Acute disseminated encephalomyelitis (ADEM) complicating dengue infection is still exceedingly rare even in endemic countries such as Malaysia. Here we report two such cases, the first in an elderly female patient and the second in a young man. Both presented with encephalopathy, brainstem involvement and worsening upper and lower limb weakness. Initial magnetic resonance imaging (MRI) of the brain was normal in the first case. Serum for dengue Ig M and NS-1 was positive in both cases. Cerebrospinal fluid (CSF) showed pleocytosis in both with Dengue IgM and NS-1 positive in the second case but not done in the first. MRI brain showed changes of perpendicular subcortical palisading white matter, callosal and brainstem disease mimicking multiple sclerosis (MS) in both patients though in the former case there was a lag between the onset of clinical symptoms and MRI changes which was only clarified on reimaging. The temporal evolution and duration of the clinical symptoms, CSF changes and neuroimaging were more suggestive of Dengue ADEM rather than an encephalitis though initially the first case began as dengue encephalitis. Furthermore in dengue encephalitis neuroimaging is usually normal or rarely edema, haemorrhage, brainstem, thalamic or focal lesions are seen. Therefore, early recognition of ADEM as a sequelae of dengue infection with neuroimaging mimicking MS and repeat imaging helped in identifying these two cases. Treatment with intravenous steroids followed by maintenance oral steroids produced good outcome in both patients.
Dengue virus (DENV) infection remains a major public health concern in many parts of the world, including Southeast Asia and the Americas. Sri Lanka experienced its largest dengue outbreak in 2017. Neurological symptoms associated with DENV infection have increasingly been reported in both children and adults. Here, we characterize DENV type 2 (DENV-2) strains, which were isolated from cerebrospinal fluid (CSF) and/or serum of patients with dengue encephalitis. Acute serum and CSF samples from each patient were subjected to dengue-specific non-structural protein 1 (NS1) antigen test, IgM and IgG enzyme-linked immunosorbent assay (ELISA), virus isolation, conventional and real-time polymerase chain reaction (PCR), and next-generation sequencing (NGS). Among the 5 dengue encephalitis patients examined, 4 recovered and 1 died. DENV-2 strains were isolated from serum and/or CSF samples of 3 patients. The highest viral genome levels were detected in the CSF and serum of the patient who succumbed to the illness. A phylogenetic tree revealed that the DENV-2 isolates belonged to a new clade of cosmopolitan genotype and were genetically close to strains identified in China, South Korea, Singapore, Malaysia, Thailand, and the Philippines. According to the NGS analysis, greater frequencies of nonsynonymous and synonymous mutations per gene were identified in the nonstructural genes. The full genomes of serum- and CSF-derived DENV-2 from the same patient shared 99.7% similarity, indicating that the virus spread across the blood-brain barrier. This is the first report to describe neurotropic DENV-2 using whole-genome analysis and to provide the clinical, immunological, and virological characteristics of dengue encephalitis patients during a severe dengue outbreak in Sri Lanka in 2017.
Involvement of the central nervous system in dengue fever and dengue hemorrhagic fever has always been thought to be secondary to vasculitis with resultant fluid extravasation, cerebral edema, hypoperfusion, hyponatremia, liver failure, and/or renal failure. Thus, the condition has been referred to as dengue encephalopathy. Encephalitis or direct involvement of the brain by the virus was thought to be unlikely. This paper reports on six children who were seen over a period of two years presenting on the second or third day of illness with dengue encephalitis. The diagnosis was based upon a clinical picture of encephalitis and confirmed by cerebrospinal fluid (CSF) microscopy and electroencephalography changes. All six cases were confirmed dengue infections. Dengue 3 virus was isolated from the CSF of four cases and in one case, dengue 2 was detected by the polymerase chain reaction in both the CSF and blood. In the sixth case, virologic evidence was negative but dengue immunoglobulin M was detected in the CSF and blood. Since the onset of encephalitis appears early in the course of illness coinciding with the viremic phase, we postulate that the virus crosses the blood-brain barrier and directly invades the brain causing encephalitis. This study provides strong evidence that dengue 2 and 3 viruses have neurovirulent properties and behave similarly to other members of the Flaviviridae.