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Table of Contents    
CASE REPORT
Year : 2021  |  Volume : 69  |  Issue : 2  |  Page : 490-492

Acute Necrotizing Encephalopathy as a Complication of Chikungunya Infection


1 Department of Neurology, National Institute of Mental Health and Neurosciences (NIMHANS) Bengaluru, Karnataka, India
2 Department of Neuroimaging and Interventional Neuroradiology (NIIR), National Institute of Mental Health and Neurosciences (NIMHANS) Bengaluru, Karnataka, India

Date of Submission18-Feb-2020
Date of Decision25-Feb-2020
Date of Acceptance25-Jun-2020
Date of Web Publication24-Apr-2021

Correspondence Address:
Dr. M Netravathi
Department of Neurology, National Institute of Mental Health and Neurosciences (NIMHANS) Hosur Road, Bangalore - 560 029, Karnataka
India
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/0028-3886.314525

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 » Abstract 


Background: Acute necrotizing encephalopathy (ANE) is a rapidly progressive encephalopathy seen commonly in children triggered by various prodromal viral infections, most common being influenza virus and Human herpes virus-6.
Objective: We report two rare cases of ANE preceded by Chikungunya infection.
Cases: A 13-year old girl presented with a three-day history of headache, fever, seizures, and altered sensorium. Another 42-year old man presented with two days history of fever and altered sensorium. Both were suspected to have viral encephalitis. Evaluation revealed serum positivity for Chikungunya virus. In both cases, diagnosis was clinched by characteristic bilateral symmetrical thalamic lesions with central necrosis and hemorrhage along with lesions in cerebral white matter, brainstem, and cerebellum.
Conclusions: ANE is reported to have high morbidity and mortality. To the best of our knowledge, this is the first report of ANE post-Chikungunya infection. Apart from being rare etiologically, the patients had excellent response to steroids.


Keywords: Acute necrotizing encephalopathy, ANE, Chikungunya, trilaminar pattern
Key Messages: Acute necrotizing encephalopathy (ANE), a rapidly progressive encephalopathy commonly seen in children triggered by various prodromal viral infections. Prompt recognition by typical MRI features helps in diagnosis.


How to cite this article:
Holla V V, Gohel AB, Kartik N, Netravathi M. Acute Necrotizing Encephalopathy as a Complication of Chikungunya Infection. Neurol India 2021;69:490-2

How to cite this URL:
Holla V V, Gohel AB, Kartik N, Netravathi M. Acute Necrotizing Encephalopathy as a Complication of Chikungunya Infection. Neurol India [serial online] 2021 [cited 2021 May 9];69:490-2. Available from: https://www.neurologyindia.com/text.asp?2021/69/2/490/314525




Acute necrotizing encephalopathy (ANE) is a rare, rapidly progressive encephalopathy observed predominantly in children with characteristic imaging finding of bilateral, symmetrical necrotic lesion of thalami and other brain regions.[1] Most cases are parainfectious triggered after viral infection including influenza-A, influenza-B, parainfluenza, varicella, herpes simplex virus, human herpesvirus-6 (HHV-6), HHV-7, enterovirus, rotavirus, measles, rubella, coxsackie-A9, and dengue virus with influenza virus and HHV-6 being most common.[2],[3] Till date there is no case to our knowledge of ANE secondary to chikungunya infection. We report two cases with ANE after chikungunya infection who had good clinical response to steroids.


 » Case Report Top


Case 1

A 13-year-old girl presented with one-week history of myalgia, arthralgia followed by high-grade fever, headache, and three episodes of left focal seizures with secondary generalization and altered sensorium of three days duration. Patient was drowsy with reduced interaction, incontinent, and not indicating her needs when she presented to emergency. There was no history suggestive of perceptual abnormality, visual, auditory, bulbar, motor, or cerebellar abnormality. Parents denied any history of rash, bleeding tendency, respiratory, or cardiac symptoms prior to onset. On examination, the patient was drowsy, mute, opening eyes, and localizing to pain with meningeal signs. Fundus and pupillary response was normal with normal examination of other cranial nerves. There were no signs of motor or sensory system involvement with normal tone, symmetrical limb movement against gravity, normal deep tendon reflex, and flexor plantar response. Other system examination was also normal.

Based on the clinical presentations, a provisional diagnosis of acute encephalitis was made and evaluated. Routine blood investigations revealed mild anemia (11.7 g/dl), leukocytosis (12,500 cells/μl) with elevated alanine aminotransferase (121 U/L), and aspartate aminotransferase (192 U/L) with normal renal parameters and serum electrolytes. Cerebrospinal fluid analysis showed elevated protein (172 mg/dl) with normal glucose and nil cells. CSF was positive for chikungunya viral RNA by real time PCR.

