Infectious Encephalitis Research Articles

Functional outcome after infectious encephalitis: a longitudinal multicenter prospective cohort study.

ObjectivesWe aimed to describe longitudinal functional outcome among survivors after an infectious encephalitis (IE) and to analyze risk factors for poor functional outcome. MethodsPatients included in the prospective ENCEIF cohort (France, 2016-2019) were followed-up at 6 months and one year after hospital discharge for assessment of i) functional outcome using modified Rankin scale (mRS); ii) cognitive function and abilities to perform activities of daily living. Risk factors for poor outcome on the full distribution of mRS were estimated using multivariable mixed ordinal regression analysis with time between hospital discharge and follow-up as a covariate. ResultsOur follow-up study included 322 patients with 896 mRS evaluations. Median age was 66 [50-74] years, 197/322 were male (61%) and 35/322 were immunocompromised (11%). Causative agents were herpes simplex virus 1 (HSV-1) in 95/322 cases (30%), varicella zoster virus (VZV) in 46/322 cases (14%), others documented IE in 90/322 cases (28%) and unknown in 91/322 cases (28%). Intensive care unit (ICU) admission was necessary for 117/322 patients (36%). Brain imaging was abnormal in 180/311 (58%) of patients.At 6 months, 95/287 (33%) had fully recovered and 181/287 (63%) had persisting symptoms. At 12 months, 124/253 (49%) had fully recovered and 108/253 (43%) had persisting symptoms. The proportion of patients who improved was 41% (117/287) during the first 6 months, and 24% (52/218) between 6 and 12 months. Factors significantly associated with poor functional outcome were age, immunosuppression, ICU admission, abnormal brain imaging and causative agents, notably HSV-1. Follow-up visit during the first 120 days did not detect significant change in functional outcome, but was strongly associated with better outcome at the subsequent evaluation. ConclusionsAfter IE, improvement may take several months. Functional outcome is associated with baseline health status (age, immunosuppression), abnormal brain imaging, ICU admission, and causative agent.

West Nile virus encephalitis: Clinical characteristics and a comparison to other infectious encephalitides

PurposeTo compare functional outcomes and help differentiate between important causative agents of acute infectious encephalitis in adults, focusing on West Nile virus encephalitis (WNVE). MethodsThe electronic database of the Tel Aviv Medical Center was screened for patients admitted during 2010–2020 with acute encephalitis. Additionally, patient laboratory results during the same period were screened for CSF samples positive for common pathogens causing encephalitis. The main patient groups were compared in terms of clinical characteristics and functional outcomes. ResultsOne hundred and five infectious encephalitis patients were identified. WNVE patients (n = 31) and VZV encephalitis (VZVE) patients (n = 31) were older than HSV1 encephalitis (HSV1E) patients (n = 15) (median ages 73, 76, 51, respectively). WNVE patients had a more prominent inflammatory profile. CSF characteristics significantly differed between groups, with an extreme mononuclear white blood cell predominance in VZVE patients (median 98 %).Functional outcomes at discharge were significantly worse in WNVE patients (median modified Rankin Scale score 4 at hospital discharge, 2.5 at last follow-up) when compared with HSV1E patients (2.5, 1, respectively) and VZVE patients (1.5, 1, respectively). ConclusionIn odds with previous reports, WNVE and VZVE in this study were far more prevalent than HSV1E. Differences in clinical characteristics could prove clinically useful early in encephalitis, including an association of WNVE with a relatively prominent inflammatory profile (somewhat resembling a bacterial infection) and an extreme mononuclear white blood cell predominance in VZVE. The detrimental outcome of WNVE emphasizes the need to advance research on WNV infection.

