Proteomic landscape subtype and clinical prognosis of patients with the cognitive impairment by Japanese encephalitis infection.

BACKGROUND: Cognitive impairment is one of the primary sequelae affecting the quality of life of patients with Japanese encephalitis (JE). The clinical treatment is mainly focused on life support, lacking of targeted treatment strategy. METHODS: A cerebrospinal fluid (CSF) proteomic profiling study was performed including 26 patients with JE in Gansu province of China from June 2017 to October 2018 and 33 other concurrent hospitalized patients who were excluded central nervous system (CNS) organic or CNS infection diseases. The clinical and proteomics data of patients with JE were undergoing combined analysis for the first time. RESULTS: Two subtypes of JE associated with significantly different prognoses were identified. Compared to JE1, the JE2 subtype is associated with lower overall survival rate and a higher risk of cognitive impairment. The percentages of neutrophils (N%), lymphocyte (L%), and monocytes (M%) decreased in JE2 significantly. CONCLUSIONS: The differences in proteomic landscape between JE subgroups have specificity for the prognosis of cognitive impairment. The data also provided some potential target proteins for treatment of cognitive impairments caused by JE. Trial registration ChiCTR, ChiCTR2000030499. Registered 1st June 2017, http://www.medresman.org.cn/pub/cn/proj/projectshow.aspx?proj=6333.

The underlying mechanism of Guillain-Barré syndrome in a young patient suffered from Japanese encephalitis virus infection: a case report.

BACKGROUND: The presentation of Guillain-Barré syndrome (GBS) caused by Japanese encephalitis virus (JEV) is uncommon, although clusters of GBS cases were observed in China in 2018. The underlying mechanism is unclear, particularly in individuals vaccinated against Japanese encephalitis in childhood. CASE PRESENTATION: We report a patient with acute flaccid paralysis involving four extremities and respiratory muscles, while magnetic resonance imaging of the brain and spine were standard. Electrophysiological examination displayed slowed motor nerve conduction speed and reduced evoked velocity amplitude. GBS was finally considered which was related to JEV infection verified by positive anti-JEV immunoglobulin M antibody and positive immunoglobulin G antibody in the serum. Unfortunately, the patient refused intravenous immunoglobulin and declined the use of mechanical ventilation again. He voluntarily withdrew from the hospital and died on the 36th day after the onset of illness. We also performed a review of previously reported related cases and discussed the underlying mechanism. CONCLUSION: JEV infection-associated GBS is unusual. We should pay attention to the atypical manifestations of JEV infection and explore possible pathogenesis in particular individuals.

Myelitis with flaccid paralysis due to Japanese encephalitis: case report and review of the literature.

BACKGROUND: Japanese encephalitis is an arthropod-borne zoonotic flavivirus infection endemic to tropical and subtropical Asia. A minority of infections leads to a symptomatic course, but affected patients often develop life-threatening encephalitis with severe sequelae. LITERATURE REVIEW: Myelitis with flaccid paralysis is a rare complication of Japanese Encephalitis, which-according to our literature search-was reported in 27 cases, some of which were published as case reports and others as case series. Overall, there is a broad clinical spectrum with typically asymmetric manifestation and partly severe motor sequelae and partly mild courses. Lower limb paralysis appears to be more frequent than upper limb paralysis. An encephalitic component is not apparent in all cases CASE PRESENTATION: We herein add the case of a 29 year-old female who developed encephalitis and myelitis with flaccid paralysis during a long-time stay in Indonesia. Diagnostic workup in Indonesia did not clearly reveal an underlying cause. Upon clinical stabilization, the patient was evacuated to her home country Germany, where further diagnostics confirmed Japanese encephalitis virus as the causative agent. The patient has partly recovered, but still suffers from residual paralysis of the upper limb. CONCLUSION: Flaccid paralysis is a rare, and likely underdiagnosed complication of Japanese encephalitis, which, to the best of our knowledge, has never been diagnosed outside endemic areas before.

Japanese Encephalitis presenting with cerebral venous sinus thrombosis: a case report.

A 17-year-old man from Sarawak presented with acute encephalitis syndrome. Serologic testing revealed raised Japanese Encephalitis (JE) IgM antibody titre in which first serum JE was negative followed by positive second serum JE IgM one week later. Magnetic resonance imaging (MRI) and Magnetic resonance venogram (MRV) showed cerebral venous sinus thrombosis (CVST) which is a rare presentation of JE. Early identification of CVST is important as anticoagulation needs to be started to reduce adverse neurological sequelae and improve prognosis.

