trial of Japanese encephalitis (22 children) contributed to the primary outcome of this review and follow-up in that study was for three to six months after hospital discharge. There was no follow-up of participants in the other two studies. We identified one ongoing trial.For the primary outcomes, the results showed no significant difference between IVIG and placebo when used in the treatment of children with Japanese encephalitis: significant disability (RR 0.75, 95% CI 0.22 to 2.60; P = 0.65) and serious adverse events (RR 1.00, 95% CI 0.07 to 14.05; P = 1.00).For the secondary outcomes, the study of Japanese encephalitis showed no significant difference between IVIG and placebo when assessing significant disability at hospital discharge (RR 1.00, 95% CI 0.60 to 1.67). There was no significant difference (P = 0.53) in Glasgow Coma Score at discharge between IVIG (median score 14; range 3 to 15) and placebo (median 14 score; range 7 to 15) in the Japanese encephalitis study. The median length of hospital stay in the Japanese encephalitis study was similar for IVIG-treated (median 13 days; range 9 to 21) and placebo-treated (median 12 days; range 6 to 18) children (P = 0.59).Pooled analysis of the results of the other two studies resulted in a significantly lower mean length of hospital stay (MD -4.54 days, 95% CI -7.47 to -1.61; P = 0.002), time to resolution of fever (MD -0.97 days, 95% CI -1.25 to -0.69; P < 0.00001), time to stop spasms (MD -1.49 days, 95% CI -1.97 to -1.01; P < 0.00001), time to regain consciousness (MD -1.10 days, 95% CI -1.48 to -0.72; P < 0.00001), and time to resolution of neuropathic symptoms (MD -3.20 days, 95% CI -3.34 to -3.06; P < 0.00001) in favour of IVIG when compared with standard care.None of the included studies reported other outcomes of interest in this review including need for invasive ventilation, duration of invasive ventilation, cognitive impairment, poor adaptive functioning, quality of life, number of seizures, and new diagnosis of epilepsy.The quality of evidence was very low for all outcomes of this review., Authors' Conclusions: The findings suggest a clinical benefit of adjunctive IVIG treatment for children with viral encephalitis for some clinical measures (i.e. mean length of hospital stay, time (days) to stop spasms, time to regain consciousness, and time to resolution of neuropathic symptoms and fever. For children with Japanese encephalitis, IVIG had a similar effect to placebo when assessing significant disability and serious adverse events.Despite these findings, the risk of bias in the included studies and quality of the evidence make it impossible to reach any firm conclusions on the efficacy and safety of IVIG as add-on treatment for children with encephalitis. Furthermore, the included studies involved only children with viral encephalitis, therefore findings of this review cannot be generalised to all forms of encephalitis. Future well-designed RCTs are needed to assess the efficacy and safety of IVIG in the management of children with all forms of encephalitis. There is a need for internationally agreed core outcome measures for clinical trials in childhood encephalitis.

Severe influenza infection represents a leading cause of global morbidity and mortality. Although influenza is primarily considered a viral infection that results in pathology limited to the respiratory system, clinical reports suggest that influenza infection is frequently associated with a number of clinical syndromes that involve organ systems outside the respiratory tract. A comprehensive MEDLINE literature review of articles pertaining to extra-pulmonary complications of influenza infection, using organ-specific search terms, yielded 218 articles including case reports, epidemiologic investigations, and autopsy studies that were reviewed to determine the clinical involvement of other organs. The most frequently described clinical entities were viral myocarditis and viral encephalitis. Recognition of these extra-pulmonary complications is critical to determining the true burden of influenza infection and initiating organ-specific supportive care., (© 2017 The Authors. Influenza and Other Respiratory Viruses Published by John Wiley & Sons Ltd.)