Prevalence of Japanese Encephalitis infection in Children below 15 years’ age, Bihar

Prevalence of Japanese Encephalitis infection in Children below 15 years’ age, Bihar

Impacts of long-term climate change on human health: a global scoping review

Abstract Introduction Research output on climate change and human health is growing rapidly. This can make it difficult to find and use relevant information to develop public health action. Methods We present a global scoping review of the rapidly growing quantitative research output on long-term climate change and human health. We searched Scopus, Embase, and PubMed for quantitative, English language literature published between January 2000 and June 2021 that referenced climate change and human health in titles, abstracts, or keywords. Results From 36,956 publications we identified 754 relevant studies. Europe, the Americas, and the Western Pacific were studied much more often than other WHO regions. Research on temperature and vectors accounted for 70% of all included publications. Malaria, diarrheal diseases, and cardiovascular diseases were the most studied specific health outcomes. We found very few studies on non-communicable diseases in low- and middle-income countries. Retrospective publications (153) showed effects of climate change are already occurring worldwide. Most studies on tick-borne encephalitis, malaria, and lower respiratory infections associated with air pollution found impacts caused by climate change have increased. The strongest attribution of climate change was found for heat-related impacts. In prospective publications (626) diarrheal diseases, and impacts associated with heat and chemical air pollution were most consistently projected to increase. Future vector-borne disease impacts were projected to be highly location specific. Some studies demonstrated adaptation can effectively reduce impacts, while noting that capacity to adapt differs greatly between population groups. Conclusions Our findings underline climate change impacts are diverse and complex. Future research should prioritize the relatively understudied regions most vulnerable to climate change, such as Africa, and impacts beyond those related to temperature and vector-borne diseases.

Prevalence & clinical outcome of autoimmune encephalitis versus viral encephalitis in children with acute encephalitis syndrome: A prospective observational study.

Background & objectives Acute encephalitic syndrome (AES), encompasses a wide spectrum of potential causes, clinical presentations, and outcomes. While infectious encephalitis is generally considered more prevalent, autoimmune encephalitis is emerging as a significant aetiology. Neuronal autoantibodies have been identified independently or in association with acute viral encephalitis. The primary objective of this study was to ascertain the prevalence and clinical manifestation of autoimmune encephalitis as well as of coexisting viral markers in children with AES. Methods This study was a prospective observational investigation conducted in a hospital setting. It involved enrolling children with AES who were admitted to specific tertiary hospitals. Children were subjected to examinations to detect the presence of viral markers and neuronal autoantibodies in both their blood and cerebrospinal fluid (CSF). All the participants received treatment based on established guidelines and was followed for six months for outcome assessment. Results During the study period, 867 children with AES were examined. Among these cases, 37 children (4.2%) were diagnosed with autoimmune encephalitis, and all of them tested positive for anti-NMDAR (N-methyl-D-aspartate receptor) antibodies. Evidence of viral infection was seen in 409 (47.1%) of cases, out of which nearly 254 (29.2%) children had detectable HSV IgM antibodies. Among the 37 children with autoimmune encephalitis, 25 (67.5%) had evidence of a viral trigger, with eight of them tested positive for HSV IgM antibodies. The clinical presentation of autoimmune-associated AES was similar to those with viral aetiology. Interpretation & conclusions Autoimmune encephalitis triggered by neurotropic (HSV) viral infection was more prevalent in this study than in the earlier reports. Typically, these children show positive responses to immunosuppressive treatments if administered promptly. It is hence advisable to assess children who exhibit behavioural issues and movement disorders for possible autoimmune encephalitis.

Autoimmune and infectious encephalitis: development of a discriminative tool for early diagnosis and initiation of therapy.

Encephalitis originates from diverse autoimmune and infectious etiologies. Diagnostic challenges arise due to the spectrum of presentation and the frequent absence of specific biomarkers. This study aimed to comprehensively characterize and differentiate autoimmune encephalitis (AE) from infectious encephalitis (IE) in adults, and disentangle clinical, paraclinical, and therapeutic differences. A cohort study spanning 10years was conducted across three Austrian tertiary care hospitals. Inclusion criteria comprised adults with probable or definite encephalitis. Demographics, clinical features, technical findings, treatment modalities, and outcomes were collected from the electronic patient files. A follow-up was performed via telephone interviews and clinical visits. Of 149 patients, 17% had AE, 73% IE, and 10% encephalitis of unknown etiology. Significant differences between AE and IE included the prevalence of acute symptomatic seizures (AE: 85% vs. IE: 20%, p < 0.001), fever (8% vs. 72%, p < 0.001), headache (15% vs. 61%, p < 0.001), and focal neurological deficits (56% vs. 23%, p = 0.004), respectively. Paraclinical differences comprised lower CSF pleocytosis in AE compared to IE (median 6 cells/µl vs. 125 cells/µl, p < 0.001). Epileptic discharges on EEG and MRI lesions were more prevalent in AE than IE (50% vs. 14%, p < 0.001; 50% vs. 28%, p = 0.037). The modified Rankin Scale scores at discharge and last follow-up (median duration 2304days, IQR 1433-3274) indicated favorable outcomes in both groups. This comprehensive analysis provides insights into the epidemiology, clinical, paraclinical, and therapeutic aspects and the outcomes of AE and IE in adults. We developed a diagnostic tool that facilitates early differentiation between AE and IE, aiding in timely therapeutic decision-making.