First co-infection case of melioidosis and Japanese encephalitis in China.

BACKGROUND: Melioidosis is endemic in Southeast Asia and northern Australia. Infection usually follows percutaneous inoculation or inhalation or ingestion of the causative bacterium, Burkholderia pseudomallei, which is present in soil and surface water in endemic regions. Japanese encephalitis (JE) is a vector-borne viral zoonosis caused by Japanese encephalitis virus (JEV), leading to epidemic encephalitis in Southeast Asia. Both B. pseudomallei and JEV have spread dominantly in the Hainan and Guangdong provinces in China. Here we reported the first case of co-infection of B. pseudomallei and JEV, which was discovered in Huizhou in the Guangdong province in June 2016. CASE PRESENTATION: A 52-year-old man was admitted to the hospital with acute febrile illness and headache, diagnosed as respiratory infection, central nervous system (CNS) infection, septicemia, and hepatic dysfunction. Based on B. pseudomallei-positive blood and cerebrospinal fluid (CSF) cultures, the patient was diagnosed with melioidosis and treated aggressively with antibiotics. However, the patient failed to make a full recovery. Further laboratory tests focused on CNS infection were conducted. The co-infection of B. pseudomallei and JEV was confirmed after the positive IgM antibodies of JEV were detected in both CSF and blood. After diagnosis of co-infection with B. pseudomallei and JEV, the patient was provided supportive care in hospital and recovered after approximately 3 weeks. CONCLUSION: Given the possibility of co-infection of B. pseudomallei and JEV, as well as variable case presentations, it is critical to enhance the awareness, detection, and treatment of co-infection in regard to melioidosis.

Regulation of inflammation in Japanese encephalitis.

BACKGROUND: Uncontrolled inflammatory response of the central nervous system is a hallmark of severe Japanese encephalitis (JE). Although inflammation is necessary to mount an efficient immune response against virus infections, exacerbated inflammatory response is often detrimental. In this context, cells of the monocytic lineage appear to be important forces driving JE pathogenesis. MAIN BODY: Brain-infiltrating monocytes, macrophages and microglia play a major role in central nervous system (CNS) inflammation during JE. Moreover, the role of inflammatory monocytes in viral neuroinvasion during JE and mechanisms of cell entry into the CNS remains unclear. The identification of cellular and molecular actors in JE inflammatory responses may help to understand the mechanisms behind excessive inflammation and to develop therapeutics to treat JE patients. This review addresses the current knowledge about mechanisms of virus neuroinvasion, neuroinflammation and therapeutics critical for JE outcome. CONCLUSION: Understanding the regulation of inflammation in JE is challenging. Elucidation of the remaining open questions will help to the development of therapeutic approaches avoiding detrimental inflammatory responses in JE.

Status and trend of acute encephalitis syndrome and Japanese encephalitis in Bihar, India.

BACKGROUND.: Acute encephalitis syndrome (AES) is a clinical condition, of which the most common cause is Japanese encephalitis (JE). Though there is deficiency of data on AES and JE from Bihar, the state ranks third in the reporting of JE cases after Uttar Pradesh and Assam. We aimed to assess the status and trends of AES and JE cases in Bihar and to know the status of the disease in the districts. METHODS.: We collected monthly epidemiological data for AES and JE for the period 2009-2014. RESULTS.: A total of 4400 cases (733 cases/year) with an average case fatality rate (CFR) of 30% for AES for the entire study period. A total of 396 cases of JE were reported with approximately 14% CFR. The disease peaks were during the start and end of the Indian summer and monsoon months for AES and JE, respectively. Districts such as Patna, Jehanabad, Nawada, Gaya and East Champaran reported the maximum number of AES and JE cases with annual incidence rates of 4.7-25.0 and 0.546-1.78 per 100 000 population, respectively. CONCLUSION.: Since 2009, the incidence of AES and JE cases has been increasing in Bihar.

Distinct dictation of Japanese encephalitis virus-induced neuroinflammation and lethality via triggering TLR3 and TLR4 signal pathways.

