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Scrub typhus is an established cause of acute encephalitis syndrome (AES) in northern states of India. We systematically investigated 376 children with AES in southern India, using a stepwise diagnostic strategy for the causative agent of scrub typhus, Orientia tsutsugamushi, including IgM and PCR testing of blood and cerebrospinal fluid (CSF) to grade its association with AES. We diagnosed scrub typhus in 87 (23%) children; of those, association with AES was confirmed in 16 (18%) cases, probable in 55 (63%), and possible in 16 (18%). IgM detection in CSF had a sensitivity of 93% and specificity of 82% compared with PCR. Our findings suggest scrub typhus as an emerging common treatable cause of AES in children in southern India and highlight the importance of routine testing for scrub typhus in diagnostic algorithms. Our results also suggest the potential promise of IgM screening of CSF for diagnosis of AES resulting from scrub typhus.

Abstract Background and Aim: The etiological profile of acute febrile encephalopathy (AFE) varies across different geographic areas and in different seasons across the world. Limited literature in children suggests central nervous system (CNS) infections to be the most common cause of AFE in India and developing countries. Most of these studies have been done in the plains of India, and no study has been done in the Himalayan region of northwestern India, where most of the vectors causing AFE in other parts of India, like mosquitoes, are not found. Therefore, this leads to a lacuna in available data on the etiological profile in this region with an elevation of 1000-21,000 ft from the sea level. Our aim was to study the clinical and etiological profile of pediatric AFE and the risk factors associated with mortality in AFE in Himachal Pradesh, a hilly Himalayan state of India located in northwestern Himalayas. Materials and Methods: This was a prospective, descriptive, observational study conducted in the pediatric intensive care unit (PICU) of Indira Gandhi Medical College Shimla, for a period of 1 year, in which all children aged from 1 to 18 years with clinical evidence of AFE and meeting the inclusion criteria were enrolled and studied for the clinical features, etiology, and risk factors for mortality. Chi-square test was used to find the significance of study parameters on a categorical scale between two or more groups. A P value of 0.05 or less was considered as statistically significant. Results: Sixty-nine patients were enrolled in the study. Fever, altered sensorium, vomiting, seizures, and headache were the most common symptoms. The most common clinical sign was raised ICT, followed by low Glasgow coma scale (GCS). The most common etiology was CNS infections. Among these, scrub encephalitis was the most common cause that was seen in 15.8%, followed by viral and tubercular meningitis in 14.4% and 11.1%, respectively. Eighteen patients out of 69 with AFE died, giving a case fatality rate of 26%. Shock, GCS <8, ventilatory support, MODS, DIC, and delayed presentation were significant risk factors associated with mortality. Conclusions: Infectious causes attributed maximum to the etiology of AFE, and among them, scrub encephalitis was the most common cause of AFE.

To clarify whether severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection cause acute encephalopathy in children and which are the most common syndromes that cause them and what are the outcomes. A nationwide web-based survey among all members of the Japanese Society of Child Neurology to identify pediatric patients aged < 18 years who developed acute encephalopathy in Japan between 1 January 2020 and 31 May 2022 associated with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection confirmed by polymerase chain reaction or antigen tests using pharyngeal swabs. Acute encephalopathy was defined as acute onset of impaired consciousness lasting > 24 h or an altered mental state; neurological symptoms arising within 2 weeks of onset of COVID-19 or multisystem inflammatory syndrome in children (MIS-C)/pediatric inflammatory multisystem syndrome (PIMS); evidence of SARS-CoV-2 infection; and reasonable exclusion of other diseases. Patients were divided into the known clinico-radiological acute encephalopathy syndrome group and unexplained or unclassifiable acute encephalopathy group. Outcomes were assessed by pediatric cerebral performance category (PCPC) score at hospital discharge. Of the 3,802 society members, 217 representing institutions responded, and 39 patients with suspected acute encephalopathy were reported, of which 31 met inclusion criteria. Of these patients, 14 were diagnosed with known clinico-radiological acute encephalopathy syndromes, with acute encephalopathy with biphasic seizures and late reduced diffusion (five patients) being the most common. Five developed acute encephalopathy associated with MIS-C/PIMS. Among 31 patients, 9 (29.0%) had severe sequelae or died (PCPC ≥ 4). Two of three patients with encephalopathy with acute fulminant cerebral edema and two with hemorrhagic shock and encephalopathy syndrome died. The PCPC scores were higher in the known clinico-radiological acute encephalopathy syndrome group than in the unexplained or unclassifiable acute encephalopathy group ( < 0.01). Acute encephalopathy related to SARS-CoV-2 infection was demonstrated to be more severe than that caused by other viruses in Japan. Acute encephalopathy syndromes characterized by specific neuroradiological findings was associated with poor clinical outcomes.

