Infectious Encephalitis Research Articles

Geo-Spatial Characteristics of 567 Places of Tick-Borne Encephalitis Infection in Southern Germany, 2018-2020.

Tick-borne encephalitis (TBE) is a growing public health problem with increasing incidence and expanding risk areas. Improved prevention requires better understanding of the spatial distribution and ecological determinants of TBE transmission. However, a TBE risk map at sub-district level is still missing for Germany. We investigated the distribution and geo-spatial characteristics of 567 self-reported places of probable TBE infection (POI) from 359 cases notified in 2018–2020 in the study area of Bavaria and Baden-Wuerttemberg, compared to 41 confirmed TBE foci and 1701 random comparator places. We built an ecological niche model to interpolate TBE risk to the entire study area. POI were distributed heterogeneously at sub-district level, as predicted probabilities varied markedly across regions (range 0–93%). POI were spatially associated with abiotic, biotic, and anthropogenic geo-spatial characteristics, including summer precipitation, population density, and annual frost days. The model performed with 69% sensitivity and 63% specificity at an optimised probability threshold (0.28) and an area under the curve of 0.73. We observed high predictive probabilities in small-scale areas, consistent with the known circulation of the TBE virus in spatially restricted microfoci. Supported by further field work, our findings may help identify new TBE foci. Our fine-grained risk map could supplement targeted prevention in risk areas.

Clinical case of anti-NMDA receptor encephalitis associated with new coronaviral infection (COVID-19)

During the outbreak of coronavirus disease 2019 (COVID-19) clinicians are increasingly involved in the observation of possible neurological complications due to the infection of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Some cases of encephalitis following COVID‐19 pandemic have been reported in literature that can mean possible damage to the central nervous system related to the SARS-CoV-2 infection. Early on, this was thought to be due to the direct effects of the virus itself, but the possibility of immune system mechanisms being implicated was gradually raised in scientific literature. The reports of anti‐NMDA receptor encephalitis among patients with COVID‐19 at different ages may be signs of this condition. We report the case of 16-year teenager with concomitant Anti-N-Methyl-D-Aspartate Receptor (Anti-NMDAR) encephalitis and COVID‐19. This clinical case brings arguments on the possible relationship between SARS-CoV-2 infection and autoimmune encephalitis.

Autoimmune encephalitis - Recent Guidelines for Diagnosis and Management

Autoimmune encephalitis (AE) is a group of acute to subacute onset, rapidly progressive, non-infectious, immune-mediated, inflammatory disorders of the brain parenchyma often affecting the cortical or deep grey matter with or without involving the white matter, meninges or spinal cord.1-4 An estimated prevalence rate for AE is 13.7/100 000, so possibly as common as infectious encephalitis.5 ‘Autoimmune neurology’ is coming up with the advent of newer antibodies and associated syndromes.6 Identifying these disorders is rewarding in view of favourable response to immunotherapy compared to infectious encephalitis with limited therapeutic options. Clinicians need to suspect AE clinically first to plan investigations and early treatment.1 Long-term management depends on antibody identified. Recent guidelines for diagnosis and management of AE are discussed here.

Outcomes of parenteral vs enteral ketogenic diet in pediatric super-refractory status epilepticus

BackgroundSuper-refractory status epilepticus (SRSE) is extremely difficult to control and associated with poor outcomes. Ketogenic diet (KD) has been increasingly used for SRSE treatment. Enteral ketosis induction in SRSE is sometimes unfeasible, leading to the use of parenteral KD which has limited data among children. ObjectivesTo assess the effectiveness of KD and compare parenteral and enteral ketosis induction as treatment options in pediatric SRSE patients. MethodsThis study is a retrospective medical record review of children < 15 years old diagnosed with SRSE who received KD as one of the treatment modalities during 2007–2021 at King Chulalongkorn Memorial Hospital, Thailand. ResultsKD was used in 14 (77.8%) of the 18 pediatric SRSE cases whose age ranged from 2 months to 13.5 years. The leading etiologies of SRSE were immune-mediated encephalitis, infectious encephalitis, and epilepsy. Ketosis was induced via enteral route (kEN) in 8/14 and parenteral route (kPN) in 6/14 cases. The median time from the onset of SRSE to KD initiation was 6 days (IQR 4.8–9.3) with no demonstrable difference between groups. The median time to achieve significant ketosis was significantly shorter in the kPN (2 days; IQR 1.8–4) compared to the kEN group (5 days (3.3–7.8)). Nonetheless, the median time after ketosis induction to SRSE termination when anesthetic infusion was stopped was not statistically difference between the kPN (14 days; IQR 8.5–18) and the kEN group (10.5 days (5.5–15.3)). Hypertriglyceridemia was found more in the kPN (6/6, 100%) compared to the kEN group (3/8, 37.5%). All survivors (12/14) were seizure free at discharge. ConclusionParenteral ketosis induction achieved the target ketosis quicker than enteral induction but showed no difference in efficacy and duration for SRSE termination in our study. The adverse effects were minimal and controllable. Both parenteral and enteral KD could be considered early during SRSE treatment.

