Rare case of dengue encephalitis with extensive brain lesions from Pakistan

Abstract

Dengue infection is common in 129 countries including Pakistan, with an estimated 390 million dengue virus infections per year. Asia accounts for 70% of the actual burden. Clinical signs and symptoms of dengue include a high fever (40°C/104 °F) accompanied by two of the following symptoms during the febrile phase: severe headache, pain behind the eyes, muscle and joint pains, nausea, vomiting, swollen glands and rash. Severe dengue is a potentially fatal complication, due to plasma leaking, fluid accumulation, respiratory distress, severe bleeding or organ impairment. Dengue virus does not usually cause neurological manifestations, unlike other arboviral infections. Encephalopathy is the most common neurological complication. Encephalitis is rare manifestation. We report a rare case of dengue encephalitis from Pakistan, with extensive brain lesions involving the thalamus, cerebellar vermis and frontoparietal periventricular regions. Therefore, we suggest dengue encephalitis should be considered in the differential diagnosis of fever with altered sensorium, especially in Asian countries such as Pakistan where dengue is rampant as dengue encephalitis can be fatal at times.

Background

Dengue is caused by four genotypes of dengue virus (DENV-1, DENV-2, DENV-3 and DENV-4). The virus belongs to the Flaviviridae family. The primary vector is the infected female Aedes aegypti mosquito.¹

It is estimated that there are around 390 million dengue virus infections per year, of which 96 million (67–136 million) manifest clinically.² Although, risk of infection exists in 129 countries, including regions of Africa, the Americas, the Eastern Mediterranean, South-East Asia and the Western Pacific. The Americas, South-East Asia and Western Pacific regions are the most seriously affected. Asia accounts for 70% of the actual burden.²

Clinical signs and symptoms of dengue include a high fever (40°C/104 °F) accompanied by two of the following symptoms during the febrile phase: severe headache, pain behind the eyes, muscle and joint pains, nausea, vomiting, swollen glands and rash. Severe dengue is a potentially fatal complication, due to plasma leaking, fluid accumulation, respiratory distress, severe bleeding or organ impairment.

Dengue virus does not usually cause neurological manifestations, unlike other arboviral infections.³ However, in recent years, neurological manifestations of dengue have been reported. Encephalopathy accounts for 80% of neurological complications. It is more related to the indirect effects of dengue infection. Encephalitis is a rare complication of dengue, which results from direct viral invasion.⁴

We report a rare case of dengue encephalitis from Pakistan. MRI brain revealed extensive involvement of brain including cerebellar vermis, thalamus and periventricular region of medial temporal region on both sides of the MRI brain, which is an uncommon manifestation of dengue fever.

Case presentation

A young man in his late 20s with no previous comorbidities presented to us with high-grade fever for 2 days, which was associated with rigours and chills. Along with that, the patient had nausea and generalised body aches. His review of systems was otherwise normal. Given the ongoing season of dengue and malaria, which are endemic in the region, he was tested for both. Malaria test was negative. Baseline investigations were otherwise normal. His investigations showed dengue NS1 antigen positive and a platelet count of 1 28 000 /µL. As the patient was otherwise stable, so he was discharged with antipyretics and an antiemetic.

Two days after discharge, the patient presented with marked confusion and drowsiness. In addition, during his admission at hospital, the patient also had two episodes of witnessed tonic–clonic seizures without any aura, lasting 1–2 min each, associated with tongue bite, frothing, urine incontinence, postictal drowsiness and confusion but no loss of consciousness. He did not have any head trauma or history of fall. On assessment, the patient had a Glasgow Coma Scale (GCS) of 9/15, blood pressure of 100/70 mm Hg and pulse of 110 bpm. Otherwise, the patient had a normal neurological examination apart from mild neck stiffness. His cardiac, respiratory, gastrointestinal examination were also unremarkable

Investigations

His base line investigations on second visit were largely normal apart from mild thrombocytopenia of 139 x10∧9/L and white cell count (WCC)=13.4 x10∧9/L. Other lab test were reported normal as haemoglobin=126 g/L, haematocrit=40.5%, serum urea=63 mg/dL, serum creatinine=1.4 mg/dL, serum alanine transaminase=36 U/L, serum alkaline phosphatase=49 U/L, total bilirubin=0.5 mg/dL. His serum electrolytes were reported as serum sodium=136 mmol/L, serum chloride=101 mmol/L, serum potassium=3.37 mmol/L. COVID-19 was not detected on PCR COVID-19 test. Malaria test was negative. His prothrombin time (PT) and activated partial thromboplastin time (APTT) were 14 and 19 seconds, respectively. Consequently, an MRI of the brain and cerebrospinal fluid (CSF) analysis were advised. His MRI brain reported T2 and fluid attenuated inversion recovery (FLAIR) hyperintensities in bilateral periventricular white matter, thalami and cerebellar vermis with subtle restriction on DW1 and meningeal enhancement- findings are suggestive of menigioencephalitis (figures 1–3). CSF analysis reported WCC=3/cmm, red cell count=5/cmm, protein=145 mg/dL, glucose=90 mg/ dL, no micro-organisms including acid fast bacilli were seen. No growth was seen on blood culture tests. CSF PCR test for herpes simplex viruses (HSV-1 and HSV-2) were negative. Due to financial constraints and limited hospital lab capabilities, CSF dengue antigen could not be tested. Seizures were well controlled without any recurrence on

Figure 1.

Arrow points to periventricular lesions on diffusion weighted image (DWI) axial sequence MRI brain.