Only 2 cases of human adenovirus type 14 (HAdV-14) have been reported in Japan since 1980. We report a 7-year-old girl with acute encephalopathy associated with HAdV-14 infection genetically similar to strains from the United States. The patient had not had contact with international travelers. HAdV-14 surveillance should be strengthened in Japan.

Background Advances in laboratory diagnostics have greatly enhanced the understanding of the infectious aetiologies of Acute Encephalitis Syndrome (AES) globally. However, these diagnostic tests are not widely utilized in many public-sector clinical settings in India. Significant gaps thus remain in the knowledge and understanding of the burden, etiological spectrum, and risk factors associated with AES occurring in India. Methods The current manuscript outlines a protocol designed to characterize the infectious causes of AES in affected regions of India through a network of 12 selected tertiary care hospitals and their associated Virus Research and Diagnostic Laboratories (VRDLs). A standardized tiered testing algorithm accounting for a wide range of possible etiological agents of infectious AES has been developed for use in the protocol, which aims to employ serological and molecular techniques to diagnose AES-causing priority pathogens. Pathogens of interest have been grouped in the testing algorithm into five levels ( Levels 1–5 ) in decreasing order of priority based on their reported incidence. Clinical samples from each patient will be collected at presentation at respective sites, and relevant demographic and clinical data will be obtained from hospital records. Approximately 20% of samples which test negative for Level 1–4 pathogens will be subjected to Next-Generation Sequencing (NGS) to identify less well known/rare infectious causes of AES ( Level 5 pathogens). De-identified clinical and laboratory data will be recorded into a web-based portal and managed by a designated nodal laboratory responsible for coordinating and overseeing the surveillance. The protocol ensures quality laboratory testing through an External Quality and Assessment Programme (EQAP). Discussion Results from this nationwide surveillance will yield crucial data to identify the causes of Acute Encephalitis Syndrome (AES) across India, supporting targeted public health interventions that could help reduce the disease burden. Additionally, this protocol serves as a model for a tiered laboratory algorithm for AES surveillance, providing a framework to guide similar initiatives in other regions.

Background Acute Encephalitis Syndrome (AES) is a critical public health issue, contributing significantly to morbidity and mortality in India, particularly among children. Despite ongoing vaccination efforts, Japanese Encephalitis (JE) remains a major cause of AES. This study analyzes the epidemiology of AES and JE in India from 2014 to 2023, using data from the Virus Research and Diagnostic Laboratory Network (VRDLN). Methods A cross-sectional analysis was conducted on AES cases reported by 159 VRDLN laboratories between 2014 and 2023. Standardized diagnostic tests such as polymerase chain reaction were used to identify causative pathogens, including JE virus. All the labs in the network followed BSL-2 standards. Descriptive analyses were performed on AES cases by year, etiology, and demographic factors. JE cases were further analyzed for geographic distribution, age, sex, and clinical characteristics. Results Over the study period, 124,890 AES cases were reported, with 16.3% testing positive for at least one pathogen, including 10% confirmed as JE. The highest JE positivity was observed in the northeastern states. An increasing trend in the number of cases tested and JE detections was noted, alongside a shift in the age distribution towards younger populations. The median (IQR) annual test positivity for JEV among tested was 16.2% (14.5%, 18.4%). Conclusions The VRDLN has substantially enhanced India’s capacity to diagnose and monitor AES and JE. Despite progress, JE transmission persists, particularly in endemic regions, posing significant public health challenges. Strengthened surveillance, improved diagnostic coverage, and integrated pathogen testing are essential for effective interventions. Targeted strategies and sustained public health efforts are critical to reducing the burden of AES and JE in India.