Genotype-driven therapeutics in DEE and metabolic epilepsy: navigating treatment efficacy and drug resistance

Neonatal intensive care unit (NICU), particularly in treating developmental and epileptic encephalopathy (DEE) and metabolic epilepsy (ME), requires a deep understanding of their complex etiologies and treatment responses. After excluding treatable cases such as infectious or autoimmune encephalitis, our focus shifted to a more challenging subgroup of 59 patients for in-depth genetic analysis using exome sequencing (ES). The ES analysis identified 40 genetic abnormalities, significantly including de novo variants. Notably, we found structural variation as duplications in regions 2q24.3, including SCN1A and SCN2A were observed in 7 cases. These genetic variants, impacting ion channels, glucose transport, transcription regulation, and kinases, play a crucial role in determining medication efficacy. More than one-third (34.2%) of patients with DEE had an unfavorable response to anti-seizure medications (ASMs) in the chronic phase. However, since the ketogenic supplementary diet showed a positive effect, more than three-quarters (80%) of these drug-resistant patients improved during a 3-month follow-up. In contrast, the ME had a lower adverse reaction rate of 9.1% (2/22) to specialized medications, yet there were 5 fatalities and 10 cases with unidentified genetic etiologies. This study suggests the potential of categorizing drug-resistant variants and that a ketogenic diet could be beneficial in managing DEE and ME. It also opens new perspectives on the mechanisms of the ketogenic diet on the discovered genetic variants.

The Clinical Manifestations, Risk Factors, Etiologies, and Outcomes of Adult Patients with Infectious Meningitis and Encephalitis: Single Center Experience.

(1) Background: Central nervous system (CNS) infections, including meningitis and encephalitis, are serious conditions which are associated with high morbidity and mortality. This study aims to identify the clinical manifestations, etiologies, and outcomes of meningitis and encephalitis in adult patients in Saudi Arabia, addressing the current gap in understanding these conditions within this population. (2) Methods: This is a single-center retrospective study which included all adult patients diagnosed with meningitis and encephalitis from March 2016 to May 2022. (3) Results: This study found that most cases of meningitis and encephalitis occurred due to unknown pathogens. Pretreatment with antibiotics prior to lumbar puncture (LP) was found in 71.2% of patients with meningitis. Altered mental status and seizures were common presenting symptoms among patients with encephalitis while altered mental status and fever were common among patients with meningitis. (4) Conclusions: Adherence to guidelines in treating meningitis and encephalitis and performing LPs in a timely manner are important. Establishing national biobanks with biological samples from patients suspected of having meningitis or encephalitis will significantly enhance our understanding of these conditions in Saudi Arabia.

Encephalitis lethargica: clinical features and aetiology.

