Dengue encephalitis – An unusual case series

ABSTRACT

Dengue infection can take on many different forms, ranging from no symptoms to a mild fever, all the way to a severe condition known as dengue shock syndrome. Although the typical symptoms of dengue are well known, the virus can also cause rare neurological complications. Dengue encephalitis is a severe form of neuroinvasive dengue that can be fatal as the virus directly affects the central nervous system. This case series provides a comprehensive overview of dengue, its clinical spectrum, and the potential for severe neurological complications such as dengue encephalitis. It highlights the importance of considering dengue as a possible diagnosis in patients with encephalitis, particularly during a dengue epidemic.

Introduction

Dengue is a viral infection spread by Aedes mosquitoes that poses a significant public health concern, particularly in tropical and subtropical regions. The dengue virus (DENV) is the causative agent of the infection. With approximately 390 million infections occurring annually, dengue has become one of the most prevalent mosquito-borne diseases worldwide. Nearly half of the world’s population is at risk of contacting this disease.[1,2,3]

Dengue infection manifests in a spectrum of clinical presentations, ranging from asymptomatic or mild febrile illness, known as dengue fever (DF), to severe and potentially life-threatening conditions, such as dengue haemorrhagic fever (DHF) and dengue shock syndrome (DSS).[1] The hallmark features of dengue fever include sudden-onset high-grade fever, severe headache, joint and muscle pain, rash, and mild bleeding manifestations.[4,5] DHF is divided into three phases: febrile phase (2–7 days), critical or leakage phase (24–48 hours), and convalescence phase (2–7 days). Encephalitis is observed during or after the critical phase but can occur early in the febrile phase. A few cases are found among DF patients.

Although the typical symptoms of dengue fever are well known, the virus can also lead to rare neurological complications such as encephalopathy, encephalitis, meningitis, myelitis, myositis, acute disseminated encephalomyelitis, neuromyelitis optica, optic neuritis, myelitis, and Guillain-Barré syndrome. Dengue encephalitis, a severe and potentially fatal form of neuroinvasive dengue, is a rare type that directly affects the central nervous system (CNS). The exact cause of dengue encephalitis is not fully understood, and ongoing research is trying to shed light on its pathogenesis. This series of cases provides a comprehensive view of dengue fever’s global impact, clinical spectrum, and potential for severe neurological complications such as dengue encephalitis.[3]

Case 1

A 37-year-old female presented to the emergency department with a high-grade fever for 3 days associated with chills, rigour, nausea, and vomiting. She had altered sensorium for 1 day. On presentation, she had a Glasgow coma score (GCS) of 8/15 with bilateral equal pupils reacting to light. She had bilateral extensor planters. Her blood pressure was 110/68 mm Hg, pulse rate 54/minute, respiratory rate 24/minute, oxygen saturation 95%, and capillary blood glucose 130 mg/dl. Clinical examination revealed positive meningeal signs. Baseline investigations, blood cultures, and acute febrile illness workups were sent [Table 1]. The patient was transferred to the Critical Care Unit and presumptively managed for viral encephalitis with intravenous acyclovir, ceftriaxone, dexamethasone, and sodium valproate. The patient required invasive mechanical ventilation due fall in GCS. MRI brain and cerebrospinal fluid (CSF) analysis were planned. Laboratory investigations unveiled thrombocytopenia and transaminitis. Dengue NS-1 and IgM antigen were positive by enzyme-linked immunosorbent assay (ELISA). CSF analysis revealed elevated white blood cells (WBCs) with clear appearance, high protein, and normal glucose levels [Table 2], while CSF Gram staining and herpes simplex virus polymerase chain reaction (HSV PCR) were negative. Empirical antibiotics and antivirals were stopped. MRI demonstrated near symmetrical areas of signal alteration involving bilateral ganglion-capsular regions, bilateral thalami, bilateral medial temporal lobes, bilateral hippocampi, brainstem, and bilateral cerebral and cerebellar peduncles [Figures 1 and 2].

Table 1.

Baseline investigations (blood and serology)

Parameters	Normal range	Case 1	Case 2	Case 3	Case 4
Haemoglobin (g/dL)	13-16	9.5	11.6	11	12
Total leukocyte count (×109/L)	4-12	12200	6700	5440	6200
Platelets (×109/L)	150-400	80	42	90	20
Bilirubin (mg/dL)	0.2-1	4	1.5	2.7	2
ALP (IU/L)	30-150	84	71	74	35
SGOT (IU/L)	10-40	73	45	701	84
SGPT (IU/L)	10-40	75	48	273	127
Albumin (gm/dL)	3.5-5.5	2.4	2.9	2.3	2.2
Sodium (mmol/L)	135-145	134	150	134	142
Potassium (mmol/L)	3.5-5.5	3.2	3.4	3.9	3.7
Urea (mg/dL)	15-40	43	30	36	50
Creatinine (mg/dL)	<1.3	1.2	1.2	1.4	0.9
Dengue IgM serology	-	+	+	+	+
Dengue NS1 serology	-	+	+	+	+
Scrub typhus serology	-	-	-	-	-
Malaria antigen	-	-	-	-	-
Leptospira IgM	-	-	-	-	-

ALP: Alkaline phosphatase, SGOT: Serum glutamic-oxaloacetic transaminase, SGPT: Serum glutamic-pyruvic transaminase

Table 2.