Antibody persistence upto 5 years after primary immunization and booster with an inactivated chromatographically purified Vero cell-derived Japanese encephalitis vaccine in Thai children

ABSTRACT Japanese encephalitis is the main cause of viral encephalitis in Asia. In a previous single-arm vaccine trial, an inactivated chromatographically purified Japanese encephalitis Vero cell vaccine (CVI-JE; JEVACTM) was safe and immunogenic in 152 Thai children aged 1–3 years receiving a 2-dose primary immunization and booster dose 1 year later. We conducted a 5-year follow-up assessment of the persistence of the immune response the 144 children remaining in this cohort after first booster dose. Immunity was assessed by 50% plaque reduction neutralization test annually for up to 5 years post-booster. Seroprotection rates (95%CI) decreased from 100% (97.1–100) at 1 year post-booster to 93% (85.0–98.3) at 5 years post-booster. No serious vaccine-related adverse events or Japanese encephalitis infections were reported. A 2-dose primary immunization and booster 1 year later with CVI-JE provided long-lasting immunity in the majority of children.

Point-of Care for Prompt Management of Infectious Meningitis and/or Encephalitis (IM/IE) in Gabon Military Hospital

Infectious meningitis (IM) and/or infectious encephalitis (IE) can cause significant and irreversible damage to the central nervous system.

Transboundary Swine Infections in India: An Overview

In the recent past, India has seen a number of outbreaks and epidemics of transboundary infectious virus diseases associated with swine. Classical swine fever (CSF), African swine fever (ASF), Porcine reproductive and respiratory syndrome (PRRS), Porcine circovirus 2 (PCV2) infections, Porcine parvovirus, Swine Influenza and Japanese Encephalitis (JE) infections are the major transboundary viral diseases prevalent in Indian swine populations. Understanding the impact of factors that provoke the emergence of viral infections is the major challenge faced in the control and prevention of emerging transboundary viral diseases. In-depth knowledge on disease status is crucial in successfully implementing disease control programs. The movement of animals influences the spread of pathogens in swine populations. This article gives insight into major emerging transboundary emerging viral infections of swine and their current status in India.

Recent Advance of Neuronal Cell Antigens and Autoimmune Encephalitis

Patients with autoimmune encephalitis rarely present to neurology clinic before presenting to memory, seizure, movement disorder, and psychiatry clinics, recent discovery of neuronal surface autoantibodies have shifted the balance towards the diagnosis of autoimmune encephalitis, patients with autoimmune encephalitis used to receive the diagnosis of infectious encephalitis, with poor response to antiseizure, antibacterial and antiviral therapy, autoimmune encephalitis has a fundamental phenotype which is very specific even if serology was negative, early diagnosis is of paramount importance due to starting immunotherapy and avoid mortality and significant morbidity.

Significance of Neuronal Autoantibodies in Comparison to Infectious Etiologies among Patients Presenting with Encephalitis in a Region with a High Prevalence of Infections.

