Chronic dengue virus encephalitis diagnosed by metagenomic analysis: a case study

Background: The dengue virus (denV) can lead to acute encephalitis during the initial infection. Chronic encephalitis with progressive dementia is rarely documented. Methods: We present a novel case of chronic encephalitis causing rapidly progressive dementia, in which a probable denV brain infection was identified through metagenomic next-generation sequencing of brain tissue. Brain pathology and molecular diagnosis are detailed. Results: A 20-year-old male from São Paulo began experiencing symptoms of rapidly progressive dementia, including speech apraxia and apathy, starting in June 2022. Initial cognitive testing in January 2023 revealed severe impairment across multiple domains, with a score of 18 points on the Mini-Mental State Examination. A brain MRI performed six months after symptom onset showed white matter abnormalities and brain atrophy. Cerebrospinal fluid (CSF) analysis indicated elevated white blood cells, increased proteins, and the presence of oligoclonal bands. An extensive diagnostic work-up ruled out common infectious and autoimmune causes of encephalitis. Over a six-month period, the patient‘s condition continued to deteriorate, resulting in progressive impairment of executive functions and language, accompanied by the onset of tremors and myoclonus. In August 2023, the patient was readmitted for further diagnostic investigation, revealing reactive denV IgG and non-reactive IgM in an arboviruses immunology panel, prompting additional investigation. Due to the lack of an etiological diagnosis and the severity of the case, a brain biopsy was performed. Histopathological examination of the brain biopsy suggested a chronic infectious etiology unrelated to bacteria, supported by the frequent presence of CD8+ T lymphocytes, plasma cells, and glioneuronal alterations. Next-generation sequencing and phylogenetic analysis of brain tissue identified DENV-1 genotype V, with the recovered sequence clustering within a clade of Brazilian sequences from 2000 to 2022. # Conclusion: This case highlights the importance of unbiased techniques like metagenomics in diagnosing encephalitis of unknown etiology, providing a potential etiological explanation for the patient‘s chronic encephalitis. While dengue virus is occasionally described as a cause of acute encephalitis/encephalopathy, this case broadens the clinical spectrum of the infection, demonstrating that it may also cause chronic encephalitis.