Case presentation

A 62-year-old Chinese woman was admitted to the hospital with a four-day history of fever associated with chills, rigors, and headache. She also complained of postural giddiness, five episodes of vomiting, and shortness of breath on exertion for one day. She denied any abdominal pain or bleeding manifestations. Her past medical history was unremarkable, and she had not travelled out of Singapore.

Clinical evaluation revealed tympanic temperature of 38.2°C, blood pressure of 140/80 mmHg, and pulse rate of 92 beats per minute. The patient was alert and orientated with a Glasgow Coma Score (GCS) of 15. She had a faint maculopapular rash, but physical examination was otherwise unremarkable; the lungs were clear to auscultation, and there was no abdominal tenderness or hepatomegaly. Hematology and biochemistry results on admission are summarised in Table 1. Chest radiograph was normal, with no radiographic evidence of pleural effusion. Serum dengue NS1 antigen was positive, and dengue IgM and IgG were negative (SD BIOLINE Dengue Duo Cassette, Alere).

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Table 1. Hematological and biochemical markers.

https://doi.org/10.1371/journal.pntd.0005369.t001

During the initial two days of her admission, the patient did not develop any further dengue warning signs, such as abdominal pain, hepatomegaly, persistent vomiting, or bleeding manifestations. Her platelet count nadir was 62 x 10⁹/L (day 5 of illness). She developed confusion and receptive and expressive aphasia with inability to recognize her family members on day 6 of illness. On examination, she was afebrile, GCS was E4V2M5, and there were no signs of meningism. Apart from the receptive and expressive aphasia, a full neurological examination did not reveal any motor or sensory deficit. A computed tomography scan of the brain that day showed no acute cerebral infarct or hemorrhage. Her hematocrit had risen by 6.8% but did not fulfil criteria for significant hemoconcentration; thrombocytopenia was mild, and although transaminitis was worse, it rapidly improved (shown in Table 1). Workup for nosocomial infection comprising blood cultures and urinalysis was unrevealing. Cerebrospinal fluid (CSF) analysis revealed a nucleated cell count of 62 cells/uL (97% lymphocytes, 2% macrophages, 1% neutrophils), an erythrocyte count of 9 cells/uL, a protein count of 2.33 g/L, and a glucose count of 3.5 mmol/L (serum glucose 5.9 mmol/L). CSF Gram stain and culture, tetraplex polymerase chain (PCR) testing for Cytomegalovirus, herpes simplex virus (HSV), varicella zoster virus (VZV), and Toxoplasma gondii were negative. CSF enterovirus PCR testing was negative, as were tests for CSF measles and mumps serology. We proceeded to do magnetic resonance imaging (MRI) of the brain and angiography with contrast the next day (day 7 of illness and day 2 of confusion) due to the persistent confusion with aphasia. There was no evidence of restricted diffusion or abnormal susceptibility, with no focal abnormal signals in the cerebrum, brainstem, or cerebellum. There was also no abnormal parenchymal or leptomeningeal enhancement seen on the contrasted images. Diffusion-weighted imaging with apparent diffusion coefficient mapping scans were normal, with no MRI evidence of blood–brain barrier leakage, and there was no hydrocephalus, midline shift, or effacement of basal cisterns.

Serum dengue PCR (on day 4 of illness) using an in-house protocol adapted from the Centers for Disease Control DENV-1-4 Real-Time PCR Assay for detection and serotype identification of dengue virus (DENV) was positive for DENV-4. CSF dengue PCR (using the same methodology) was negative on day 6 of illness. NS1 antigen from the CSF was negative, while both dengue IgM and IgG were positive (SD BIOLINE Dengue Duo Cassette, Alere).

Although the patient was afebrile at the onset of confusion, there was recrudescence of low-grade fever within 24 hours, which persisted until day 7 of illness. She was empirically treated with intravenous acyclovir until the VZV and HSV PCR results were available. By day 8 of illness, she was able to verbalise and recognise family members but still not orientated as to the time and place. In view of her improved mentation, electroencephalography (EEG) was not performed, although nonconvulsive seizures should be a consideration of altered mentation in patients with suspected encephalitis. She made a complete clinical recovery at day 10 of illness. Repeat clinical examination when she was lucid and cooperative revealed no symptoms or signs suggesting peripheral nerve, spinal cord, or ocular involvement. At follow-up, she had no neurological sequelae. She recollected seeing herself “locked in a cage,” trying to get out on the day she had developed confusion, but was unable to recall any other details regarding the episode of confusion or aphasia. She reported no other psychotic symptoms.

Case discussion

The presenting case

Our patient with DENV-4 infection developed new acute neurological symptoms of confusion and expressive aphasia at day 6 of her acute dengue illness. CSF showed lymphocytic pleocytosis with a positive CSF dengue IgM and IgG. Testing for other pathogens in CSF was negative. She had not travelled to areas endemic for other flaviviruses. Although DENV-4 has been reported to potentially cause encephalitis, those cases were fatal, with multiorgan involvement and dengue haemorrhagic fever. [6,7] By contrast, our patient had no other features of severe dengue, such as severe plasma leakage, bleeding, or other organ impairment. This is the first known case of DENV-4 encephalitis with complete recovery.