Encephalitis lethargica, an epidemic neurological illness, typically involved a severe sleep disorder and progressive parkinsonism. A century later, our understanding relies on seminal descriptions, more recent historical research and the study of small numbers of possible sporadic cases. Theories around infection, environmental toxins, catatonia and autoimmune encephalitis have been proposed. We aimed to describe the presentation of encephalitis lethargica and test these diagnostic and aetiological theories. Subjects with encephalitis lethargica were identified in the archives of the National Hospital for Neurology and Neurosurgery, UK between 1918 and 1946. Case notes were examined to establish illness temporality, clinical features and cerebrospinal fluid results. Controls from the archives were identified for 10% of cases, matching on discharge year, sex and neurologist. Clinical presentation was compared to modern diagnostic criteria for encephalitis lethargica, catatonia and autoimmune encephalitis. In a case-control design, a multilevel logistic regression was conducted to ascertain whether cases of encephalitis lethargica were associated with febrile illnesses and with environmental exposures. Six hundred and fourteen cases of encephalitis lethargica and 65 controls were identified. Cases had a median age of 29 years (interquartile range 18) and a median time since symptomatic onset of 3.00 years (interquartile range 3.52). Motor features were present in 97.6%, cranial nerve findings in 91.0%, ophthalmological features in 77.4%, sleep disorders in 66.1%, gastrointestinal or nutritional features in 62.1%, speech disorders in 60.8% and psychiatric features in 53.9%. Of the 167 cases who underwent lumbar puncture, 20 (12.0%) had a pleocytosis. The Howard and Lees criteria for encephalitis lethargica had a sensitivity of 28.5% and specificity of 96.9%. Among the cases, 195 (31.8%, 95% confidence interval 28.1-35.6%) had a history of febrile illness within one calendar year prior to illness onset, which was more common than among the controls (odds ratio 2.70, 95% confidence interval 1.02-7.20, P = 0.05), but there was substantial reporting bias. There was no evidence that occupational exposure to solvents or heavy metals was associated with encephalitis lethargica. Two hundred and seventy-six (45.0%) of the cases might meet criteria for possible autoimmune encephalitis, but only 3 (0.5%) might meet criteria for probable NMDA receptor encephalitis. Only 11 cases (1.8%) met criteria for catatonia. Encephalitis lethargica has a distinct identity as a neuropsychiatric condition with a wide range of clinical features. Evidence for a relationship with infectious or occupational exposures was weak. Autoimmune encephalitis may be an explanation, but typical cases were inconsistent with NMDA receptor encephalitis.

A comparison of infectious and autoimmune meningoencephalitis: Clinical presentation, biochemical markers and MRI findings

Objective: This study investigates distinguishing patterns in lesion distribution, relevant clinical presentation and biochemical markers in MRI to differentiate infective encephalitis (IE) and autoimmune encephalitis (AE). Methods: Retrospective study of adult patients with a confirmed diagnosis of IE and AE admitted to the Neurology unit from January 2012 to December 2020 with MRI Brain. Selected cases with confirmed IE (according to the 2013 Infective Encephalitis Consortium diagnostic criteria) or antibody-positive AE (detection of Neuronal auto-antibody from blood or CSF), coupled by clinical presentation. MRI brain lesion distribution, lobar involvement, enhancement, haemorrhage, vasculopathy and atrophy were analysed. Results: Forty-seven patients (21 IE and 26 AE, respectively) were selected. IE group are older (48.0 ± 16.81) compared to AE (28.4 ± 14.10). Fever and vomiting were significant in IE (p&lt;0.001), whereas psychosis, seizure, movement disorder, and tumour (ovarian teratoma) were significant in the AE cohort. Cerebrospinal fluid (CSF) analysis showed elevated leucocytes with polymorphism and high protein levels in IE (2.081 g/L ± 2.93 vs AE (0.352g/L ± 0.18). MR imaging detected abnormal findings in 61.9% of cases with infectious encephalitis (IE), while 76.9% of cases with autoimmune encephalitis (AE) exhibited normal MRI results. Asymmetrical lesions and inferior frontal lobe distribution (57.1%) were significantly prevalent in IE (p&lt;0.05). Enhancement patterns and haemorrhage were rarely observed in AE patients. Conclusion: IE presented at an older age, with the majority having MRI findings such as asymmetrical lesions, leptomeningeal enhancement, and involvement of medial temporal, hippocampus and inferior frontal cortex. IE clinically presents with fever, vomiting, and elevated CSF leucocytes and protein levels. AE presents at a younger age with seizure, psychosis, movement disorder, tumour (ovarian teratoma). Fewer AE have MRI findings, and if present, tend to be symmetrical in distribution. Lobar involvement in the inferior frontal was the MRI feature that significantly favoured the diagnosis of IE compared to AE. IE and AE have distinct clinical, biochemical, and MRI abnormalities that can be discriminated between the 2 entities.