CSF finding

Parameters	Normal range	Case 1	Case 2	Case 3	Case 4
Colour	Colourless	Colourless	Colourless	Colourless	Colourless
Appearance	Clear	Clear	Clear	Clear	Clear
Glucose (mg/dl)	40-70	74	112	92	58
Protein (mg/dl)	12-60	170	162	126	83
Total Leukocytes count (/cumm)	<5	10	5	3	5
Differential Leukocytes count	100% lymphocytes	100% lymphocytes	100% lymphocytes	100% lymphocytes	100% lymphocytes
Gram stain	-	-	-	-	-
Culture	-	-	-	-	-
ADA	-	-	-	-	-
HSV1/HSV2	-	-	-	-	-

ADA: Adenosine deaminase, HSV: Herpes simplex virus

Figure 1.

a. T2 FLAIR showing near symmetrical areas of signal alteration involving bilateral ganglion-capsular regions, bilateral thalami, and bilateral medial temporal lobes. b. DWI showing corresponding hyperintense lesion

Figure 2.

a. T2 FLAIR showing near symmetrical areas of signal alteration involving bilateral hippocampi, brainstem, and bilateral cerebral and cerebellar peduncles. b. DWI showing corresponding hyperintense lesion

Findings were suggestive of encephalitis. With ongoing supportive care, GCS improved, after which she was successfully weaned off the ventilator on day 7.

Case 2

A 59-year-old male with type 2 diabetes mellitus (DM) and chronic obstructive pulmonary disease (COPD) presented to the emergency department with altered sensorium and high-grade, intermittent fever accompanied by chills and rigour for 2 days. On examination, he had a fever (104°F), tachycardia (129 beats/min), hypotension (86/44 mmHg), and a GCS score of 11/15. Meningeal signs were absent with no focal deficits. The patient was resuscitated with fluids, and vasopressors were started. Baseline investigations, blood cultures, and acute febrile illness workups were sent [Table 1]. The patient was transferred to the Critical Care Unit and presumptively managed conservatively for viral encephalitis with acyclovir, ceftriaxone, dexamethasone, and sodium valproate. Laboratory reports were suggestive of dengue [Tables 1 and 2]. CSF analysis revealed normal WBC with a clear appearance, high protein, and normal glucose levels. MRI showed areas of signal alteration in subcortical and adjacent deep white matter in bilateral frontal-parietal-occipital regions, suggesting infarcts. VA few other patchy focal areas of signal alteration in the pons and middle cerebella peduncles were present bilaterally [Figures 3 and 4]. Gradually, GCS improved and the patient was shifted out of ICU after 10 days of ICU stay.

Figure 3.

a. T2 FLAIR showing patchy focal areas of signal alteration in the pons and middle cerebella peduncles bilaterally. b. T2W showing corresponding hyperintense lesion

Figure 4.

a. T2W showing areas of signal alteration in subcortical and adjacent deep white matter in bilateral frontal-parietal-occipital regions, suggesting infarcts. b. T2W FLAIR showing corresponding hyperintense lesion

Case 3

A 30-year-old female who presented to the emergency department with rapid onset altered mental status with no antecedent febrile illness. On examination, she was disoriented, GCS 9/15, with bilaterally reactive pupils with no focal neurological deficits. The patient was transferred to ICU and underwent an urgent MRI brain, which revealed near symmetrical areas of signal alteration involving bilateral cerebral and cerebella hemispheres with areas of haemorrhage, mass effect, supratentorial ventricular system dilatation with periventricular ooze, herniations, and diffuse cerebral and cerebellar oedema [Figure 5]. The patient was initiated on empiric antiviral therapy and acyclovir while awaiting definitive test results. CSF analysis was consistent with viral aetiology, showing a normal white blood cell count with clear appearance, normal glucose, and high protein levels [Tables 1 and 2]. Supportive measures, including close neurological monitoring, fluid management, and seizure prophylaxis, were implemented. Intermittent fluctuations in consciousness marked the patient’s clinical course. Gradually, GCS improved and the patient was shifted out of ICU.