Magnetic resonance imaging (MRI) of brain revealed bilateral thalamic T1 hypointense, T2 hyperintense, diffusion restricting lesions with central hemorrhagic necrosis along with T2 hyperintensity with diffusion restriction of bilateral medial temporal lobes, corona radiata, centrum semiovale, and cerebellar white matter [Figure 1]. Based on characteristic clinical, radiological, blood and CSF pictures, a diagnosis of acute necrotizing encephalopathy of childhood secondary to chikungunya infection was made. The patient was managed with five days of daily 700 mg intravenous methyl prednisolone, levetiracetam, and other supportive medication. Low-dose levodopa/carbidopa (50/5 mg thrice daily) and modafinil (200 mg per day) were added in view of poor alertness. At discharge (10th day), the patient had improved to spontaneous eye opening, verbalizing, ambulant with one-person support, continent, and indicating her needs with the normalization of deranged blood parameters. She was discharged on oral levetiracetam, levodopa, and modafinil along with 30 mg prednisolone. At one-month follow-up, she was completely independent with no neurological deficits and had returned to school.
Figure 1: The 13-year old girl (Case 1) (A-L) Plain CT (A) and MRI brain T1 (B), T2 (C), FLAIR (D), DWI (E), ADC (F), SWI (G), T1 Contrast (H) imaging of the patient showing bilateral thalamic lesion with central necrosis and haemorrhage, cytotoxic edema with surrounding vasogenic edema and contrast uptake in centre of lesion (H). Trilaminar pattern in ADC (F) can be seen with central high ADC value, middle low ADC value suggesting cytotoxic oedema with peripheral high ADC suggesting vasogenic oedema. Symmetrical FLAIR hyperintense lesions can also be seen in cerebellar (I) and temporal region (K) with diffusion restriction in these areas (J, L). Figures of the 42-year old gentleman (Case 2) (M-P) MRI brain T2 FLAIR (M), DWI (N), ADC (O), SWI (P) imaging of the patient showing typical bilateral thalamic lesion with central necrosis and haemorrhage along with trilaminar pattern in ADC (O)

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Case 2

A 42-year-old man presented with a two-day history of high-grade fever and altered sensorium. There were no other neurological or systemic symptoms. On examination patient was drowsy, mute, opening eyes spontaneously, and localizing to pain with terminal neck stiffness. Fundus and pupillary response were normal. Patient had complete supranuclear gaze palsy with restricted doll's eye movement in horizontal gaze and ocular bobbing with bifacial weakness and dysphagia. There was spasticity of all four limbs, spontaneous limb movements with brisk deep tendon reflexes, and withdrawal plantars.

Routine blood investigations revealed leukocytosis (13,100 cells/μl) with elevated alanine aminotransferase (144 U/L), aspartate aminotransferase (331 U/L), blood urea (66 mg/dl), serum creatinine (2.0 mg/dl) and normal serum electrolytes. Cerebrospinal fluid analysis showed elevated protein (188.5 mg/dl) with normal glucose and nil cells. IgM antibodies against chikungunya virus was positive in serum.

MRI of brain showed bilateral thalamic T2 hyperintense, T1 hypointense, diffusion restricting necrotising lesions with central hemorrhage along with T2 hyperintensity of bilateral medial temporal lobes, brainstem tegmentum, and cerebellar white matter in these areas [Figure 2]. There was no contrast uptake in the lesions. Diagnosis of acute necrotizing encephalopathy, probably secondary to chikungunya infection was made based on MRI and blood reports. Patient was managed with five days of intravenous methyl prednisolone followed by oral steroid. At two weeks, patient sensorium had improved, extraocular movements were full, was able to speak and swallow, ambulant with one-person support, continent, and indicating his needs with normalization of deranged blood parameters. He was discharged on 40 mg prednisolone.{Figure 2}


 » Discussion Top


Acute necrotizing encephalopathy was first proposed by Mizuguchi et al. in 1995 with 13 cases.[4] It is a rapidly progressive encephalopathy initially reported in South Asia region but later observed globally. Although viral infections play an important role in triggering ANE, genetic predisposition is noted especially in familial and recurrent cases.[5] The development of ANE is considered independent of the infectious agents with all having similar clinical, biochemical, and radiological pictures.[2] The exact pathogenesis of ANE is still not clear. The most prevalent hypothesis is the increased cytokine levels causing “cytokine storm” resulting in brain injury by altering vessel wall permeability without vessel wall disruption or inflammation; shock, liver dysfunction, acute renal failure, and disseminated intravascular coagulation.[6] ANE is not considered inflammatory encephalitis due to the minimal inflammation in histopathological studies compared to marked necrosis and also the absence of CSF pleocytosis in most cases. Genetic predisposition has been noted especially in familial and recurrent cases. Ran Binding Protein-2 (RANBP2) is one such gene, missense mutations predispose to ANE in autosomal dominant pattern with incomplete penetrance with some cases occurring without infectious trigger.[5]