Japanese encephalitis (JE) is major emerging neurologic disease caused by JE virus. To date, the impact of TLR molecules on JE progression has not been addressed. Here, we determined whether each TLR modulates JE, using several TLR-deficient mouse strains (TLR2, TLR3, TLR4, TLR7, TLR9). Surprisingly, among the tested TLR-deficient mice there were contrasting results in TLR3(-/-) and TLR4(-/-) mice, i.e. TLR3(-/-) mice were highly susceptible to JE, whereas TLR4(-/-) mice showed enhanced resistance to JE. TLR3 ablation induced severe CNS inflammation characterized by early infiltration of inflammatory CD11b(+)Ly-6Chigh monocytes along with profoundly increased viral burden, proinflammatory cytokine/chemokine expression as well as BBB permeability. In contrast, TLR4(-/-) mice showed mild CNS inflammation manifested by reduced viral burden, leukocyte infiltration and proinflammatory cytokine expression. Interestingly, TLR4 ablation provided potent in vivo systemic type I IFN innate response, as well as ex vivo type I IFN production associated with strong induction of antiviral PRRs (RIG-I, MDA5), transcription factors (IRF-3, IRF-7), and IFN-dependent (PKR, Oas1, Mx) and independent ISGs (ISG49, ISG54, ISG56) by alternative activation of IRF3 and NF-κB in myeloid-derived DCs and macrophages, as compared to TLR3(-/-) myeloid-derived cells which were more permissive to viral replication through impaired type I IFN innate response. TLR4 ablation also appeared to mount an enhanced type I IFN innate and humoral, CD4(+) and CD8(+) T cell responses, which were mediated by altered immune cell populations (increased number of plasmacytoid DCs and NK cells, reduced CD11b(+)Ly-6C(high) monocytes) and CD4(+)Foxp3(+) Treg number in lymphoid tissue. Thus, potent type I IFN innate and adaptive immune responses in the absence of TLR4 were closely coupled with reduced JE lethality. Collectively, these results suggest that a balanced triggering of TLR signal array by viral components during JE progression could be responsible for determining disease outcome through regulating negative and positive factors.

A possible case of acute disseminated encephalomyelitis after Japanese encephalitis.

PURPOSE: Acute disseminated encephalomyelitis (ADEM) is a monophasic demyelination disease of central nervous system (CNS) with presentations of impaired consciousness, neurologic deficits and diffuse white matter lesions on magnetic resonance imaging (MRI). Predisposing infection can be identified in around 50 to 77% of all patients with ADEM. Post-infectious autoimmune events associated with Japanese encephalitis have been limited to case reports of Guillain-Barre syndrome after Japanese encephalitis and Japanese encephalitis virus vaccine-related ADEM. We herein report the first possible patient with Japanese encephalitis developed a subsequent ADEM after recovery from Japanese encephalitis. CASE REPORT: A 50-year-old man suffered from an acute onset of headache, fever, and disturbance of consciousness. Japanese encephalitis was diagnosed by virological and image study. He recovered gradually and was discharged about 1.5 months later. However, another episode of consciousness impairment with violent behavior occurred 21 days after discharge. Acute disseminated encephalomyelitis was confirmed by brain MRI which showed newly developed diffuse white matter lesions. His clinical symptoms and abnormal brain lesions on MRI improved gradually after combination of high-dose intravenous methylprednisolone and oral steroid therapy. CONCLUSION: Our patient is a possible case of ADEM developing after Japanese encephalitis. High dose steroid therapy resulted in good outcome of ADEM.

A case of new onset refractory status epilepticus in a U.S. traveler with Japanese encephalitis.

New onset refractory status epilepticus (NORSE) is a rare but critical condition characterized by refractory status epilepticus (RSE) in an individual without prior history of epilepsy or known structural, toxic, or metabolic cause. Postinfectious immune activation is an important cause of NORSE. Early testing for autoimmune antibodies is strongly recommended (Wickstrom et al., 2022). We report a case of NORSE triggered by Japanese encephalitis (JE) in an unvaccinated US adult traveler. Her CSF later revealed positive anti-N-methyl-d-aspartate (NMDA)-receptor antibody. The patient responded well to first line immunotherapy with favorable functional outcome. This case highlights the diagnostic and treatment challenges in this rare presentation.

Japanese encephalitis accompanied by cerebral venous sinus thrombosis: a case report.

