Letter to the Editor: Dengue virus as an underrecognized cause of encephalitis in tropical Asia - Bridging diagnostic and surveillance gaps

Abstract

Arboviral encephalitis remains a major public health concern in tropical Asia, where the etiology of a substantial proportion of central nervous system infections remains undetermined despite endemic circulation of dengue virus (DENV) and Japanese encephalitis virus. Laboratory confirmation is frequently absent in clinically suspected encephalitis. Perera et al recently published a study in World Journal of Virology, highlight this diagnostic gap by identifying DENV infection in 6.06% of encephalitis cases, including molecular evidence of DENV-3 neuroinvasion. These findings add to the growing evidence that DENV can cause encephalitis and meningoencephalitis across age groups. However, encephalitis in endemic settings is etiologically heterogeneous, and dengue represents only one of several infectious and immune-mediated contributors. Neurological dengue is likely under-recognized due to overlapping clinical presentations and limited diagnostic capacity. The identification of DENV-3 is noteworthy given its recurrent association with neurological disease. Limited concordance between reverse transcription polymerase chain reaction and immunoglobulin M assays reflects challenges related to viral kinetics, timing of specimen collection, and flaviviral serological cross-reactivity. Strengthening surveillance through integrated molecular and serological diagnostic strategies, including multiplex polymerase chain reaction and metagenomic next-generation sequencing, is essential to reduce undiagnosed encephalitis and improve clinical management and public health preparedness in tropical Asia.

Key Words: Dengue virus; Encephalitis; Neurotropic arboviruses; Acute encephalitis syndrome; Neuroinflammation; Tropical Asia

Core Tip: Dengue virus is an under-recognized but clinically relevant cause of encephalitis in tropical Asia, where acute encephalitis syndrome remains etiologically heterogeneous. Emerging evidence of dengue virus serotype 3 neuroinvasion highlights diagnostic gaps arising from overlapping clinical features and limitations of conventional assays. Incorporating dengue testing within integrated, multi-pathogen diagnostic frameworks - combining molecular, serological, and advanced platforms such as metagenomic next-generation sequencing - can improve etiological attribution, surveillance accuracy, and patient management.

TO THE EDITOR

Encephalitis in tropical Asia represents a biologically and etiologically heterogeneous syndrome, in which pathogen-specific laboratory confirmation is frequently low despite extensive testing. Within this complex framework, the dengue virus constitutes one of several infectious contributors rather than a dominant or exclusive cause. Arboviral encephalitis, therefore, continues to pose a significant public health challenge across the region, with the etiology of a substantial proportion of central nervous system (CNS) infections remaining undetermined despite the endemicity of dengue virus (DENV) and Japanese encephalitis virus (JEV). In this context, Perera et al[1] recently published a study in World Journal of Virology, reported evidence of DENV infection in 6.06% of patients with clinically suspected encephalitis in Sri Lanka, including molecular confirmation of DENV-3 neuroinvasion; this finding is cited solely to contextualize the diagnostic yield of dengue testing and does not imply prevalence or causality. These observations further strengthen the growing body of evidence indicating that dengue is a neurotropic virus capable of causing encephalitis and meningoencephalitis in both pediatric and adult populations[2,3].

CLINICAL RECOGNITION AND THE WORLD HEALTH ORGANIZATION DENGUE SEVERITY FRAMEWORK

According to the World Health Organization dengue severity classification, dengue infection spans a clinical spectrum ranging from dengue without warning signs to severe dengue, the latter defined by severe plasma leakage, hemorrhage, or central organ involvement, including CNS manifestations[4]. Classical dengue typically presents with fever, headache, myalgia, arthralgia, and gastrointestinal symptoms. However, the development of neurological features - such as altered consciousness, seizures, focal neurological deficits, or meningeal signs - should prompt evaluation for dengue-associated encephalitis. Dengue encephalitis is thought to arise through direct viral neuroinvasion and/or immune-mediated neuroinflammatory mechanisms, supported by the detection of viral RNA or intrathecal dengue-specific immunoglobulin M (IgM) antibodies in cerebrospinal fluid (CSF), along with inflammatory CSF changes[5,6]. Historically, in many dengue-endemic regions, patients presenting with encephalitic manifestations were not routinely evaluated for dengue infection in the absence of classical clinical features, contributing to systematic under-recognition of dengue-associated acute encephalitis syndrome (AES). This entity is distinct from dengue encephalopathy, which results from systemic complications such as hepatic failure, shock, or metabolic disturbances and is typically associated with normal CSF findings[2]. Importantly, neurological manifestations may occur at any stage of dengue illness, even in the absence of classical warning signs, further contributing to diagnostic oversight in arbovirus-endemic settings.

CHANGING EPIDEMIOLOGY OF JAPANESE ENCEPHALITIS AND THE PERSISTENT AES BURDEN

Across tropical Asia, the epidemiology of viral encephalitis has shifted substantially over the past two decades. Reported JEV incidence has declined following the introduction of large-scale vaccination programs, although reductions are heterogeneous and localized outbreaks continue to occur[7]. Indian studies, including mechanistic and clinical investigations led by Ghildiyal et al[8,9] and Singh et al[10], demonstrate that while JEV vaccination has markedly reduced confirmed JEV cases, the overall burden of AES remains high, indicating that non-JEV etiologies now predominate. These studies further highlight the contributions of neuroinflammation, oxidative stress, macrophage-derived vesicles, and microglial activation to JEV pathogenesis, underscoring that viral encephalitis in the region is biologically heterogeneous and mechanistically complex[8-10]. Similar epidemiological trends have been reported from Sri Lanka, Vietnam, and Bangladesh, where declining JEV notifications have not been accompanied by proportional reductions in encephalitis incidence[11,12].

