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 Table of Contents  
CASE REPORT
Year : 2021  |  Volume : 1  |  Issue : 1  |  Page : 21-24

Expanding the phenotype of neurological manifestations of dengue fever: Acute necrotizing encephalopathy


Department of Pediatrics, Pt B D Sharma Postgraduate Institute of Medical Sciences, Rohtak, Haryana, India

Date of Submission07-Oct-2020
Date of Decision15-Oct-2020
Date of Acceptance03-Nov-2020
Date of Web Publication27-Feb-2021

Correspondence Address:
Dr. Arpit Mittal
Department of Pediatrics, Pt B D Sharma Postgraduate Insititute of Medical Sciences, Rohtak - 124 001, Haryana
India
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/ipcares.ipcares_2_21

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  Abstract 


Background: Neurological manifestations following dengue fever are increasingly reported and include encephalopathy, encephalitis, neuro-ophthalmic manifestations or Guillain–Barre syndrome-like presentation. Herein, we expand the clinical spectrum of this neurological repertoire by describing two patients presenting with acute necrotizing encephalopathy of childhood (ANEC) following dengue fever. Clinical Description: Both patients presented with features of acute febrile encephalopathy following an acute febrile illness that proved to be dengue fever. Laboratory investigations revealed thrombocytopenia (patient 1), transaminitis and normal findings on cerebrospinal fluid analysis (patient 1 and 2). Both the patients tested positive for NS1 antigen and dengue serology. Neuroimaging revealed bilateral symmetrical thalamic lesions with cerebellar, midbrain, and cortical white matter lesions suggestive of ANEC. Management: Patient 1 received supportive treatment while patient 2 received pulse methylprednisolone therapy along with supportive treatment. Both the patients had complete clinic-radiological recovery. Conclusion: ANEC following dengue fever may have a relatively benign course, besides the fulminant course that has been described earlier in a single case.

Keywords: Dengue, encephalopathy of childhood, leukoencephalitis, thalamus, transaminases


How to cite this article:
Mittal A, Kumar S, Rana R, Kaushik JS. Expanding the phenotype of neurological manifestations of dengue fever: Acute necrotizing encephalopathy. Indian Pediatr Case Rep 2021;1:21-4

How to cite this URL:
Mittal A, Kumar S, Rana R, Kaushik JS. Expanding the phenotype of neurological manifestations of dengue fever: Acute necrotizing encephalopathy. Indian Pediatr Case Rep [serial online] 2021 [cited 2023 Feb 3];1:21-4. Available from: http://www.ipcares.org/text.asp?2021/1/1/21/310218

Acute necrotizing encephalopathy of childhood (ANEC) is a distinct clinicoradiological entity seen almost exclusively in infants or young children. Clinically, it presents with a sudden onset of encephalopathy, seizures, signs, and symptoms of raised intracranial pressure (ICP), extrapyramidal symptoms, liver dysfunction, and rapid clinical deterioration.[1] ANEC is usually preceded by respiratory tract or gastrointestinal infections.[2] It is characterized by multiple bilateral brain lesions that usually involves the thalamus, but may also involve the brainstem, cerebellum, or internal capsule. Characteristic abnormalities on magnetic resonance imaging (MRI) are hyperintensities in T2-weighted imaging, hypointensities in T1-weighted imaging, diffusion restriction on diffusion-weighted imaging, and central hemorrhagic foci on susceptibility weighted imaging.[3] Additional laboratory findings include elevated transaminase levels and raised cerebrospinal fluid (CSF) proteins.

Neurological manifestations of dengue are increasingly being recognized. These include encephalopathy, encephalitis, myelitis, myositis, Guillain–Barre syndrome and mononeuropathies.[4] ANEC following dengue fever has been reported once earlier.[5] In contrast to the previously reported case, we present two cases of ANEC that developed after dengue fever and demonstrated complete clinicoradiological recovery.


  Clinical description Top


A 12-year-girl presented with fever and vomiting for 5 days, with abnormal behavior for the past 2 days. The fever was high grade and was associated with chills and rigors. Behavioral manifestations appeared on the 3rd day of illness. Despite being alert, her eye contact was poor and she was unable to speak, though she occasionally followed verbal commands and could indicate her needs by gestures. There was no history of headache, blurring of vision, altered sensorium, or seizures. The illness was not preceded by any rash, diarrhea, or bleeding from any site. Past history, family history, immunization status, personal, and social history were not contributory. Her vital parameters were within age norms. General physical examination was unremarkable with absence of pallor, rash, icterus, or lymphadenopathy. There were no signs of focal neurological deficits, cranial nerve palsies, increased ICP, or meningeal signs. Fundus, motor, and sensory examination was normal. The rest of the systemic examination was unremarkable. The possibility of acute febrile encephalopathy with differentials of viral encephalitis, cerebral malaria, pyogenic meningitis, and enteric encephalopathy was considered. Severe dengue was also thought of because of the season and index cases in the community. The patient was started on ceftriaxone (100 mg/kg/day), vancomycin (60 mg/kg/day), and acyclovir (60 mg/kg/day) along with artesunate (2.4 mg/kg/day).