BACKGROUND: Cerebral venous sinus thrombosis (CVST) is a relatively rare cerebrovascular condition which accounts for 0.5% of all strokes. Risk of CVST has been documented in patients with numerous conditions including central nervous system infections, however, Japanese encephalitis (JE, epidemic encephalitis type B) with CVST has not been reported previously. CASE PRESENTATION: Here, we present a case of JE with CVST in a 17-year-old man. On admission, the patient was initially diagnosed as intracranial infection, and soon after, brain magnetic resonance (MR) imaging (MRI) and MR Venography (MRV) confirmed the diagnosis of CVST. Moreover, the blood JE-specific IgM antibody which proved weakly positive at first, turned positive one week later. Consequently, our patient was diagnosed as CVST accompanied by JE. Anticoagulant and anti-infective therapy were initiated, which eventually lead to gradual recovery of the patient. CONCLUSIONS: To our knowledge, this is the first case report of CVST associated with JE. MRI and MRV represent a prime method for the diagnosis of CVST, while the positivity of JE virus IgM antibody, especially increased antibody levels within a short period, is of great significance to diagnose JE. The early diagnosis and timely treatment of this potentially lethal condition would improve its prognosis significantly.

Neuroprotective effects of minocycline on double-stranded RNA-induced neurotoxicity in cultured cortical neurons.

1. Minocycline, memantine,and glycoconjugate were assessed for their ability to protect cultured primary cortical neurons against double-stranded RNA-induced neurotoxicity. 2. Minocycline but not memantine or glycoconjugate protected cultured cells and warrants further investigation.

Label-free proteomics-based analysis of peripheral nerve injury induced by Japanese encephalitis virus.

Japanese encephalitis (JE) is just an acute encephalitis syndrome contributed to Japanese encephalitis virus (JEV) infection. It the chief causes of viral encephalitis in Asia. In recent years, association of JEV infection with neurological problems such as Guillain-Barré syndrome(GBS) had reported. Nevertheless, its potential pathogenic mechanism has not previously been reported. Therefore, it is urgent to study the relationship between peripheral nerve injury (PNI) and JEV infection. Here, we use the liquid chromatography-tandem mass spectrometry (LC-MS/MS) technique to make out the protein expression levels of mice sciatic nerve between JEV infection group and the sham group. In general, 4303 proteins were designated by MS, and 187 differentially expressed proteins(DEPs) were found. There were 105 proteins up-regulated in the injured sciatic nerve, and 82 proteins were down-regulated. Functional enrichment analysis of DEPs showed that the up-regulated proteins were mainly related to immune regulatory response, and down-regulated proteins were related to ribosomal structural components and translation. SIGNIFICANCE: The Japanese encephalitis virus, a member of the flavivirus, is a Mosquito borne virus. It leads to central nervous system injury by the immune response and inflammation in the brain. In addition, the virus also gave rise to PNI. It is a major public health problem in Asia. The diversity of clinical symptoms has brought serious challenges to the diagnosis and treatment of the disease. Label-Free Proteomics was undertaken to explore the potential mechanisms between JEV and peripheral nervous system in this study. It provided strong evidence that tissue damage is caused by the immune-mediated mechanisms rather than the virus, which offers a basis for the prevention of the disease and further looking for treatment targets.

Clinical spectrum and management of dystonia in patients with Japanese encephalitis: A systematic review.

BACKGROUND: Japanese encephalitis (JE) is a potentially fatal viral infection with a wide range of manifestations and can also present with a variety of movement disorders (MD) including dystonia. Dystonic features in JE are uncommon. Here, we have tried to summarize the clinical features and management of dystonia among JE patients with a comprehensive literature search. METHODS: Various databases, including PubMed, Embase, and Google Scholar, were searched against the predefined criteria using suitable keywords combination and boolean operations. Relevant information from observational and case studies was extracted according to the author, dystonic features, radiological changes in the brain scans, treatment options, and outcome wherever provided. RESULT: We identified 19 studies with a total of 1547 JE patients, the diagnosis of which was confirmed by IgM detection in serum and/or cerebrospinal fluid in the majority of the patients (88.62%). 234 (15.13%) of JE patients had dystonia with several types of focal dystonia being present in 131 (55.98%) either alone or in combination. Neuroimaging showed predominant involvement of thalami, basal ganglia, and brainstem. Oral medications including anticholinergics, GABA agonists, and benzodiazepines followed by botulinum toxin were the most common treatment modalities. CONCLUSION: Dystonia can be a disabling consequence of JE, and various available medical therapies can significantly improve the quality of life. Owing to insufficient studies on the assessment of dystonia associated with JE, longitudinal studies with a larger number of patients are warranted to further clarify the clinical course, treatment, and outcome of dystonia.