In this post-JEV vaccination landscape, DENV has emerged as an increasingly important yet underrecognized contributor to CNS infections. The detection of DENV-3 is particularly significant, as this serotype has been repeatedly associated with neurological complications, including encephalitis, across endemic regions in South and Southeast Asia[2,13]. Recent data from western India demonstrate a serotype-specific risk, with DENV-3 accounting for the majority of dengue-associated neurological manifestations[13]. These observations reinforce the need to routinely consider dengue in the differential diagnosis of encephalitis, even in the absence of classical dengue manifestations, particularly in regions where multiple flaviviruses co-circulate.

DIAGNOSTIC DISCORDANCE AND METHODOLOGICAL CONSTRAINTS

A notable finding in the Sri Lankan study by Perera et al[1] is the marked discrepancy between CSF reverse transcription polymerase chain reaction (PCR) positivity (1.01%) and dengue IgM detection (5.05%). This pattern reflects well-recognized virological and immunological kinetics of flaviviral CNS infections. Viral RNA in blood and CSF is typically transient and present at low copy numbers during early illness, rendering PCR sensitivity highly dependent on early sampling, adequate CSF volume, and assay performance[14]. In contrast, virus-specific IgM antibodies generally appear 5-7 days after symptom onset. They may persist for weeks to months, increasing serological detection beyond the viremic window but introducing challenges related to flaviviral cross-reactivity in endemic regions[4]. Comparable diagnostic discordance has been consistently reported in AES studies from India and Sri Lanka, where DENV, JEV, and other arboviruses account for only a minority of laboratory-confirmed cases, leaving a substantial proportion of encephalitis etiologically unexplained[11]. The identification of DENV-3 neuroinvasion, therefore, carries essential clinical and epidemiological implications and further supports the need for expanded, integrated diagnostic strategies in AES surveillance.

IMMUNOPATHOGENESIS AND AGE DISTRIBUTION

The predominance of adult cases among dengue-positive encephalitis patients in Sri Lankan study by Perera et al[1] the likely reflects immunopathogenic mechanisms shaped by age-specific exposure histories. In endemic settings, adults are more likely to have experienced prior dengue infections, predisposing them to secondary infection in which antibody-dependent enhancement facilitates increased viral entry, higher viral burden, and amplified inflammatory responses[15,16]. Once CNS involvement occurs, intrathecal antibody production becomes a hallmark of dengue encephalitis, with dengue-specific IgM synthesis in CSF correlating with neurological manifestations[5]. Serotype-specific effects further modulate risk; notably, DENV-3 - resurgent in India and Sri Lanka since 2019 - has been repeatedly associated with neurological disease[4]. In contrast, pediatric patients, more often experiencing primary infection, may develop CNS disease through direct viral neurotropism rather than enhancement-driven immunopathology.

ALTERNATIVE AND COMMON CAUSES OF ENCEPHALITIS

Dengue represents one of several infectious causes of AES and should be considered alongside well-established viral and immune-mediated etiologies. Herpesviruses - particularly herpes simplex virus type 1[17] and varicella-zoster virus[18] - remain leading causes of sporadic infectious encephalitis in adults, while enteroviruses[19] are common in children and immunocompromised individuals. Cytomegalovirus may cause severe CNS disease in immunocompromised patients. In parallel, immune-mediated encephalitis, such as anti-N-methyl-D-aspartate receptor encephalitis, are increasingly recognized as major non-infectious causes of encephalitis[20]. Notably, data from the California encephalitis project demonstrated that anti-N-methyl-D-aspartate receptor encephalitis exceeded individual viral etiologies among younger patients, highlighting the importance of considering autoimmune mechanisms when virological investigations are negative[21]. Subsequent studies across multiple continents have further established autoimmune encephalitis as a globally relevant and increasingly recognized differential diagnosis[22,23]. Collectively, these observations underscore the need for routine evaluation of common infectious and autoimmune etiologies when clinically indicated.

FUTURE DIRECTIONS AND CONCLUSION

Collectively, these findings underscore the urgent need for integrated and tiered diagnostic strategies for encephalitis in tropical Asia, where DENV and JEV coexist with a broad spectrum of infectious and immune-mediated causes. In this context, incorporation of dengue testing into encephalitis diagnostic protocols is intended to improve recognition of a potentially under-diagnosed but clinically relevant etiology, rather than to imply that dengue accounts for the majority of encephalitis cases, the relative contribution of which remains to be defined through systematic multi-pathogen studies. Future approaches should move beyond single-pathogen testing and incorporate broad-range molecular screening followed by virus-specific confirmation, together with paired serum-CSF analysis, neutralization assays, and systematic application of advanced molecular platforms, including multiplex PCR panels, digital PCR, and metagenomic next-generation sequencing[24]. Thus, a stepwise diagnostic algorithm integrating rapid syndromic testing, unbiased pathogen discovery, and high-sensitivity confirmatory assays offers a practical framework to address the persistent etiological gap in AES. Importantly, parallel evaluation for autoimmune encephalitis should be embedded within AES workups, particularly in virology-negative cases, to reduce misclassification and delayed diagnosis. Strategic adoption of such integrated diagnostic pathways within regional surveillance systems is likely to improve diagnostic yield, guide targeted therapy, enhance outbreak detection, and ultimately strengthen public health preparedness in the post-JEV vaccination era.