Viral encephalitis causes acute inflammation of the brain parenchyma and is a significant cause of human morbidity and mortality. Although Herpes Simplex encephalitis is the most frequent known cause of fatal sporadic encephalitis in humans, an increasingly wide range of viruses and other microbial pathogens are implicated. Up to 60% of cases of presumed viral encephalitis remain unexplained due to the failure of conventional laboratory techniques to detect an infectious agent. High-throughput DNA sequencing technologies have the potential to detect any microbial nucleic acid present in a biological specimen without any prior knowledge of the target sequence. While there remain challenges intrinsic to these technologies, they have great promise in virus discovery in unexplained encephalitis., Competing Interests: The authors declare no conflict of interest.

Chikungunya fever is an Aedes mosquito-transmitted infection caused by chikungunya virus, an RNA virus in the family Togaviridae. The disease is characteristically manifested as fever, arthralgia, and/or rash. Various neurological manifestations like meningoencephalitis, myelitis, and myeloneuropathy have been mentioned in various reports. We present a rare case of chikungunya fever presenting with mild encephalitis with a reversible lesion of the splenium (MERS), which showed complete clinical and radiological recovery.

Background: The objective of this study is to assess standardized histograms of signal intensities of T1 signal and T2 signal on sagittal view without enhancement during (1) acute stage, and (2) convalescence stage of pediatric patients with Enterovirus 71 related brainstem encephalitis (BE), and with respect to (3) healthy normal., Methods: Our subjects were hospitalized between March 2010 and October 2012, and underwent pre- and post-contrast MRI studies. The research question to be answered is whether the comparison of the MRI image intensity histograms and relevant statistical quantification can add new knowledge to the diagnosis of BE patients. So, both 25 cases in acute stage with prolonged T1 and T2 signal, without enhancement, and 13 cases in convalescence stage were introduced. In additional, a healthy group with 25 cases was recruited for comparison., Results: MRI signal intensity histogram changes of the lesions were compared at the acute and convalescence stages of the disease. Our preliminary results suggest that standardized histograms of signal intensities and their statistical properties are able to provide diagnostic information for the clinical assessment of the disease. Different stages pertaining to the histogram plots comparison showed that overall T1 signal intensity values increase as we traverse from the acute stage to the convalescence stage. And then for the healthy subjects, the T2 signal intensity values changed their magnitudes in a reverse direction. However, exceptions of this can happen in four cases where the primary lesions occurred in the brainstem that developed encephalomalacia resulting in a lower signal in T1WI and higher signal in T2WI. Statistical analysis revealed there was significant difference of T1 signal intensity among the three groups; and also, the T2 signal intensity was lower than other two groups., Conclusions: Standardized histogram of T1 and T2 intensity provide valuable and useful information for disease diagnosis and evaluation, which can potentially help medical doctors to save the lives of children.

The genus Henipavirus within the family Paramyxoviridae includes the Hendra virus (HeV) and Nipah virus (NiV) which were discovered in the 1990s in Australia and Malaysia, respectively, after emerging to cause severe and often fatal outbreaks in humans and animals. While HeV is confined to Australia, more recent NiV outbreaks have been reported in Bangladesh, India and the Philippines. The clinical manifestations of both henipaviruses in humans appear similar, with a predominance of an acute encephalitic syndrome. Likewise, the pathological features are similar and characterized by disseminated, multi-organ vasculopathy comprising endothelial infection/ulceration, vasculitis, vasculitis-induced thrombosis/occlusion, parenchymal ischemia/microinfarction, and parenchymal cell infection in the central nervous system (CNS), lung, kidney and other major organs. This unique dual pathogenetic mechanism of vasculitis-induced microinfarction and neuronal infection causes severe tissue damage in the CNS. Both viruses can also cause relapsing encephalitis months and years after the acute infection. Many animal models studied to date have largely confirmed the pathology of henipavirus infection, and provided the means to test new therapeutic agents and vaccines. As the bat is the natural host of henipaviruses and has worldwide distribution, spillover events into human populations are expected to occur in the future., (© 2015 International Society of Neuropathology.)