Background:Prevalence of antibody-mediated autoimmune encephalitis (AE) is reported to be comparable to infectious encephalitis in Western populations. We evaluated the frequency and significance of AE and neuronal autoantibodies in comparison to infectious etiologies among patients presenting with encephalitis in a South Asian population.Methods:Ninety-nine consecutive patients with a clinical diagnosis of encephalitis/meningoencephalitis admitted to two of the largest tertiary-care hospitals in Sri Lanka were studied. PCR and ELISA were used to screen viruses while Gram stain and culture were used to screen bacteria. Sera were tested for antibodies binding to primary embryonic rat hippocampal neuronal cultures and cell-based assays for antibodies to NMDAR, LGI1, CASPR2, Contactin2, AMPAR, GABAAR, GABABR, aquaporin-4 and MOG.Results:Patient ages ranged from 1 month to 73 years (mean = 24.91; SD = 21.33) with a male: female ratio of 1.75:1. A viral etiology was identified in 27.3% and bacterial meningoencephalitis was diagnosed in 17.1%. Sera of nine patients had antibodies binding to live primary neurons, but only five had specific antibodies to CASPR2 (n = 1), NMDAR (n = 2) or GABABR-antibodies (n = 2). Moreover, the patients with CASPR2 antibodies and NMDAR-antibodies were also positive for dengue antibodies. Only the two patients with NMDAR-antibodies had features and responses to immunotherapy consistent with AE.Conclusions:Identified infectious forms of meningoencephalitis (44.4%) greatly exceeded the occurrence of neuronal autoantibodies (9.1%) and AE (2%) in Sri Lanka, and this may be common in those regions where infections are prevalent.

Altered Behavior in Encephalitis: Insights From the Australian Childhood Encephalitis Study, 2013-2018.

Altered mental status is a major criterion for a diagnosis of encephalitis to be made with alteration in behavior, a key manifestation of altered mental status. We reviewed all evaluated cases identified by the Australian Childhood Encephalitis study between May 2013 and June 2018, to review the frequency and features of altered behavior (ALB). ALB was reported in >72% of cases of childhood encephalitis in all three major etiologic groups (infectious, immune-mediated, and unknown). The duration of ALB was >7 days in a minority, but significantly more frequent in immune-mediated compared with infectious encephalitis (27 and 10%, respectively, p < 0.01). ALB was most frequently characterized as irritability/agitation (47%), which predominated in children aged <1 year, and among the leading infectious causes in this age group (enterovirus, parechovirus, and bacterial meningoencephalitis). ALB in the form of disorientation/confusion (25%) was most prominent in those aged >1 year and most frequent in immune-mediated encephalitis. Hallucinations, paranoia, and aggression were all infrequent; suicidality/self-harm was not observed. ALB was reported in 20 of 21 cases of anti-N-methyl-d-aspartate receptor (anti-NMDAr), 19% for >7 days, and disorientation/confusion was the most frequent feature. Only one case was reported as presenting with “psychosis” and was diagnosed with anti-NMDAr encephalitis. Clinician-reported ALB is frequent but most often non-specific in childhood encephalitis. A longer duration of ALB is associated with an immune-mediated cause. More specific psychiatric symptoms (hallucinations, paranoia) are very infrequent. ALB is a hallmark of anti-NMDAr encephalitis, but psychosis is uncommon in contrast to the disorder in adults.

Pediatric Autoimmune encephalitis: Experience from a Tertiary Care Hospital in Bangladesh

Background: Autoimmune encephalitis (AIE) are distinct group of encephalitis where production of autoimmune antibody causes neuroinflammation. The core clinical features are encephalopathy, psychiatric disorder, movement disorder and seizure. The investigation and treatment modalities are different from that of infectious encephalitis. There are limited studies in pediatric population in particularly in developing country like Bangladesh. Thus this study has been done to describe patients with AIE from a tertiary care hospital.&#x0D; Method: This is a retrospective study done in children of 1-16 year from January 2018 to December 2019. AIE was diagnosed on the basis of clinical, electrographic and neuroimaging features and was confirmed with detection of autoantibody in CSF. Treatment was given according to the published literature with immunotherapy mainly.&#x0D; Results: Total 15 children were studied, 14 patients were antiNMDAR encephalitis and 1 was antiMOG antibody syndrome. Mean age was 5.98 and 4.5 year respectively. Seizure was the most common clinical feature, mostly focal in nature. Other manifestations were movement disorder, psychiatric disorder, loss of consciousness etc. Most of the patients had abnormal EE, focal epileptic discharge being the commonest. Eight out of 15 had abnormal MRI of brain. Cortical hyperintensity was important feature located mostly in temporal region. In the case of antiMOG antibody syndrome there was demyelinating lesion in multiple areas. Cornerstone of the treatment was mostly combination immunotherapy with IV methylprednisolone and IV immunoglobulin followed by oral steroid. Majority of the patients showed improvement however 3 patients had complete recovery. Complications observed were epilepsy, speech disorder, cognitive disorder, behavioural disorder, ataxia and visual impairment.&#x0D; Conclusion: Timely diagnosis and prompt treatment of AIE is very important as proper treatment can cause significant improvement.