Management and Outcome

Initial laboratory work-up revealed hemoglobin level of 13 g/dl with hematocrit of 40%, total leukocyte count (TLC) 5200 cells/cmm with 72% polymorphs, and thrombocytopenia (platelet count 1.0 lakh/cmm). Malaria was excluded by peripheral smear and rapid malarial test didnot reveal any malarial parasite. Serum glucose, electrolytes, and renal function levels were normal. Serum aminotransferases were elevated (alanine aminotransferase [ALT]-380U/L, aspartate aminotransferase [AST]-340 U/L), while other liver function parameters and coagulation profile were normal. C-reactive protein was negative. Dengue NS1 antigen and dengue serology (IgM) were positive. Widal titers TO/TH were <1:40. CSF examination was acellular with normal proteins (38 mg/dl) and sugar (66 mg/dl) levels and sterile culture. In view of altered behavior, a MRI brain was planned. This revealed T2-hyperintensities involving right cerebellum, dorsal brainstem, and bilateral thalamus. With central hemorrhage [Figure 1]a and [Figure 1]b. These findings suggestive of demyelination (acute necrotizing encephalitis) in association with the transaminitis led us to make a diagnosis of severe dengue with ANEC. The patient improved dramatically within 48 h of admission with normalization of behavior, speech, aminotransferases, and platelet count. Since there were no poor prognostic factors and dramatical improvement, steroids were not considered. She remained asymptomatic at 3-month follow-up, wherein repeat neuroimaging revealed complete resolution of radiological abnormalities.
Figure 1: Magnetic resonance imaging brain T2 axial images showing right-sided cerebellar, dorsal brainstem (a) and bilateral symmetrical thalamic lesions with central hemorrhage (b) in Patient 1

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  Clinical description Top


A 10-year-old boy presented with fever, headache, and vomiting for 5 days, followed by multiple right-sided focal seizures and altered level of consciousness for a day. There were no preceding diarrheal illness, rashes, or bleeding from any site. There was no past or family history of similar episodes. Remaining histories were unremarkable. Vital parameters included tachycardia (heart rate 130/min), respiratory rate of 38/min but rapid and deep in character (Kussmaul's respiration), normal blood pressure (108/68 mmHg), but cold extremities. Maculopapular erythematous blanchable macules were seen over bilateral lower limbs. Pallor, icterus, or lymphadenopathy was absent. Salient neurological findings were minimal conscious state without any cranial nerve palsies, normal fundus, right-sided hemiparesis with exaggerated reflexes and extensor plantar reflex and terminal neck rigidity. Remaining systemic examination was noncontributory. Considering a clinical phenotype of acute febrile encephalopathy (viral encephalitis or pyogenic meningitis) with complications (increased ICP), he was started on intravenous fluids, broad-spectrum antibiotics, acyclovir, antiepileptic drugs and hypertonic saline. Investigations were planned accordingly.

Management and Outcomes

Preliminary investigations revealed hemoglobin 12.2 gm%, hematocrit 43.6%, TLC 3800/mm3 with 65% polymorphs and platelet count 2.0 lac/mm3. Renal functions, serum electrolytes, and glucose levels were normal. Liver function test revealed elevated transaminases (AST-2470 U/L, ALT-3090 U/L) with normal bilirubin, albumin, and coagulation profile. Both Dengue NS1 antigen as well as dengue serology (IgM) was positive. CSF cytology, biochemistry, and cultures were normal, and viral markers (Japanese encephalitis, enterovirus, HSV, influenza) and tuberculosis (TB) polymerase chain reaction were negative. MRI Brain revealed symmetrical thalamic and cerebral white matter T2-hyperintensities [Figure 2]a and [Figure 2]b suggestive of ANEC. A final diagnosis of severe dengue with ANEC was kept. The patient was started on pulse methylprednisolone (30 mg/kg/day for 5 days) therapy on day 2. There was gradual improvement in the sensorium over 7 days. At the time of discharge, he had residual subtle hemiparesis that resolved completely along with radiological resolution of lesion at 3-month follow-up.
Figure 2: Magnetic resonance imaging brain T2 images of patient 2 reveal bilateral white matter signal changes in centrum semiovale (a) along with bilateral thalamic lesions (b)