Objective: The aim of this study was to clarify characteristics of post-encephalopathic epilepsy (PEE) in children after acute encephalopathy with biphasic seizures and late reduced diffusion (AESD), paying particular attention to precise diagnosis of seizure types., Methods: Among 262 children with acute encephalopathy/encephalitis registered in a database of the Tokai Pediatric Neurology Society between 2005 and 2012, 44 were diagnosed with AESD according to the clinical course and magnetic resonance imaging (MRI) findings and were included in this study. Medical records were reviewed to investigate clinical data, MRI findings, neurologic outcomes, and presence or absence of PEE. Seizure types of PEE were determined by both clinical observation by pediatric neurologists and ictal video-electroencephalography (EEG) recordings., Results: Of the 44 patients after AESD, 10 (23%) had PEE. The period between the onset of encephalopathy and PEE ranged from 2 to 39 months (median 8.5 months). Cognitive impairment was more severe in patients with PEE than in those without. Biphasic seizures and status epilepticus during the acute phase of encephalopathy did not influence the risk of PEE. The most common seizure type of PEE on clinical observation was focal seizures (n = 5), followed by epileptic spasms (n = 4), myoclonic seizures (n = 3), and tonic seizures (n = 2). In six patients with PEE, seizures were induced by sudden unexpected sounds. Seizure types confirmed by ictal video-EEG recordings were epileptic spasms and focal seizures with frontal onset, and all focal seizures were startle seizures induced by sudden acoustic stimulation. Intractable daily seizures remain in six patients with PEE., Significance: We demonstrate seizure characteristics of PEE in children after AESD. Epileptic spasms and startle focal seizures are common seizure types. The specific seizure types may be determined by the pattern of diffuse subcortical white matter injury in AESD and age-dependent reorganization of the brain network., (Wiley Periodicals, Inc. © 2015 International League Against Epilepsy.)

Background: Central nervous system infections can have devastating clinical outcomes if not diagnosed and treated promptly. There is a documented gap between recommended and actual practice and a limited understanding of its causes. We identified and explored the reasons for this gap, focusing on points in the patient pathway most amenable to change and the development of a tailored intervention strategy to improve diagnosis and treatment., Methods: Using theoretically-informed semi-structured interviews, we explored barriers and enablers to diagnosing and managing patients with suspected encephalitis, specifically performing lumbar punctures and initiating antiviral therapy within 6 h. We purposively sampled hospitals and hospital staff in the UK. We audio recorded and transcribed all interviews prior to a framework analysis. We mapped identified barriers and enablers to the patient pathway. We matched behaviour change techniques targeting clinicians to the most salient barriers and enablers and embedded them within an intervention package., Results: We interviewed 43 staff in six hospitals. Clinical staff expressed uncertainty when and how to perform lumbar punctures and highlighted practical difficulties in undertaking them within busy clinical settings. Once treatment need was triggered, clinicians generally felt able to take appropriate therapeutic action, albeit within organisational and resource constraints. Matched behaviour change techniques largely targeted antecedents of treatment. These included decision support to prompt recognition, highlighting the consequences of missed diagnoses for clinicians and patients, and practical support for lumbar punctures. We subsequently devised an evidence-informed package comprising 'core' interventions and, to allow for local flexibility, 'optional' interventions., Conclusions: We identified several points in the patient pathway where practice could improve, the most critical being around clinical suspicion and initial investigation. Interventions targeting professional beliefs and behaviours whilst optimising their clinical environment were amongst the most promising approaches to improve the care of suspected encephalitis., Trial Registration: Randomised trial registered with Controlled Trials ISRCTN06886935 .

Background: Viral encephalitis is a devastating condition for which delayed treatment is associated with increased morbidity and mortality. Clinical audits indicate substantial scope for improved detection and treatment. Improvement strategies should ideally be tailored according to identified needs and barriers to change. The aim of the study is to evaluate the effectiveness and cost-effectiveness of a tailored intervention to improve the secondary care management of suspected encephalitis., Methods/design: The study is a two-arm cluster randomised controlled trial with allocation by postgraduate deanery. Participants were identified from 24 hospitals nested within 12 postgraduate deaneries in the United Kingdom (UK). We developed a multifaceted intervention package including core and flexible components with embedded behaviour change techniques selected on the basis of identified needs and barriers to change. The primary outcome will be a composite of the proportion of patients with suspected encephalitis receiving timely and appropriate diagnostic lumbar puncture within 12 h of hospital admission and aciclovir treatment within 6 h. We will gather outcome data pre-intervention and up to 12 months post-intervention from patient records. Statistical analysis at the cluster level will be blind to allocation. An economic evaluation will estimate intervention cost-effectiveness from the health service perspective., Trial Registration: Controlled Trials: ISRCTN06886935.