An attachment glycoprotein nanoparticle elicits broadly neutralizing antibodies and protects against lethal Nipah virus infection

Nipah virus (NiV) is a zoonotic emergent paramyxovirus that can cause severe encephalitis and respiratory infections in humans, with a high fatality rate ranging from 40% to 75%. Currently, there are no approved human vaccines or antiviral drugs against NiV. Here, we designed a ferritin-based self-assembling nanoparticle displaying the NiV G head domain on the surface (NiV G-ferritin) and assessed immune responses elicited by the soluble NiV G head domain (NiV sG) or NiV G-ferritin. Immunization with NiV G-ferritin or NiV sG conferred complete protection against lethal NiV challenge without detection of viral RNA in Syrian golden hamsters. Compared to NiV sG, NiV G-ferritin induced significantly faster, broader, and higher serum neutralizing responses against three pathogenic henipaviruses (NiV-Malaysia, NiV-Bangladesh, and Hendra virus). Moreover, NiV G-ferritin induced a durable neutralizing immunity in mice as antisera potently inhibited NiV infection even after six months of the third immunization. Additionally, we isolated a panel of 27 NiV G-binding monoclonal antibodies (mAbs) from NiV G-ferritin immunized mice and found that these mAbs targeted four distinct antigenic sites on NiV G head domain with two sites that have not been defined previously. Notably, 25 isolated mAbs have potent neutralizing activity with 50% inhibitory concentrations less than 10 ng/mL against NiV pseudovirus. Collectively, these findings provide new insights into the immunogenicity of NiV G protein and reveal that NiV G-ferritin is a safe and highly effective vaccine candidate against Nipah virus infection.

Post-Herpetic Anti-NMDAR Encephalitis in Denmark: Current Status and Future Challenges.

It is well known that N-methyl-D-aspartate receptor encephalitis (NMDARE) can be triggered by infectious encephalitis such as herpes simplex virus 1 encephalitis (HSE). However, the incidence of post-HSE NMDARE in Denmark is unknown. We reviewed literature cases and compared these to retrospectively identified cases of post-HSE NMDARE in Denmark, using a national cohort database of autoimmune encephalitis (AE) and two regional databases of infectious encephalitis patients. We identified 80 post-HSE NMDARE cases in the literature, 66% being children, who more often presented movement disorders, decreased consciousness, and sleep disturbances compared to adults. Eight patients with post-HSE NMDARE were identified from the national cohort database of AE, none being children. Forty-four HSE patients were identified from the regional infectious encephalitis databases. Of these, 16 (36%) fulfilled the Graus criteria for probable/definite NMDARE, and eight (18%) presented a prolonged/relapsing disease course. Ten (23%) were tested for AE during hospitalization. Six (14%) had leftover cerebrospinal fluid available for retrospective autoantibody testing. One out of these six patients (17%) harbored NMDARE antibodies. Thus, in total, nine post-HSE NMDARE patients have been identified in Denmark from 2009 to 2021. Comparing the adult Danish patients to the literature, Danish patients were older, but the clinical phenotype and paraclinical findings were similar. Overall, the incidence of adult post-HSE NMDARE in the Region of Southern Denmark was 0.17 per million people per year and only 7% of adult HSE patients in the region were diagnosed with post-HSE NMDARE. Our findings suggest that adult patients are still underdiagnosed and the absence of pediatric cases diagnosed with post-HSE NMDARE in Denmark is highly concerning.

Development and validation of a novel enzyme-linked immunosorbent assay for the differentiation of tick-borne encephalitis infections caused by different virus subtypes.