Changing profile of encephalitis: Results of a 4-year study in France

ContextIn 2007, we performed a nationwide prospective study to assess the epidemiology of encephalitis in France. We aimed to evaluate epidemiological changes 10years later. MethodsWe performed a 4-year prospective cohort study in France (ENCEIF) from 2016 to 2019. Medical history, comorbidities, as well as clinical, biological, imaging, and demographic data were collected. For the comparison analysis, we selected similar data from adult patients enrolled in the 2007 study. We used Stata statistical software, version 15 (Stata Corp). Indicative variable distributions were compared using Pearson's Chi2 test, and means were compared using Student's t-test for continuous variables. ResultsWe analyzed 494 cases from 62 hospitals. A causative agent was identified in 65.7% of cases. Viruses represented 81.8% of causative agents, Herpesviridae being the most frequent (63.6%). Arboviruses accounted for 10.8%. Bacteria and parasites were responsible for respectively 14.8% and 1.2% of documented cases. Zoonotic infections represented 21% of cases. When comparing ENCEIF with the 2007 cohort (222 adults patients from 59 hospitals), a higher proportion of etiologies were obtained in 2016–2019 (66% vs. 53%). Between 2007 and 2016–2019, the proportions of Herpes simplex virus and Listeria encephalitis cases remained similar, but the proportion of tuberculosis cases decreased (P=0.0001), while tick-borne encephalitis virus (P=0.01) and VZV cases (P=0.03) increased. In the 2016–2019 study, 32 causative agents were identified, whereas only 17 were identified in the 2007 study. ConclusionOur results emphasize the need to regularly perform such studies to monitor the evolution of infectious encephalitis and to adapt guidelines.

Prevalence, Causes and Management of Encephalitis

Encephalitis is a major cause of morbidity, mortality, and permanent neurological disability in both adults and children. The term "encephalitis" literally means inflammation of part or all of the "brain" or the brain parenchyma. Encephalitis affects people of all ages; however, the incidence is higher in the pediatric population. Although both genders are affected, most studies showed slight dominance in men. There are two main types with different causes: primary or infectious encephalitis can develop when a fungus, virus, or bacteria infects the brain and accounts for approximately 70% of confirmed cases of encephalitis, and secondary or post-infectious encephalitis when the immune system is active and reacts. to a previous infection and mistakenly attacks the brain. The clinical manifestations depend on whether the brain parenchyma or the meninges are predominantly involved and cause an encephalitic or meningitis syndrome. Diagnostic tests should include a lumbar puncture, an MRI of the brain, and an EEG for suspected encephalitis. In encephalitis, a broad differential diagnosis, both infectious and non-infectious, should be considered. These alternatives include malignancy, autoimmune or paraneoplastic diseases (eg, anti-NMDA receptor encephalitis), brain abscess, drug-induced tuberculosis or delirium, neurosyphilis, or bacterial, fungal, protozoal, or helminthic encephalitis. Antiviral medications, such as intravenous acyclovir, are often given at the initial diagnosis of encephalitis before the cause is known. Acyclovir is the best treatment for herpes simplex encephalitis. If medication can be started soon after symptoms appear, the chance of a full recovery is much higher.

Quercus acuta Thunb. (Fagaceae) and Its Component, Isoquercitrin, Inhibit HSV-1 Replication by Suppressing Virus-Induced ROS Production and NF-κB Activation.

