Beyond the Usual Features-Expanded Dengue Syndrome in Association With Possible Pre-existing Neurological Disease: A Case Report

Abstract

Dengue virus infection is a significant public health concern, particularly in endemic areas. This case report highlights the difficulties in diagnosing expanded dengue syndrome (EDS) in a dengue-endemic region. This case report emphasizes keeping high suspicion of index for (EDS) among patients presenting with fever and neurological manifestations particularly in regions where dengue is endemic. The atypical neurological symptoms and inconclusive initial investigations underscore the diagnostic challenges associated with (EDS). Prompt recognition and appropriate laboratory testing, such as detecting dengue NS1 antigen, can aid in accurate diagnosis and subsequent management of patients with this condition. Increased awareness among healthcare providers in endemic regions is crucial for timely identification and intervention in case of dengue-associated neurological complications. Therefore, a multidisciplinary approach is required for time-effective management.

Introduction

Dengue fever is a viral disease that is transmitted from the bite of an infected Aedes species mosquito to humans. The condition presents a considerable danger to public health within warm, humid climates favorable for mosquito breeding, notably endemic Pakistan. ¹ Dengue infection typically presents with fever ranging from mildly elevated body temperature to high-grade with manifestations of disrupted hemostasis manifesting as dengue hemorrhagic fever (DHF) and dengue shock syndrome (DSS), which can have significant mortality. ¹ Neurological manifestations of dengue infection are not common but can be life-threatening while causing long-term disability. ² Unusual presentation of (DHF) and (DSS) beyond the usual features is referred to as expanded dengue syndrome (EDS).

We present a case of a 47-year-old Asian female with no known co-morbidities and no history of similar complaints in family from a dengue-endemic area in Pakistan who presented with high-grade fever and generalized tonic-clonic seizure. The patient had associated symptoms such as arthralgia, myalgia, headache, and vomiting. No signification past medical and surgical history was found. No regular use of any medication was reported. Neurological examination revealed altered consciousness level, bilateral papilledema, and spastic paraparesis. Initial investigations, including lumbar puncture and brain imaging, were inconclusive. However, further evaluation revealed positive serum dengue nonstructural protein 1 (NS1) antigen, confirming the diagnosis of (EDS). This case highlights the importance of considering dengue infection as a differential diagnosis in patients presenting with fever and neurological manifestations in dengue-endemic regions.

Case Summary

A 47-year-old Asian female, resident of a dengue-endemic area with no known co-morbidities and no history of similar complaints in family presented with a 3-day history of high-grade fever and generalized tonic-clonic (GTC) seizures. The fever was continuous without chills and was associated with arthralgia, myalgia, headache, and 1 episode of vomiting. The seizures started on the second day of illness and lasted for 10 minutes, followed by postictal drowsiness. The patient’s consciousness level deteriorated progressively after the first seizure episode.

The vital signs were found to be temperature of 38.33°C (101°F), pulse of 105 beats per minute, blood pressure of 124/84 mm Hg, respiratory rate of 25 breaths per minute with a blood oxygen saturation of 97%. On neurological examination, she was drowsy with the consciousness level corresponding to a Glasgow Coma Scale (GCS) of 7/15 (eye 3, verbal 1, and motor 3) with normally reactive pupils of 3 mm, and no gaze palsy. There were no signs of meningism. The motor examination showed asymmetrical weakness with power as 2/5 on the right half and 3/5 on the left half of body. Deep tendon reflexes and extensor plantar response were hyper reflexive in all 4 limbs. Fundoscopy revealed grade I bilateral papilledema. Cerebellar signs were prominent; however, cranial nerves examination was unremarkable.

An urgent non-contrast computerized tomography (NCCT) of her brain ruled out any cerebrovascular event. Cerebrospinal fluid (CSF) analysis was found unremarkable. CSF Gram stain and bacterial culture were negative; a contrast magnetic resonance imaging (MRI) brain showed symmetrical confluent hyperintensity areas in the white matter of both cerebral and cerebellar hemispheres and medial aspect of thalami as shown in Figure 1. T2WI/fluid-attenuated inversion recovery (FLAIR) sequence images showed punctate diffusion restriction foci as shown in Figure 2, however no blooming observed on GRE (gradient echo sequence) or post-contrast enhancement suggesting encephalitis. Electroencephalography (EEG) showed generalized slow waves (moderate cortical dysfunction) with no spike and wave discharges compatible with organic brain disease as shown in Figure 3. Based on medical history and clinical presentation, it was presumed as a case of viral encephalitis.

