Introduction: The Expanding Clinical Spectrum of Dengue
Dengue virus (DENV) infection has long been characterized by its classic presentation of high fever, retro-orbital pain, and hemorrhagic manifestations. However, as the global footprint of this mosquito-borne illness expands due to urbanization and climate change, clinicians are increasingly observing a wider array of atypical manifestations. Among these, neurological complications have emerged as a significant area of concern. While previously considered rare or isolated to severe cases of dengue hemorrhagic fever, new evidence suggests that neurological events may be more prevalent and consequential than formerly recognized.
The neurotropic potential of DENV has been a subject of debate for decades. Unlike Japanese encephalitis or West Nile virus, DENV was traditionally viewed as primarily non-neurotropic. However, increasing reports of encephalitis, meningitis, and Guillain-Barré syndrome following acute infection have challenged this view. Despite these reports, large-scale, population-based data quantifying the excess burden and specific risks of neurological events in the post-infectious period have been sparse. A landmark study recently published in JAMA Neurology provides much-needed clarity on this association, leveraging high-quality registry data from Singapore.
Study Design: A Population-Based Approach in Singapore
To evaluate the risk and excess burden of neurological events following acute DENV infection, researchers conducted a retrospective, population-based cohort study. Singapore, with its robust national registries and endemic dengue status, provided an ideal setting for such an investigation. The study period spanned from January 1, 2017, through December 31, 2023, capturing data through the COVID-19 pandemic.
Cohort Construction
The study utilized national registries to identify 65,207 confirmed DENV-infected adults (aged 18 years or older). The index date (T0) was defined as the date of notification. These cases were compared against a massive cohort of 1,616,865 uninfected population-based comparators. To ensure the accuracy of the findings, the researchers excluded individuals who were infected with SARS-CoV-2 within 30 days of the index date, as COVID-19 is itself associated with neurological sequelae. They also excluded individuals who died before the index date and uninfected comparators who had no prior healthcare contact to mitigate selection bias.
Outcomes and Statistical Analysis
The primary focus was on new-incident neurological events occurring within 30 to 90 days following infection. These events included memory loss, movement disorders (such as parkinsonism or tremors), and other neurological disorders (including fatigue, malaise, encephalitis, or encephalopathy). The researchers utilized overlap-weighted logistic regression to estimate adjusted odds ratios (aORs), accounting for various confounders to ensure that the observed associations were robust.
Key Findings: Quantifying the Neurological Risk
The results of the study underscore a significant association between acute DENV infection and subsequent neurological complications. While the absolute excess burden remained modest, the relative risk was strikingly high.
Elevated Odds of Neurological Sequelae
At 30 days post-infection, individuals who had contracted dengue were found to have significantly elevated odds of experiencing any new-incident neurological event, with an adjusted odds ratio (aOR) of 9.69 (95% CI, 6.59-14.90). This nearly ten-fold increase highlights the acute impact of the virus on the nervous system. Specifically:
- Memory loss: aOR 3.19 (95% CI, 1.36-8.69)
- Movement disorders: aOR 7.10 (95% CI, 2.49-29.18)
- Other neurological events (including encephalopathy): aOR 14.32 (95% CI, 8.61-26.04)
Interestingly, the risk trajectories for these conditions were shown to diverge and persist for up to 90 days after the initial infection, suggesting that the neurological impact of dengue is not merely a transient feature of the acute febrile phase but a post-infectious phenomenon that requires longer-term monitoring.
Vulnerable Populations and Serotype Specificity
The study provided critical granular data regarding which patients are most at risk. The increased odds of memory loss and movement disorders were specifically pronounced among adults aged 60 years or older. For this demographic, the aOR for memory loss was 2.99 and for movement disorders was 6.38. This suggests that the aging brain may be more susceptible to the inflammatory or neurotoxic effects of the virus.
Furthermore, the study identified a specific association with DENV serotype 3 (DENV-3). Cases infected during periods of DENV-3 dominance showed a higher propensity for neurological outcomes compared to other serotypes. This finding is particularly relevant for public health authorities monitoring circulating strains, as it may signal periods of increased need for neurological surveillance.
Expert Commentary: Mechanistic Insights and Clinical Utility
The findings presented in this study offer a significant advancement in our understanding of dengue’s clinical footprint. The high odds ratios for neurological events, even if the absolute burden is less than one excess event per 100 cases, suggest that clinicians must maintain a high index of suspicion for cognitive and motor changes in recovering dengue patients.
Biological Plausibility
Mechanistically, the association between DENV and neurological events may be driven by several pathways. First, direct viral invasion of the central nervous system (CNS) is possible, as DENV has been detected in cerebrospinal fluid. Second, the systemic inflammatory response—often referred to as a cytokine storm—can lead to blood-brain barrier disruption and neuro-inflammation. Third, immune-mediated mechanisms, such as post-infectious molecular mimicry, may contribute to disorders like movement abnormalities or demyelinating conditions. The specific vulnerability of older adults may be explained by inflamm-aging or pre-existing cerebrovascular fragility that lowers the threshold for clinical manifestation of neurological deficits.
Study Strengths and Limitations
A major strength of this study is its population-based design and the use of national-level data, which minimizes the referral bias often seen in hospital-based studies. The exclusion of COVID-19-affected cases also strengthens the causal inference specifically toward DENV. However, limitations include the reliance on healthcare claims records, which may under-capture milder neurological symptoms that do not prompt a formal medical consultation. Additionally, while the aORs are high, the low absolute incidence means that screening every dengue patient may not be cost-effective; instead, a targeted approach for high-risk groups is warranted.
Clinical Implications: A Call for Vigilance
For clinicians, the primary takeaway is that the resolution of fever and the recovery of platelet counts do not necessarily mark the end of a dengue patient’s journey. The post-infectious period, particularly the first 90 days, represents a window of vulnerability for neurological complications.
Recommendations for Practice
1. Targeted Monitoring: Older adults (60+) should be specifically monitored for cognitive changes, memory lapses, or the onset of tremors and gait instability following a dengue diagnosis.
2. Patient Education: Patients and their families should be informed about the potential for lingering fatigue and subtle neurological symptoms, encouraging them to seek medical advice if these symptoms interfere with daily living.
3. Serotype Awareness: Public health departments should communicate circulating serotype data to clinicians, as DENV-3 outbreaks may necessitate heightened vigilance for neurological presentations.
Conclusion
Acute dengue infection is associated with a significantly increased risk of new-incident neurological events in the post-infectious period. Although the overall excess burden is modest, the nearly ten-fold increase in risk for conditions like movement disorders and encephalopathy cannot be ignored. As dengue continues to threaten larger portions of the global population, integrating neurological assessment into routine follow-up care—especially for the elderly—will be essential to mitigating the long-term morbidity associated with this multifaceted virus.
References
1. Wee LE, Tan WZ, Chow JY, et al. Neurological Events Associated With Acute Dengue Infection. JAMA Neurol. Published online November 24, 2025. doi:10.1001/jamaneurol.2025.4608
2. Mustafa MS, Rasotgi V, Jain S, Gupta V. Discovery of Dengue Virus and Its Evolution at a Glance. Med J Armed Forces India. 2015;71(1):28-39.
3. Li GH, Pan ZQ, Cheng JZ, et al. Neurological Manifestations of Dengue Infection. Front Cell Infect Microbiol. 2017;7:147.