Antiretroviral drug therapy plays a cornerstone role in the treatment of human immunodeficiency virus (HIV)/acquired immunodeficiency syndrome patients. Despite obvious advances over the past 3 decades, new approaches toward improved management of infected individuals are still required. Drug distribution to the central nervous system (CNS) is required in order to limit and control viral infection, but the presence of natural barrier structures, in particular the blood-brain barrier, strongly limits the perfusion of anti-HIV compounds into this anatomical site. Nanotechnology-based approaches may help providing solutions for antiretroviral drug delivery to the CNS by potentially prolonging systemic drug circulation, increasing the crossing and reducing the efflux of active compounds at the blood-brain barrier, and providing cell/tissue-targeting and intracellular drug delivery. After an initial overview on the basic features of HIV infection of the CNS and barriers to active compound delivery to this anatomical site, this review focuses on recent strategies based on antiretroviral drug-loaded solid nanoparticles and drug nanosuspensions for the potential management of HIV infection of the CNS.

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.

Justification: Viral encephalitis is an important cause of mortality and morbidity in children. The etiological agents are varied, and physicians treating such children often feel limited by the lack of uniform guidelines on evaluation and management of these critically ill children in resource-constrained settings., Process: An Expert Group Meeting on Viral Encephalitis in Children was held on 19th January, 2012 in Gurgaon, Haryana (under the aegis of PEDICON 2012, the National Conference of Indian Academy of Pediatrics). The invited experts included pediatricians and microbiologists with expertise in the relevant field. Various issues related to the subject were discussed and it was decided to bring out recommendations on the topic. The final recommendations were produced after circulating the draft document, and incorporating/discussing all changes, by email., Objectives: To aid the pediatrician in the evaluation and management of children with suspected viral encephalitis and to assist the public health authorities in acute encephalitis surveillance. These guidelines do not cover viral encephalitis in the neonatal period and in immunocompromised children, Rabies encephalitis, and chronic viral encephalitis such as Subacute sclerosing panencephalitis (SSPE)., Recommendations: Recommendation for evaluation and management of suspected viral encephalitis in children are presented. In any acute encephalitis outbreak, pediatricians should be aware of the common viral causes of encephalitis in their area, what information and samples they should collect, and the contact details of the District Surveillance Unit. Pending specific diagnosis and therapy (which may or may not be possible), prompt empirical therapy and meticulous supportive care are important to prevent ongoing brain damage, and improve outcome.

Fibrous dysplasia (FD) is categorized as either monostotic or polyostotic and may occur as a component of McCune-Albright syndrome (MAS). Imaging findings can mimic neoplastic diseases. We present a case of MAS initially suspected to have neoplastic disease. A 9-year-old girl was admitted to pediatric emergency with ataxia. Upon hospitalization, an extradural mass was seen on cranial magnetic resonance imaging (MRI) and the bone survey showed lytic lesions in the long bones. The patient was referred to the pediatric oncology department with a presumptive diagnosis of Langerhans cell histiocytosis or metastatic tumor. Further investigations demonstrated that the patient had MAS and coexisting postinfectious cerebellitis. The findings in this patient demonstrate that the radiographic findings and the clinical presentation of FD and MAS may be similar to those of malignant diseases.

In October 2011, an Indian man resident in Italy was admitted to a hospital in Mantua, Italy with symptoms of acute encephalitis. Due to a recent history of bite by a suspected rabid dog in India, where he had received incomplete post-exposure treatment, rabies was suspected. The patient died after 22 days of intensive care treatment and rabies was confirmed post mortem. This report stresses the need of appropriate post-exposure prophylaxis in rabies-endemic countries.