Figure 5.

a. T2W showing near symmetrical areas of signal alteration involving bilateral cerebral and cerebella hemispheres with areas of haemorrhage, mass effect, supratentorial ventricular system dilatation with periventricular ooze, herniations, and diffuse cerebral and cerebellar oedema. b. T2FLAIR showing corresponding hyperintense lesion

Case 4

A 50-year-old male presented to the emergency department with a 7-day history of persistent fever, myalgia, and malaise. On examination, he had a fever (102°F), tachycardia (140 beats/min), and a GCS score of 14/15. The patient was shifted to the ICU with profound thrombocytopenia [Tables 1 and 2]. Baseline investigations were sent [Table 1]. CSF and MRI brain were done. CSF analysis revealed normal WBC with a clear appearance, high protein, and normal glucose levels. Serology confirmed the diagnosis, with thrombocytopenia evident on routine blood workup. GCS dropped on day 2, for which the patient was intubated. MRI brain revealed multiple patchy and confluent asymmetrical areas of signal alteration in bilateral fronto-temporo-parieto-occipital regions and left cerebella hemisphere, midbrain, left superior cerebella peduncle, bilateral ganglio-capsulo-thalamic regions, the body of corpus callosum and centrum semiovale bilaterally with areas of internal haemorrhage, mass effect, and midline shift [Figure 6]. Despite aggressive management, the patient’s clinical course was marked by persistent neurological compromise and he expired on the 12^th day after admission.

Figure 6.

a. T2W showing multiple patchy and confluent asymmetrical areas of signal alteration in bilateral cerebral hemispheres (bilateral fronto-temporo-parieto-occipital regions) and left cerebella hemisphere, midbrain, left superior cerebella peduncle, bilateral ganglio-capsulo-thalamic regions, the body of corpus callosum, corona radiata and centrum semiovale bilaterally with areas of internal haemorrhage, mass effect, and midline shift as described. b. DWI showing corresponding hyperintense lesion. c. T2W showing areas of internal haemorrhage, mass effect, and midline shift

Discussion

DENV (DENV1-4) along with St. Louis encephalitis virus, Japanese encephalitis, West Nile encephalitis virus, tick-borne encephalitis virus, and yellow fever belongs to the family of Flaviviridae known to cause neurotropism. Dengue usually presents with rashes, fever, headache, and haemorrhagic manifestations. Dengue is considered non-neurotropic, but recent trends have shown DENV 2 and 3 to be frequently implicated in causing neurological manifestation. Various theories have been postulated for dengue encephalopathy: 1. Prolonged DHF with fluid extravasation and hyponatremia causing cerebral oedema. 2. Direct invasion of the virus into the central nervous system. 3. Autoimmune reactions and metabolic variations worsening neurological infirmity.[1,2,3,6]

Very few cases of dengue encephalitis have been reported. The main symptoms of dengue encephalitis are headache, focal neurological deficit, altered consciousness, and seizures. Typical symptoms of dengue like myalgias, rash, and bleeding are seen in less than 50% of encephalitis. Although CSF analysis reveals pleocytosis, CSF with normal cellularity can be seen in 75% of cases of dengue encephalitis. In our study, 2 out of 4 patients had a normal CSF cell count. All 4 patients had increased protein with positive dengue serology. None of our patients had the classical features of dengue shock, that is, rashes or hypotension. We also ruled out other possible causes of encephalitis in our patient by appropriate investigations. Our patients satisfied the criteria for dengue encephalitis: 1. fever, 2. acute signs of cerebral involvement, 3. presence of antidengue IgM antibodies in the serum, and 4. exclusion of other causes of viral encephalitis and encephalopathy.

The majority of the patients with dengue encephalitis have normal findings on neuroimaging. MRI in dengue may vary from normal to areas of haemorrhages, oedema, or focal abnormalities involving the cerebrum, basal ganglia, hippocampus, and thalamus. It can also show extensive lesions involving the midbrain, cerebellum, and medial temporal region. MRI brain varied in all 4 patients.

Adequate hydration with intravenous fluids, antipyretics for fever, seizure control with antiepileptic drugs, and transfusion of blood products (if required) form the fundamental treatment. There is no role of antibiotics and antiviral for the treatment of dengue encephalitis, and any if started empirically should be stopped after CSF and serology reports. Raised intracranial pressure can be treated with head elevation, mannitol, and steroids, with regular monitoring of consciousness level. Our patients were managed similarly; nevertheless, the patient in case 4 succumbed to his illness. The prognosis in dengue encephalitis is good, although mortality can range up to 3.7%.[1]

Conclusion

This case series highlights the significance of considering dengue as a possible diagnosis, along with other conditions such as cerebral malaria, scrub, tubercular, herpes encephalitis, and pyogenic meningitis, in a patient with encephalitis, particularly during a dengue epidemic. Although dengue encephalitis is believed to be a mild condition, it can be fatal. A combination of clinical signs and basic investigations such as WBC, PLT, liver enzymes, serology, CSF, and MRI can aid in diagnosis. This series stresses the importance of having a national guideline for managing dengue encephalitis.

Declaration of patient consent

The authors certify that they have obtained all appropriate patient consent forms. In the form the patient (s) has/have given his/her/their consent for his/her/their images and other clinical information to be reported in the journal. The patients understand that their names and initials will not be published and due efforts will be made to conceal their identity, but anonymity cannot be guaranteed.

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Conflicts of interest

There are no conflicts of interest.