Figure 2.

Thalamic lesions on fluid attenuated inversion recovery (FLAIR) axial sequence MRI brain.

Figure 3.

Cerebellar lesions on fluid attenuated inversion recovery (FLAIR) axial sequence MRI brain.

follow-up, thus patient deferred EEG test on account of non-affordability.

Treatment

This patient was started empirically on acyclovir at a dose of 15 mg/kg 8 hourly, dexamethasone 6 mg intravenous once daily and sodium valproate intravenously at a dose of 15 mg/kg/24 hours divided into two doses. Once HSV-1 and HSV-2 were ruled out, acyclovir was stopped.

Outcome and follow-up

The patient responded to the management over the next 10 days. On discharge, his platelet count improved to 234 x10⁹/L ' and WCC=9.5 x10⁹/L. Furthermore, he was oriented to time, place, person and situation. His GCS was 15/15. He had no episode of seizure recorded on follow-up.

Discussion

The neurological complications of dengue can be divided in three groups. ‘Mild non-specific symptoms of headache, dizziness, slight alteration in sensorium, decreased sleep and restlessness; severe syndromes of depressed sensorium, confusion, seizures, meningismus, myelitis, encephalitis or encephalopathy; and delayed syndromes of paralysis of extremities, Guillain–Barré syndrome, amnesia, loss of sensation and different psychiatric manifestations’.⁵

Neurological manifestations can be due to neurotropic effects and consequence of systemic complications of dengue virus or immune mediated.^{4 5}

Encephalitis is a severe manifestation of dengue virus infection. Cristiane S, Marzia PS et al. proposed a criteria for diagnosis of dengue encephalitis.⁶ Criteria include the presence of fever, acute signs of cerebral involvement such as altered consciousness or personality and/or seizures and/or focal neurological signs. Diagnostic tests include reactive IgM dengue antibody, NS1 antigen or positive dengue PCR on serum and/or cerebrospinal fluid.⁶ In our case, patient had fever, seizures and positive NS1 antien test. Given his recent diagnosis of dengue infection, the immediate episodes of seizures within 2 days of diagnosis, coupled with the MRI findings, are strongly suggestive of dengue encephalitis. Soares et al mention that normal CSF cellularity cannot rule out dengue encephalitis as it is the prime differential diagnosis of encephalitis with normal CSF cellularity in almost two-thirds of patients with viral meningitis and encephalitis in a dengue endemic region, followed by HSV-1.⁷

We found only three case reports with this type of extensive brain lesions of dengue encephalitis reported by Kamble et al and Borawake K et al and Rao et al.^8–10 The aetiology of encephalitis is wide and can be narrowed down based on clues from history, examination and investigations. A trip to Africa, Asia, Europe and north America will hint towards trypanosomiasis, Japanese encephalitis and Lyme or tick born infections, respectively.¹¹ Season and occupation can also be helpful in diagnosis. Tickborne infections are common in forest workers and more common in summer or autumn. Japanese encephalitis is common during rainy season. Listeriosis, cryptococcus, cytomegalovirus is common cause of encephalitis in immunosuppressed individuals. Cold sores and rashes may be observed in case of HSV and VZV. A recent animal bite may suggest tickborne encephalitis or even rabies, and recent exposure to infectious diseases such as tuberculosis, childhood exanthems or polio may also aid in diagnosis.¹¹ Chest X-ray is helpful in case of encephalitis caused by legionella, mycoplasma and tuberculosis. HSV typically affects the temporal lobes, insular cortex and angular gyrus as evidenced by typical findings of MRI brain.¹¹ Acute demyelinating encephalomyelitis (ADEM) can also cause symptoms, such as encephalitis. However, ADEM usually occurs in a young person with a history of vaccination or infection abruptly, without fever at onset of symptoms, with multifocal neurological signs. Findings of peripheral nerves involvement favour the possibility of encephalitis being ADEM or an infection with VZV, CMV, EBV.¹¹ Our patient had fever, no history of recent vaccination and no peripheral neurological signs. Two articles reporting the normal finding on CSF analysis in dengue encephalitis and the spectrum of MRI findings in dengue further support our diagnosis.^{12 13}

Dengue encephalitis should be considered in the differential diagnosis of fever with altered sensorium, especially in Asian countries, such as Pakistan where dengue is rampant as dengue encephalitis can be fatal at times. Our patient was sent back home as dengue usually requires only symptomatic treatment and observation. However, physicians should be vigilant for this complication and counsel appropriately for immediate return to receive appropriate care and treatment.

Patient’s perspective.

Dengue is common in our region. I was assured I need symptomatic treatment and I will be fine. I could not believe I would return back to emergency department so quick. I did not know what was wrong with me. I was not in my senses and having body jerks. My family was worried. Even the doctors were surprised to see the extent to which it involved my brain. I am lucky I recovered. I better rest and take care of my diet to get stronger and fight these infections.

Learning points.

• Unlike other arboviral infections dengue virus does not usually cause neurological manifestations, however, in recent years, neurological manifestations of dengue have been reported.

• Dengue encephalitis should be considered in the differential diagnosis of fever with altered sensorium, especially in regions where dengue is common.

• In rare cases, dengue encephalitis can cause extensive involvement of brain including cerebellar vermis, thalamus and periventricular region of medial temporal region.

• Physicians should be vigilant for this complication and counsel patients for immediate return to receive appropriate care and treatment.

Ethics statements

Patient consent for publication

Consent obtained directly from patient(s).