Figure 1.

T2-weighted brain MR image shows periventricular subcortical white matter hyperintensities (red arrow; a) axial view (b) sagittal view.

Figure 2.

Axial FLAIR sequences reveal white matter hyperintensities involving periventricular subcortical white matter (red arrow).

Figure 3.

Diffuse Theta wave slowing mild to moderate generalized cortical dysfunction.

The patient was started on acyclovir 500 mg 8 hourly intravenously (IV), ceftriaxone 2 g 12 hourly IV, dexamethasone 4 mg 8 hourly IV, and levetiracetam 500 mg 12 hourly IV. She was given supportive care with continuous observation within the neurology intensive care unit.

On day 5 of illness, fever was persistent and a marked rise in serum transaminases corresponding with ultrasonographic evidence of free fluid in the hepatorenal pouch and gallbladder wall edema were noted. The fever pattern over 30 days of hospitalization is shown in Figure 4. At this point, full blood count revealed an elevated packed cell volume (PCV), thrombocytopenia and leukopenia. A workup for alternative diagnosis was considered due to deviating laboratory values from presumptive diagnosis. Thrombocytopenia and the ongoing dengue endemic prompted investigation for dengue fever. Serum dengue nonstructural protein 1 (NS1) antigen was performed, which was positive. Due to the unavailability of the CSF for dengue immunoglobulin M (IgM) antibody and NS1 antigen, they could not be performed. The biofire film array (meningitis panel) for neuroinvasive viruses in the serum was negative on day 7 of the illness. IgM antibodies for varicella, cytomegalovirus, and Epstein–Barr virus performed via ELISA method was negative. Laboratory investigations during illness are mentioned in Table 1.

Figure 4.

Fever pattern during hospitalization.

Table 1.

Significant laboratory investigation values on the fifth day of illness.

Laboratory investigations	Reported values	Normal ranges
Hematocrit	42.2	Female (35-47) Vol %
Hemoglobin	7.6	(11.0-14.5) gm/Dl
M.C.V	81.5	(76-100) Fl
M.C.H	28.0	(27-32) pg
M.C.H.C	34.4	(31-34) gm/Dl
RBC	5.18	Female (3.8-5.2) 10^12/L
TLC	3.7	(4.0-11.0) 3.7 * 10^9/L
Platelet count	70	(150-450) 10^9/L
ESR	30	Female (0-29) mm/h
Pro-BNP	3287	Female 45-54 y (169) pg/ml
CRP	23.7	(<10) mg/L
Total bilirubin	0.86	Adult (0.3-1.2) mg/Dl
Direct bilirubin	0.14	(<0.15) mg/Dl
Indirect bilirubin	0.72	(0.0-1.0) mg/Dl
ALT	135	Female (3-35) U/L
AST	221	Female (10-36) U/L
GGT	290	Female (<38) U/L
Alkaline phosphatase	20	Adult female (<65-240) U/L
Dengue Ns-1 antigen	Positive
CSF protein	113	Female (20-40) mg%
CSF glucose	65	(40-80) mg%
CSF chloride	127	(122-132) mEq/L
CSF gram stain	No organisms seen
CSF microscopy	Cells 5/cmm

Abbreviations: FBC, full blood count; RBC, red blood cell; M.C.V, mean corpuscular volume; M.C.H, mean corpuscular hemoglobin; M.C.H.C, mean corpuscular hemoglobin concentration; TLC, total leukocyte count; mm/h, millimeter per hour; LFT, liver function tests; ALT, alanine transaminase; GGT, gamma glutamyl transferase; CSF, cerebrospinal fluid; mg, milligram; ml, milliliter; m Eq/L, milli equivalent per liter; ft, Femtoliter; pg, picogram U/L, unit per liter; BNP, brain natriuretic peptide.