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  Discussion Top


ANEC is a fatal clinical condition among infants and young children that is presumed to follow infections by Mycoplasma, influenza, herpes simplex virus, human herpes virus-6, and parvovirus B19.[3],[6] Familial or recurrent cases of ANEC have been reported that are associated with missense mutation in the gene encoding RAN Binding Protein 2.[7]

The exact pathogenesis remains nebulous, though it is hypothesized to be associated with an immune mediated reaction. Viral infection triggers a cytokine storm with elevated levels of tumor necrosis factor-alpha and interleukin-6. Till date, there is no specific treatment of ANEC and it has been associated with dismal prognosis, with <10% patients having complete recovery. Poor prognostic factors include advanced neurological signs such as decorticate/decerebrate posturing or long tract signs. Factors associated with a better prognosis are low transaminase levels, low CSF proteins, asymmetrical thalamic lesions, and/or absence of brainstem lesion.[8] Steroids given early in the course of illness have demonstrated improved survival among children with ANEC, postulated to be suppression of the uncontrolled cytokine release.[9] Pulse methylprednisolone is commenced after ruling out latent TB (negative Mantoux test at 48–72 h) and normal CSF. Pulse methylprednisolone had been deferred in the first case considering the remarkable improvement within 48 h. In contrast, pulse steroids were indicated in the second patient to which a good response was seen.

ANEC following dengue fever is rare. A previously reported case of a 15-year-old girl, who presented with altered consciousness and multiple seizures following an acute febrile illness, was diagnosed as ANEC with dengue fever based on characteristic MRI findings and transaminitis. She had an aggressive clinical course and succumbed to the illness despite pulse steroids and intravenous immunoglobulin on day-3 of admission.[5] [Table 1] compares the clinical presentation of all three cases.
Table 1: Comparison of clinical features, management, and outcomes of three children with acute necrotizing encephalopathy of childhood associated with dengue fever

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The present report highlights two cases of ANEC associated with dengue fever who had a benign disease course. In contrast to the classical presentation of ANEC, these children had complete radiological and neurological recovery. The present report emphasizes the addition of ANEC to the existing spectrum of neurological manifestations of dengue fever. ANEC should be considered as a differential in patients with acute febrile encephalopathy in whom other causes are excluded and dengue testing is positive. Typical MRI findings and transaminitis can help to identify ANEC. The role of steroids, immunotherapy, other immunomodulating agents, and plasmapheresis is still uncertain and requires further supportive evidence, before it can be considered recommended therapy.

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.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.

 
  References Top

1.
Wu X, Wu W, Pan W, et al. Acute necrotizing encephalopathy: An underrecognized clinicoradiologic disorder. Mediators Inflamm 2015;2015:792578.  Back to cited text no. 1
    
2.
Wang GF, Li W, Li K. Acute encephalopathy and encephalitis caused by influenza virus infection. Curr Opin Neurol 2010;23:305-11.  Back to cited text no. 2
    
3.
Biswas A, Varman M, Gunturi A, et al. Teaching NeuroImages: Acute necrotizing encephalopathy of childhood: Neuroimaging findings. Neurology 2018;90:e177-8.  Back to cited text no. 3
    
4.
Li GH, Ning ZJ, Liu YM, et al. Neurological manifestations of dengue infection. Front Cell Infect Microbiol 2017;7:449.  Back to cited text no. 4
    
5.
Abbas Q, Jafri SK, Ishaque S, et al. Acute necrotizing encephalopathy of childhood secondary to dengue infection: A case report from Pakistan. J Pediatr Neurosci 2017;12:165-7.  Back to cited text no. 5
[PUBMED]  [Full text]  
6.
Mittal A, Kuntar S, Vaswani ND, et al. Acute necrotizing encephalopathy of childhood associated with human parvovirus B19 infection. Indian J Pediatr 2020;87:648-9.  Back to cited text no. 6
    
7.
Sell K, Storch K, Hahn G, et al. Variable clinical course in acute necrotizing encephalopathy and identification of a novel RANBP2 mutation. Brain Dev 2016;38:777-80.  Back to cited text no. 7
    
8.
Mastroyianni SD, Gionnis D, Voudris K, et al. Acute necrotizing encephalopathy of childhood in non-Asian patients: Report of three cases and literature review. J Child Neurol 2006;21:872-9.  Back to cited text no. 8
    
9.
Kansagra SM, Gallentine WB. Cytokine storm of acute necrotizing encephalopathy. Pediatr Neurol 2011;45:400-2.  Back to cited text no. 9
    


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