Tick-borne encephalitis (TBE) is an infection caused by the tick-borne encephalitis virus (TBEV) that can lead to symptoms of central nervous system inflammation. There are five subtypes of TBEV, three of which - European, Siberian and Far Eastern - occur in Europe. As it is thought that different subtype infections exhibit varying clinical courses and outcomes, serological differentiation of the virus subtypes is clearly important. However, to date, this has proved difficult to achieve. An ELISA format was developed based on TBE virus NS1 antigen against the European, Siberian and Far Eastern subtype. The three NS1 antigens were biotechnologically produced in a human cell line and used for ELISA coating. Sera from German (European subtype) and Russian (Siberian and/or Far Eastern subtypes) TBE patients with positive TBEV IgG were used to test the reactivity against these three NS1 antigens. Testing of 23 German and 32 Russian TBEV IgG-positive sera showed that the ELISA was able to differentiate between TBEV European subtype and TBEV Siberian and Far Eastern subtype infections. In geographical areas where two or more TBEV subtype infections can occur, the NS1-IgG ELISA developed here constitutes an important diagnostic tool to differentiate between European subtype infections and Siberian/Far Eastern subtype infections and to use the new assay for epidemiological studies to clarify the importance of particular subtype infections in an area. Consequently, it may help to better describe and anticipate the clinical courses and outcomes of particular TBEV subtype infections.

Mogad may not only Mimic Immune or Infectious Encephalitis, but can also be Triggered by Viral Infections.

Mogad may not only Mimic Immune or Infectious Encephalitis, but can also be Triggered by Viral Infections.

Development of a cell culture-based method for detecting infectious tick-borne encephalitis virus (TBEV) in milk products

Tick-borne encephalitis outbreaks have been reported in Europe after consumption of raw milk products from infected animals. While molecular methods are commonly used in viral foodborne outbreak investigations due to their sensitivity, specificity and rapidity, there are very few methods to detect infectious tick-borne encephalitis virus (TBEV) in milk products for routine use/analyses. To address this gap, we developed a cell culture-based method to detect infectious TBEV in artificially contaminated raw goat milk and raw goat cheese, and evaluated the sensitivity of TBEV infectivity assays. Raw goat milk samples were spiked with TBEV to achieve inoculation levels ranging from 106 to 100 TCID50/mL, and Faisselle and Tomme cheese samples were spiked so their TBEV concentrations ranged from 9.28 × 105 to 9.28 × 101 TCID50 per 2.5g. To detect infectious TBEV, Vero cells were infected by raw goat milk. For cheese samples, after homogenisation and membrane filtration, Vero cells were infected with samples adsorbed on the filter (method A) or with samples eluted from the filter (method B). After 5 days, cytopathic effects (CPEs) were observed and TBEV replication in Vero cells was confirmed by an increase in the number of genome copies/mL that were detected in cell supernatant. Infected Vero cells exhibited CPEs for both milk and cheese samples. Infectious TBEV was detected to 103 TCID50/mL in raw milk samples and to 9.28 × 101 TCID50 from Faisselle samples using both methods A and B. For Tomme samples, method A was able to detect TBEV to 9.28 × 102 TCID50/2.5g and method B to 9.28 × 103 TCID50/2.5g. The number of positive samples detected was slightly higher with method A than with method B. To conclude, this qualitative cell culture-based method can detect infectious TBEV artificially inoculated into raw milk and cheese; it should be further evaluated during foodborne outbreak investigations to detect infectious TBEV from naturally contaminated milk and cheese.

Longitudinal Study of Cognitive Function in People with HIV and Toxoplasmic Encephalitis or Latent toxoplasma Infection.

Neurocognitive impairment (NCI) may occur during and persist even after recovery from HIV-related CNS co-infections such as toxoplasmic encephalitis (TE). The long-term cognitive effects of TE and latent toxoplomasmic infections (LTI) among persons with HIV (PWH) are unknown. We measured longitudinal effects on NC functioning in PWH with TE compared to LTI or no toxoplasmal infection. PWH (n = 345) followed in two longitudinal cohort studies underwent comprehensive neurocognitive assessments and an anti-Toxoplamic IgG assay. Participants were classified into one of three groups: TE+ (n = 39), LTI+ (n = 34), LTI- (n = 272). The primary outcome was change in neurocognitive function between baseline and 7-year visit. The mean age was 48 ± 11 years, mean educational level 13 ± 3 years, and 13% were female. TE+ patients were less likely to have undetectable viral loads (≤50 copies/mL) and had lower absolute CD4 counts. The TE+ group had the highest prevalence of NCI globally and in domains of verbal, executive function, learning, recall, working memory, processing speed and motor at baseline and at 7-year follow-up. Changes in longitudinal NC function over 7 years were small and did not differ significantly among all groups, except that speed of information processing improved more in TE+ compared with LTI- participants. PWH with a history of TE had cognitive impairment over a broad range of severity at both baseline and last follow-up. Changes in cognition from baseline to last examination in all groups were minimal and did not differ significantly among the groups with the exception of speed of information processing.