Encephalitis generally results in a serious illness requiring hospitalization. The aim of this study was to describe the epidemiology of hospitalization for encephalitis in Italy, taking into account the geographical distribution, aetiology, seasonality and evolution of hospitalization rates over recent years. The mean hospitalization rate was 5·88/100 000. For most of these hospitalizations (n=13 119, 55·6%), no specific cause of encephalitis was reported. The most common aetiological category was 'viral', which accounted for 40·1% (n=4205) of such hospitalizations (rate 1·05/100 000). Within this category, herpes virus was the leading causative agent (n=1579, 0·39/100 000). This report highlights a significant increase of 'viral encephalitis not otherwise specified' (ICD-9 code 049·9) vs. a reduction of all other causes. A seasonal pattern was noted in people aged ≥65 years in this group. Specific surveillance of encephalitis without known origin should be reinforced in order to identify the potential role of emerging pathogens and to design preventive interventions.

Enterovirus 71 (EV71) is one of the most important causes of herpangina and hand, foot, and mouth disease. It can also cause severe complications of the central nervous system (CNS). Brain stem encephalitis with pulmonary edema is the severe complication that can lead to death. EV71 replicates in leukocytes, endothelial cells, and dendritic cells resulting in the production of immune and inflammatory mediators that shape innate and acquired immune responses and the complications of disease. Cytokines, as a part of innate immunity, favor the development of antiviral and Th1 immune responses. Cytokines and chemokines play an important role in the pathogenesis EV71 brain stem encephalitis. Both the CNS and the systemic inflammatory responses to infection play important, but distinctly different, roles in the pathogenesis of EV71 pulmonary edema. Administration of intravenous immunoglobulin and milrinone, a phosphodiesterase inhibitor, has been shown to modulate inflammation, to reduce sympathetic overactivity, and to improve survival in patients with EV71 autonomic nervous system dysregulation and pulmonary edema.

Vesicular stomatitis virus (VSV) has long been regarded as a promising recombinant vaccine platform and oncolytic agent but has not yet been tested in humans because it causes encephalomyelitis in rodents and primates. Recent studies have shown that specific tropisms of several viruses could be eliminated by engineering microRNA target sequences into their genomes, thereby inhibiting spread in tissues expressing cognate microRNAs. We therefore sought to determine whether microRNA targets could be engineered into VSV to ameliorate its neuropathogenicity. Using a panel of recombinant VSVs incorporating microRNA target sequences corresponding to neuron-specific or control microRNAs (in forward and reverse orientations), we tested viral replication kinetics in cell lines treated with microRNA mimics, neurotoxicity after direct intracerebral inoculation in mice, and antitumor efficacy. Compared to picornaviruses and adenoviruses, the engineered VSVs were relatively resistant to microRNA-mediated inhibition, but neurotoxicity could nevertheless be ameliorated significantly using this approach, without compromise to antitumor efficacy. Neurotoxicity was most profoundly reduced in a virus carrying four tandem copies of a neuronal mir125 target sequence inserted in the 3'-untranslated region of the viral polymerase (L) gene.

Although polymerase chain reaction (PCR) is a highly sensitive procedure for the diagnosis of enteroviruses, it has never been systemically applied to the treatment of enteroviral encephalitis using intravenous immunoglobulin (IVIg). We conducted a 2-year randomized, controlled comparison of reverse transcription (RT)-PCR of cerebrospinal fluid (CSF) with traditional viral isolation to guide IVIg treatment. Seventy-five patients were enrolled and classified into three groups: one group with clinical manifestations of enteroviral infections and two without. The latter two groups were separated on the basis of whether IVIg treatment was guided by RT-PCR or virus culture assay. CSF specimens from the 18 confirmed cases of enteroviral encephalitis were RT-PCR positive for enterovirus in all but one case. Of the remaining 57 cases of nonenteroviral encephalitis, only 4 were positive for enterovirus RT-PCR. One patient in the group of IVIg treatment guided by viral isolation subsequently displayed a sequel of epilepsy. No patients in the IVIg treatment groups guided by RT-PCR had any neurological sequelae. In conclusion, the use of RT-PCR allowed rapid, sensitive, and specific detection of enteroviral RNA in CSF. When used to guide IVIg treatment, RT-PCR may shorten hospitalization and improve outcomes of patients with enteroviral encephalitis.