Background & objectives: In India, spotted fever group rickettsiae (SFGR) are an underdiagnosed cause of acute febrile illness (AFI). The non-specific Weil-Felix test is the first diagnostic modality for the diagnosis of SFGR in many laboratories due to the lack of advanced diagnostic facilities in developing countries. The aim of this study was to detect SFGR using molecular methods in the patients, presenting with AFI in a tertiary care centre in north India. Methods: Consecutive patients (>14 yr of age) with AFI were enrolled over a six month period. Standard investigations for common pathogens causing AFI in India (malaria, dengue, scrub typhus, leptospirosis and enteric fever) were carried out. In patients who were negative for all of the above investigations, blood was subjected to polymerase chain reaction (PCR) targeting outer membrane protein A (ompA) gene of Rickettsia. Results: Of the 51 patients with an undiagnosed aetiology, three were positive by ompA PCR. Two of the PCR products produced good sequences and BLAST identification confirmed them as Rickettsia conorii. The sequences of R. conorii reported from south India clustered with two previously reported novel rickettsial genotypes. The study sequences clustered in a group different from that of Rickettsia spp. of the south Indian sequences reported earlier. Interpretation & conclusions: This study showed the existence of R. conorii in north India. Testing for SFGR may be included in the diagnostic workup of AFI for better disease management.

Objective To compare the clinical and biochemical parameters and outcomes in children with acute encephalitis syndrome (AES) with and without hyponatremia. Methods A prospective observational study conducted at a tertiary care teaching hospital included children aged 6 months to 12 years with AES defined as acute fever (< 7 days) and neurological symptoms such as new-onset seizures or altered mental status lasting more than 12 h. AES was categorized as neurological or systemic AES. Serum electrolyte samples were collected upon admission and daily for three days to assess the occurrence of hyponatremia (serum sodium < 135 mmol/L). Outcomes were assessed one-month after discharge using the Pediatric Modified Rankin Scale (mRS). Results Out of 200 children with AES, 49 (24.5%) had hyponatremia. Hyponatremia was significantly associated with hepatomegaly ( P  = 0.002), elevated blood urea ( P  = 0.033), elevated serum creatinine ( P  = 0.038), decreased serum albumin ( P  = 0.013) and decreased serum calcium ( P  = 0.002). Children with hyponatremia experienced significantly greater mortality ( P  = 0.020) and a longer hospital stay ( P  = 0.047). Multivariate analysis revealed significant associations between hyponatremia and hepatomegaly (OR 2.22) and mortality (OR 3.17). Hyponatremia and poor outcomes were more common in children with neurological AES compared to systemic AES syndrome. Conclusion Hyponatremia was found in one-fourth of cases of AES and had a significant association with mortality and longer hospital stay.

Objective To describe the utility of film array meningoencephalitis (FAME) panel in the management of children with acute encephalitis syndrome (AES). Methods A retrospective audit was conducted between January 2017 to July 2022. We included children aged < 18 years with a diagnosis of AES for whom a CSF analysis study including FAME panel testing performed within 48 hours of admission was available. Electronic medical records were reviewed for details including demographic profile, clinical presentation, investigations and outcome. Results Out of 157 CSF samples sent for FAME panel testing, 49 were positive (31.4%.) Viral pathogens were identified in 42 (Enterovirus: 31, Human herpes virus 6: 9, Varicella zoster virus: 1, and Cytomegalovirus: 1) Bacterial pathogens were identified in 6 ( Streptococcus pneumoniae : 2, Streptococcus agalactiae : 2, Hemophilus influenzae : 1, and Escherischia coli : 1). Fungal etiology ( Cryptococcus neoformans ) was detected in one child. Antibiotics could be stopped within 72 hours of initiation in 42 children in whom a viral etiology was established. Acyclovir could be stopped in 21 out of 32 children within 72 hours after the FAME panel testing. FAME panel was presumed to be false positive in 4 children. Conclusion Etiology of AES could be established in nearly a third of children with AES using the rapid diagnostic FAME panel testing in CSF and it was found to be effective in reducing empirical antibiotic/antiviral therapy.

Fever-associated seizures and febrile encephalopathy are common neurological problems in children. Infections of the nervous system are responsible for the majority of cases. However, there is a spectrum of infection-associated and inflammatory conditions associated with the triad of fever, seizures, and encephalopathy. Apart from complex febrile seizures and febrile status epilepticus, fever infection-related epilepsy syndrome of childhood (FIRES), infantile hemiconvulsion hemiplegia epilepsy syndrome (IHHE), acute encephalopathy with delayed diffusion restriction (AESD), acute necrotizing encephalopathy of childhood (ANE), and reversible splenial lesion syndrome (RESLES) are age-related clinical phenotypes of fever-related epilepsy and encephalopathy. Awareness of these entities is important for appropriate diagnosis and the prompt use of immunomodulatory/immunosuppressive therapies. In this review, we discuss the pathophysiology, clinical phenotypes, and management approaches of these fever-related seizure and encephalopathy states.