Absence of Cerebrospinal Fluid Pleocytosis in Encephalitis.

Early diagnosis of encephalitis involves identifying signs of neuroinflammation, including cerebrospinal fluid (CSF) pleocytosis. However, absence of CSF pleocytosis in encephalitis has been described, most notably in autoimmune encephalitis. We examined clinical characteristics and outcomes associated with the absence or presence of CSF white blood cell pleocytosis (≥ 5 cells/µL), to inform timely diagnosis and management of encephalitis. This retrospective study compares initial CSF profiles in 597 adult patients with all-cause encephalitis. Of the 597 patients, 446 (74.7%) had CSF pleocytosis while 151 (25.3%) did not. CSF pleocytosis occurred more commonly in infectious cases (200/446, 44.8%), along with 59 (13.2%) autoimmune cases, comprised chiefly of anti-NMDAR encephalitis (37/59, 62.7%). Notably, the group without pleocytosis was comprised of similar proportions of infectious (47/151, 31.1%) and autoimmune (38/151, 25.92%; p>0.05) encephalitis. Among those with infectious encephalitis, 47/247 (19%) had absent pleocytosis, including 18/76 (23.7%) with HSV-1 encephalitis. The absence of pleocytosis was associated with a decreased rate of acyclovir administration (47.7% in patients without pleocytosis vs. 71.1% in patients with pleocytosis, p<0.001). Despite pleocytosis being associated with some measures of clinical severity at admission such as a Full Outline of UnResponsiveness (FOUR) score ≤14, it was not associated with mortality or prolonged hospitalization. CSF pleocytosis is an important criterion for encephalitis diagnosis, but 25.3% of patients with all-cause encephalitis and 23.7% of those with HSV-1 encephalitis exhibit absence of pleocytosis on initial LP. Acyclovir initiation should not be delayed in the absence of pleocytosis in patients with suspected encephalitis.

Autoimmune Encephalitis.

This article focuses on the clinical features and diagnostic evaluations that accurately identify patients with ever-expanding forms of antibody-defined encephalitis. Forms of autoimmune encephalitis are more prevalent than infectious encephalitis and represent treatable neurologic syndromes for which early immunotherapies lead to the best outcomes. A clinically driven approach to identifying many autoimmune encephalitis syndromes is feasible, given the typically distinctive features associated with each antibody. Patient demographics alongside the presence and nature of seizures, cognitive impairment, psychiatric disturbances, movement disorders, and peripheral features provide a valuable set of clinical tools to guide the detection and interpretation of highly specific antibodies. In turn, these clinical features in combination with serologic findings and selective paraclinical testing, direct the rationale for the administration of immunotherapies. Observational studies provide the mainstay of evidence guiding first- and second-line immunotherapy administration in autoimmune encephalitis and, whereas these typically result in some clinical improvements, almost all patients have residual neuropsychiatric deficits, and many experience clinical relapses. An improved pathophysiologic understanding and ongoing clinical trials can help to address these unmet medical needs. Antibodies against central nervous system proteins characterize various autoimmune encephalitis syndromes. The most common targets include leucine-rich glioma inactivated protein 1 (LGI1), N-methyl-d-aspartate (NMDA) receptors, contactin-associated proteinlike 2 (CASPR2), and glutamic acid decarboxylase 65 (GAD65). Each antibody-associated autoimmune encephalitis typically presents with a recognizable blend of clinical and investigation features, which help differentiate each from alternative diagnoses. The rapid expansion of recognized antibodies and some clinical overlaps support panel-based antibody testing. The clinical-serologic picture guides the immunotherapy regime and offers valuable prognostic information. Patient care should be delivered in conjunction with autoimmune encephalitis experts.