Infections of the central nervous system are frequent diseases in emergency care. They can have a bacterial, parasitic or viral origin. Initial symptoms can be non-specific, which can complicate and delay diagnosis, hence the extreme importance of all the information that can be obtained through anamnesis and physical exploration, with frequent complementary explorations. In the last hundred years, with the introduction of antibiotic drugs, there has been a significant fall in mortality secondary to meningoencephalitis, but in spite of that they continue to provoke high morbidity and mortality. Other phenomena, such as vaccination campaigns, migratory movements, infection by HIV and other states of immunosuppression, have given rise to important epidemiological changes such as the virtual disappearance of some infections or the appearance of others that rarely existed previously. The list of potential infections of the central nervous system is extensive, which is why in this review we set out, from the clinical, diagnostic and therapeutic point of view, those that are most frequent in our environment and some that, although very infrequent, might require emergency attention due to their severity.

Objective: Transcranial magnetic stimulation (TMS) is a non-invasive tool for the electrical stimulation of neural tissue. TMS can be applied as single pulses of stimulation, pairs of stimuli separated by variable intervals to the same or different brain areas, or as trains of repetitive stimuli at various frequencies., Case Report: A 2-years-old male infant was referred to our department with a history of Epstein-Barr virus (EBV) encephalitis, treated with foscarnet and steroids, for he developed mutism and ataxia and loss of the ability to eat, walk and talk. Brain imaging revealed loss of white matter around ventricles and progressive global brain atrophy, findings consistent with encephalopathy. Serology for antibodies against EBV infection was positive and the diagnosis of acute and prolonged EBV infection was made. There was an improvement of the clinical findings after the application of TMS with proper field characteristics (intensity: 1-7.5 pT, frequency: 8-13 Hz)., Conclusions: Our case illustrates the possibility of therapeutic applications of TMS (in the order of pT) with proper field characteristics to normalize pathologically decreased levels of brain cortex activity. TMS might provide novel insights into the pathophysiology of the neural circuitry, be developed into clinically useful diagnostic and prognostic tests, and have therapeutic uses in various diseases.

Indoleamine 2,3-dioxygenase (IDO) is the rate-limiting enzyme in the kynurenine pathway of tryptophan metabolism. IDO activity is linked with immunosuppression by its ability to inhibit lymphocyte proliferation, and with neurotoxicity through the generation of quinolinic acid and other toxins. IDO is induced in macrophages by HIV-1 infection, and it is up regulated in macrophages in human brain tissue with HIV-1 encephalitis (HIVE). Using a model of HIVE, we investigated whether IDO inhibitor 1-methyl-d-tryptophan (1-MT) could affect the generation of cytotoxic T lymphocytes (CTLs) and clearance of virus-infected macrophages from the brain. Severe combined immunodeficient mice were reconstituted with human peripheral blood lymphocytes, and encephalitis was induced by intracranial injection of autologous HIV-1-infected monocyte-derived macrophages (MDMs). Animals treated with 1-MT demonstrated increased numbers of human CD3+, CD8+, CD8+/interferon-gamma+ T cells, and HIV-1(gag/pol)-specific CTLs in peripheral blood compared with controls. At week 2 after MDM injection in the basal ganglia, mice treated with 1-MT showed a 2-fold increase in CD8+ T lymphocytes in the areas of the brain containing HIV-1-infected MDMs compared with untreated controls. By week 3, 1-MT-treated mice showed 89% reduction in HIV-infected MDMs in brain as compared with controls. Thus, manipulation of immunosuppressive IDO activity in HIVE may enhance the generation of HIV-1-specific CTLs, leading to elimination of HIV-1-infected macrophages in brain.