HSV-1 is a neurotropic virus that replicates lytically during acute infection and establishes latency in peripheral neurons. Currently, the clinically approved compounds for the prevention of HSV-1 infection include acyclovir and penciclovir; however, long-term use of the drug is associated with serious side effects, and drug-resistant strains often appear. Therefore, it is important to find a safe and novel antiviral agent for HSV-1 infection. Quercus acuta Thunb. (Fagaceae) (QA) is widely distributed as an ornamental and dietary plant in Korea, Taiwan, China, and Japan. Thus far, the effects of QA extract and its active ingredients are known to have antioxidant, antibacterial, and anti-inflammatory activity, but studies of possible antiviral effects have not been reported. We studied the antiviral effects and molecular mechanism of QA after HSV-1 infection at the cellular level. We confirmed that QA suppresses ROS expression after HSV-1 infection and also suppresses inflammatory cytokine expression through inhibition of NF-кB activity. In addition, we found that QA increases the phosphorylation activity of IRF3 through induction of TBK1 activity during HSV-1 infection. QA exhibits an antiviral effect, and we confirmed through UPLC-DAD-mass spectrometer (MS)/MS analysis that it contains five main components: catechin, chlorogenic acid, fraxin, isoquercitrin, and taxifolin. Of these, isoquercitrin was confirmed to exhibit an antiviral effect on SK-N-SH cells through ICP27 inhibition. Overall, our results suggest that QA is a novel inhibitor with antiviral effects against HSV-1 infection and may be used specifically to prevent and treat of herpes simplex virus encephalitis infection.

Encephalitis during first year of SARS-COV-2 pandemic– first results of the European ENCOVID registry

Objective: Several preclinical and clinical investigations have argued for nervous system involvement in SARS-CoV-2 infection. No data about clinical, imaging and biomarkers presentations as well as long-term outcomes are available for SARS-CoV-2 encephalitis in comparison with infectious and autoimmune encephalitis.

Managing encephalitis on the intensive care unit

Acute encephalitis although a rare syndrome in absolute numbers is a common differential diagnosis for unexplained encephalopathy in patients presenting to both neurological and general intensive care units. This talk will review management of the critically ill patient with suspected encephalitis. The broad differential diagnosis will be considered and diagnostic approaches to seek both infectious and immune-mediated causes for encephalitis discussed. The importance of antibody-mediated forms of encephalitis and differences in aetiologies of infectious encephalitis relating to geography will be emphasised. Both antimicrobial and immunomodulatory treatments for encephalitis will be reviewed. The importance of control of seizures and management of intracranial pressure will be outlined. The audience will be directed to guidelines from specialist societies for reference.

Vaccination in acute immune-mediated/inflammatory disorders of the central nervous system.

This review article covers the vaccination related issues in autoimmune disorders of central nervous system (CNS) including narcolepsy, anti-NMDAR encephalitis, Rasmussen encephalitis and febrile infection related epilepsy syndrome (FIRES). Beyond these conditions the immune mediated epilepsies related with autoimmune CNS disorders are discussed and indications and contraindications of vaccinations in these cases are also considered.

Astrocyte inflammatory signaling mediates α-synuclein aggregation and dopaminergic neuronal loss following viral encephalitis

Viral infection of the central nervous system (CNS) can cause lasting neurological decline in surviving patients and can present with symptoms resembling Parkinson's disease (PD). The mechanisms underlying postencephalitic parkinsonism remain unclear but are thought to involve increased innate inflammatory signaling in glial cells, resulting in persistent neuroinflammation. We therefore studied the role of glial cells in regulating neuropathology in postencephalitic parkinsonism by studying the involvement of astrocytes in loss of dopaminergic neurons and aggregation of α–synuclein protein following infection with western equine encephalitis virus (WEEV). Infections were conducted in both wildtype mice and in transgenic mice lacking NFκB inflammatory signaling in astrocytes. For 2 months following WEEV infection, we analyzed glial activation, neuronal loss and protein aggregation across multiple brain regions, including the substantia nigra pars compacta (SNpc). These data revealed that WEEV induces loss of SNpc dopaminergic neurons, persistent activation of microglia and astrocytes that precipitates widespread aggregation of α-synuclein in the brain of C57BL/6 mice. Microgliosis and macrophage infiltration occurred prior to activation of astrocytes and was followed by opsonization of ⍺-synuclein protein aggregates in the cortex, hippocampus and midbrain by the complement protein, C3. Astrocyte-specific NFκB knockout mice had reduced gliosis, α-synuclein aggregate formation and neuronal loss. These data suggest that astrocytes play a critical role in initiating PD-like pathology following encephalitic infection with WEEV through innate immune inflammatory pathways that damage dopaminergic neurons, possibly by hindering clearance of ⍺-synuclein aggregates. Inhibiting glial inflammatory responses could therefore represent a potential therapy strategy for viral parkinsonism.