Inhibition of mitophagy via the EIF2S1-ATF4-PRKN pathway contributes to viral encephalitis

IntroductionMitophagy, a selective form of autophagy responsible for maintaining mitochondrial homeostasis, regulates the antiviral immune response and acts as viral replication platforms to facilitate infection with various viruses. However, its precise role in herpes simplex virus 1 (HSV-1) infection and herpes simplex encephalitis (HSE) remains largely unknown. ObjectivesWe aimed to investigate the regulation of mitophagy by HSV-1 neurotropic infection and its role in viral encephalitis, and to identify small compounds that regulate mitophagy to affect HSV-1 infection. MethodsThe antiviral effects of compounds were investigated by Western blot, RT-PCR and plaque assay. The changes of Parkin (PRKN)-mediated mitophagy and Nuclear Factor kappa B (NFKB)-mediated neuroinflammation were examined by TEM, RT-qPCR, Western blot and ELISA. The therapeutic effect of taurine or PRKN-overexpression was confirmed in the HSE mouse model by evaluating survival rate, eye damage, neurodegenerative symptoms, immunohistochemistry analysis and histopathology. ResultsHSV-1 infection caused the accumulation of damaged mitochondria in neuronal cells and in the brain tissue of HSE mice. Early HSV-1 infection led to mitophagy activation, followed by inhibition in the later viral infection. The HSV-1 proteins ICP34.5 or US11 deregulated the EIF2S1-ATF4 axis to suppress PRKN/Parkin mRNA expression, thereby impeding PRKN-dependent mitophagy. Consequently, inhibition of mitophagy by specific inhibitor midiv-1 promoted HSV-1 infection, whereas mitophagy activation by PRKN overexpression or agonists (CCCP and rotenone) attenuated HSV-1 infection and reduced the NF-κB-mediated neuroinflammation. Moreover, PRKN-overexpressing mice showed enhanced resistance to HSV-1 infection and ameliorated HSE pathogenesis. Furthermore, taurine, a differentially regulated gut microbial metabolite upon HSV-1 infection, acted as a mitophagy activator that transcriptionally promotes PRKN expression to stimulate mitophagy and to limit HSV-1 infection both in vitro and in vivo. ConclusionThese results reveal the protective function of mitophagy in HSE pathogenesis and highlight mitophagy activation as a potential antiviral therapeutic strategy for HSV-1-related diseases.

Predicting immune response targets in orthoflaviviruses through sequence homology and computational analysis.

Flaviviruses cause severe encephalitic or hemorrhagic diseases in humans. Its members, Kyasanur forest disease virus (KFDV) and Alkhumra hemorrhagic fever virus (ALKV), cause hemorrhagic fever and are prevalent in India and Saudi Arabia, respectively, while the tick-borne encephalitis virus (TBEV) causes a dangerous encephalitic infection in Europe and Asia. However, little information is available about the targets of immune responses for these deadly viruses. Here, we predict potential antigenic peptide epitopes of viral envelope protein for inducing a cell-mediated and humoral immune response. Using the Immune Epitope Database and Analysis Resource (IEDB-AR), we identified 13 MHC-I and two MHC-II dominant conserved epitopes in KFDV and ALKV and six MHC-I and three MHC-II epitopes in TBEV envelope proteins. Parallelly, we also predicted B-cell linear and discontinuous envelope protein epitopes for these viruses. Interestingly, the epitopes are conserved in all three viral envelope proteins. Further, the discontinuous epitopes are structurally compared with the available DENV, ZIKV, WNV, TBEV, and LIV envelope protein antibody structures. Overall structural comparison analyses highlight (i) lateral ridge epitope in the ED-III domain of E protein, and (ii) envelope dimer epitope (EDE) could be targeted for developing potent vaccine candidates as well as therapeutic antibody production. Moreover, existing structural and biochemical functions of the same epitopes in homologous viruses are predicted to have a reduced antibody-dependent enhancement (ADE) effect on flaviviral infection.