Most of the viruses involved in causing encephalitis are arthropod-borne viruses, with the exception of arenaviruses that are rodent-borne. Even if little information is available, there are indications that, most of these encephalitis-associated viruses could be used by aerosolisation during a bioterrorist attack. Viral transfer from blood to the CNS through the olfactory tract has been suggested. Another possible route of contamination is by vector-borne transmission such as infected mosquitoes or ticks. Alphaviruses are the most likely candidates for weaponisation. The clinical course of the diseases caused by these viruses is usually not specific, but differentiation is possible by using an adequate diagnostic tool. There is no effective drug therapy for the treatment of these diseases and treatment is mainly supportive, but vaccines protecting against some of these viruses do exist.

Acute encephalitis constitutes a medical emergency. In most cases, the presence of focal neurological signs and focal seizures will distinguish encephalitis from encephalopathy. Acute disseminated encephalomyelitis is a non-infective inflammatory encephalitis that may require to be treated with steroids. Acute infective encephalitis is usually viral. Herpes simplex encephalitis (HSE) is the commonest sporadic acute viral encephalitis in the Western world. Magnetic resonance imaging of brain is the investigation of choice in HSE and the diagnosis may be confirmed by the polymerase chain reaction test for the virus in the cerebrospinal fluid. In this article, we review the diagnosis, investigations, and management of acute encephalitis. With few exceptions (for example, aciclovir for HSE), no specific therapy is available for most forms of viral encephalitis. Mortality and morbidity may be high and long term sequelae are known among survivors. The emergence of unusual forms of zoonotic encephalitis has posed an important public health problem. Vaccination and vector control measures are useful preventive strategies in certain arboviral and zoonotic encephalitis. However, we need better antiviral therapy to meet the challenge of acute viral encephalitis more effectively.

In the new Japanese control law for infectious diseases, most varieties of acute viral encephalitis belong to Category IV requiring report of all cases at sentinel hospitals. Herpes simplex virus type 1 (HSV-1) encephalitis comprises the majority of cases. With the increased prevalence of diagnostic procedures such as polymerase chain reaction (PCR), several forms of HSV-1, and -2 central nervous system (CNS) infections, including acute disseminated encephalomyelitis, brainstem encephalitis, and myelitis, have been clarified. Since 1990 we have conducted a survey of HSV CNS infections in the Kyushu and Okinawa regions, and the data are reviewed here. Trends include an increase in a new subtype of non-herpetic acute limbic encephalitis. In contrast, the incidence of Japanese encephalitis (JE) in Japan has dramatically decreased to a few patients per year; however, JE remains a threat for those with decreased or absent immunity to the JE virus. Imported emerging and reemerging CNS infections such as Murray Valley and West Nile encephalitis can occur in Japan. Influenza-associated encephalitis/encephalopathy is also described as a threat for adults as well as young children.

Finding an effective treatment for viral infections that cause encephalitis remains an important problem. A model of human alphavirus infections, Semliki Forest virus, causes lethal encephalitis in weanling mice. Mice are viremic within 24 hr of an intraperitoneal challenge with the equivalent of three 75% lethal doses of Semliki Forest virus. Virus reaches the brain by 48 hr, and mortality results in all mice in 5-7 days. Introduction of virus intracranially accelerates the course of the infection. Neither anti-Semliki Forest virus hyperimmune serum nor the potent interferon inducer poly I:CLC given intraperitoneally are protective when used therapeutically after an intracranial virus infection, but a combination of 1,000 U hyperimmune serum and 80 micrograms/mouse of poly I:CLC results in a 50% survival rate. This combination treatment of intracranial Semliki Forest virus infection eliminates detectable viremia and reduces virus load in the brain over the course of the infection. These data show that when combined, specific antibody and an interferon inducer can interact synergistically to protect mice from alphavirus infections of the central nervous system even when given after the virus is replicating in the target organ.