Monitoring and management were employed in concordance with national guidelines for dengue. The patient had deteriorating GCS and withdrawal seizures despite the escalation of antiseizure medications. Imaging scans were repeated and reviewed by the neurology and radiology team. A diagnosis of para infectious demyelination (PID) secondary to (EDS) was made, with a possibility of a pre-existing undiagnosed neurological condition. Auto encephalitis mosaic 6 turned out negative. Pulse therapy with solumedrol 1 gm IV once a day for 5 days was started, followed by deltacortil in a tapering manner. Her seizures were controlled with midazolam infusion, which was later tapered till she was seizure-free. A repeat EEG showed severe cortical dysfunction with no epileptiform discharges. She continued to deteriorate, therefore, 5 sessions of plasmapheresis were performed every alternate day. The patient developed a grade 3 bedsore. Blood culture showed growth of Klebsiella immediately sensitive to Polymyxin B, which was started immediately. The plan was to start an immunosuppressant, likely cyclophosphamide, but the patient expired on the 30th day of her admission, succumbing to sepsis.

Discussion

Neurological manifestations of dengue infection are uncommon but can be life-threatening. The exact mechanism of dengue virus-induced neurological involvement is not yet fully understood. It is believed to be multifactorial, involving direct viral invasion of the central nervous system (CNS), immune-mediated mechanisms, and metabolic disturbances. ¹ Dengue encephalitis, characterized by the involvement of brain tissue and altered consciousness, is a severe but rare neurological complication of dengue infection. PID refers to a process of demyelination that occurs after an infectious illness. Several cases of PID have been reported after dengue infection. Although PID in this case can also be attributed to a possibility of acute disseminating encephalomyelitis superimposed on dengue infection. This possibility arises due to presentation of neurological symptoms quite early in the course of disease as opposed to what would have been expected in a case of (EDS). Demyelination refers to myelin loss from the myelin sheath, the protective covering of nerve fibers resulting in various neurological symptoms.^3,4 The mechanism by which dengue infection leads to demyelination is unclear. However, it is believed that dengue infection can cause an immune-mediated reaction that leads to damage to the myelin sheath. The prevalence of dengue encephalitis ranges from 0.5% to 6.2%,^3,5 which is worrisome in the dengue endemic and epidemic areas such as the one from where this case is being presented.

In some cases, dengue-associated demyelination can present symptoms like those of multiple sclerosis, such as optic neuritis, transverse myelitis, and other focal neurological deficits. ⁶ Some studies have reported cases of dengue-associated acute disseminated encephalomyelitis, which is a demyelinating disorder characterized by multifocal neurological deficits and encephalopathy. In most cases, the diagnosis is based on clinical presentation and brain imaging, and treatment is primarily supportive, with the use of immunomodulatory therapy in some cases.^6,7

In the presented case, the patient presented with high-grade fever and generalized tonic-clonic seizure, followed by altered consciousness level, bilateral papilledema, and spastic paraparesis. Initial investigations, including lumbar puncture and brain imaging, were inconclusive. However, further evaluation revealed positive serum dengue nonstructural protein 1 (NS1) antigen, confirming the diagnosis of (DES). However, the possibility of patient having an undiagnosed pre-existing neurological condition remains. This highlights the importance of considering dengue infection as a possibility in patients presenting with prominent neurological symptoms, especially in dengue-endemic regions.

Dengue encephalitis is difficult to diagnose since no particular test exists. It is primarily a clinical diagnosis based on clinical presentation as well as exclusion of other differentials. Positive serum dengue NS1 antigen, a sensitive and specific marker for acute dengue infection, validated the diagnosis in the given patient.^8,9 Other diagnostic procedures, such as reverse transcriptase-polymerase chain reaction (RT-PCR) and dengue IgM/IgG antibody testing, can be performed to confirm dengue infection, but their sensitivity and specificity may vary depending on the stage of sickness and the testing facility’s quality.

Treatment for dengue encephalitis/(EDS) is mostly supportive because there is no definitive antiviral drug available for dengue viruses. Close monitoring of vital signs, hydration, and electrolyte balance correction are all critical in treating severe dengue patients, including dengue encephalitis. In case of the patient’s respiratory arrest, the patient may require intubation. To avoid additional morbidity and death, problems such as cerebral edema, seizures, and elevated intracranial pressure must be identified and managed as soon as possible.^10,11

Conclusion

In conclusion, dengue encephalitis is an uncommon but deadly neurological consequence of (EDS). Healthcare practitioners should be aware of this possible consequence, particularly in dengue-endemic areas, and include dengue illness in the differential diagnosis of patients with neurological symptoms. Prompt diagnosis and supportive care are critical in the treatment of (EDS) to avoid additional morbidity and fatality. The case report also stresses on the need for clinical trials and drugs development for the fatal disease such as (EDS).