Encephalitis and Brain Abscess.

This article reviews infections of the brain parenchyma and includes an overview of the epidemiology, pathogenesis, diagnostic approach, and management of infectious encephalitis and brain abscess. The epidemiology of infectious encephalitis and brain abscess has changed in recent years. Vaccination has reduced the incidence of certain viruses associated with encephalitis, while a decrease in fulminant otogenic infections has led to fewer brain abscesses associated with otitis media. However, changes in climate and human population density and distribution have enabled the emergence of newer pathogens and expanded the geographic range of others, and greater adoption of intensive immunosuppressive regimens for autoimmune conditions has increased the risk of opportunistic infections of the brain. The widespread use of early neuroimaging, along with improved diagnostic methodologies for pathogen detection, newer antimicrobial therapies with better brain penetration, and less invasive neurosurgical techniques, has resulted in better outcomes for patients with infectious encephalitis and brain abscess. Novel technologies including metagenomic next-generation sequencing are increasingly being applied to these conditions in an effort to improve diagnosis. Nevertheless, both infectious encephalitis and brain abscess continue to be associated with substantial mortality. Infectious encephalitis and brain abscess can present as neurologic emergencies and require rapid assessment, thorough and appropriate diagnostic testing, and early initiation of empiric therapies directed against infectious agents. Close clinical follow-up, proper interpretation of diagnostic results, and appropriate tailoring of therapeutic agents are essential to optimizing outcomes. Diagnosis and management of parenchymal brain infections are complex and often best achieved with a multidisciplinary care team involving neurologists, neurosurgeons, neuroradiologists, infectious disease physicians, and pathologists.

Benchmark of thirteen bioinformatic pipelines for metagenomic virus diagnostics using datasets from clinical samples.

Metagenomic sequencing is increasingly being used in clinical settings for difficult to diagnose cases. The performance of viral metagenomic protocols relies to a large extent on the bioinformatic analysis. In this study, the European Society for Clinical Virology (ESCV) Network on NGS (ENNGS) initiated a benchmark of metagenomic pipelines currently used in clinical virological laboratories. Metagenomic datasets from 13 clinical samples from patients with encephalitis or viral respiratory infections characterized by PCR were selected. The datasets were analyzed with 13 different pipelines currently used in virological diagnostic laboratories of participating ENNGS members. The pipelines and classification tools were: Centrifuge, DAMIAN, DIAMOND, DNASTAR, FEVIR, Genome Detective, Jovian, MetaMIC, MetaMix, One Codex, RIEMS, VirMet, and Taxonomer. Performance, characteristics, clinical use, and user-friendliness of these pipelines were analyzed. Overall, viral pathogens with high loads were detected by all the evaluated metagenomic pipelines. In contrast, lower abundance pathogens and mixed infections were only detected by 3/13 pipelines, namely DNASTAR, FEVIR, and MetaMix. Overall sensitivity ranged from 80% (10/13) to 100% (13/13 datasets). Overall positive predictive value ranged from 71-100%. The majority of the pipelines classified sequences based on nucleotide similarity (8/13), only a minority used amino acid similarity, and 6 of the 13 pipelines assembled sequences de novo. No clear differences in performance were detected that correlated with these classification approaches. Read counts of target viruses varied between the pipelines over a range of 2-3 log, indicating differences in limit of detection. A wide variety of viral metagenomic pipelines is currently used in the participating clinical diagnostic laboratories. Detection of low abundant viral pathogens and mixed infections remains a challenge, implicating the need for standardization and validation of metagenomic analysis for clinical diagnostic use. Future studies should address the selective effects due to the choice of different reference viral databases.