Bilateral, symmetrical brain lesions involving thalamus, brainstem, cerebrum, and cerebellum affecting both grey and white matter with necrosis and hemorrhage is the characteristic feature of ANE.[1] Thalamus is involved in most of the cases along with involvement of brainstem, cerebral, and cerebellar white matter. The pattern of thalamic involvement is the hallmark of ANE aiding in clinching the diagnosis.[1] The trilaminar pattern is the hallmark pattern of involvement which is best seen in apparent diffusion coefficient image with higher than normal ADC values at the center of lesion due to hemorrhage, surrounded by low ADC values at the peripheral portion of central lesions suggesting cytotoxic edema with very high ADC value at the outermost region suggesting vasogenic edema.[1] Gradient echo imaging show blooming in central of lesion with surrounding hyperintensity of swollen thalami. Similar pattern has been described in dengue encephalitis as double doughnuts sign by Kumar et al.[7] Other areas of cerebellar and brainstem are also affected in ANE which may suggest that the case described by Kumar et al. and others as double doughnuts sign in dengue may actually be cases of ANE secondary to dengue infection. ANE due to genetic causes may have atypical radiological involvement with additional MRI changes in medial temporal lobes, external capsule, claustrum, insular cortices, hippocampi, amygdala, mammillary and spinal cord with some cases without thalamic involvement.[2],[8] Bilateral medial temporal involvement in our case suggested the possibility of genetic predisposition in our case, but genetic analysis for RANBP2 gene analysis was normal in case 1.

ANE carries significant morbidity and mortality with long-term sequelae usually observed in children less than four years, or when they present with shock, thrombocytopenia, brainstem lesions, hemorrhage, and cavitation.[9],[10] Early steroid treatment is associated with better prognosis while gammaglobulin treatment does not show any benefit.[11]

In conclusion, ANE can be triggered by chikungunya virus apart from other various viral infections. The hallmark trilaminar pattern of involvement helps in the diagnosis of ANE. Prompt recognition of characteristic imaging patterns in a patient with acute encephalopathy is crucial for early diagnosis as they have favorable long-term prognosis with steroids.

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.
Albayram S, Bilgi Z, Selcuk H, Selcuk D, Cam H, Koçer N, et al. Diffusion-weighted MR imaging findings of acute necrotizing encephalopathy. Am J Neuroradiol 2004;25:792-7.  Back to cited text no. 1
    
2.
Wu X, Wu W, Pan W, Wu L, Liu K, Zhang H-L. Acute necrotizing encephalopathy: An underrecognized clinicoradiologic disorder. Mediators Inflamm 2015;2015:792578.  Back to cited text no. 2
    
3.
Abbas Q, Jafri S, Ishaque S, Jamil M. Acute necrotizing encephalopathy of childhood secondary to dengue infection: A case report from Pakistan. J Pediatr Neurosci 2017;12:165.  Back to cited text no. 3
[PUBMED]  [Full text]  
4.
Mizuguchi M, Abe J, Mikkaichi K, Noma S, Yoshida K, Yamanaka T, et al. Acute necrotising encephalopathy of childhood: A new syndrome presenting with multifocal, symmetric brain lesions. J Neurol Neurosurg Psychiatry 1995;58:555-61.  Back to cited text no. 4
    
5.
Neilson DE, Adams MD, Orr CMD, Schelling DK, Eiben RM, Kerr DS, et al. Infection-triggered familial or recurrent cases of acute necrotizing encephalopathy caused by mutations in a component of the nuclear pore, RANBP2. Am J Hum Genet 2009;84:44-51.  Back to cited text no. 5
    
6.
Kansagra SM, Gallentine WB. Cytokine storm of acute necrotizing encephalopathy. Pediatr Neurol 2011;45:400-2.  Back to cited text no. 6
    
7.
Kumar A, Mehta S, Singh P, Lal V. Dengue encephalitis: “Double doughnut” sign. Neurol India 2017;65:670.  Back to cited text no. 7
[PUBMED]  [Full text]  
8.
Singh RR, Sedani S, Lim M, Wassmer E, Absoud M. RANBP2 mutation and acute necrotizing encephalopathy: 2 cases and a literature review of the expanding clinico-radiological phenotype. Eur J Paediatr Neurol 2015;19:106-13.  Back to cited text no. 8
    
9.
Yamamoto H, Okumura A, Natsume J, Kojima S, Mizuguchi M. A severity score for acute necrotizing encephalopathy. Brain Dev 2015;37:322-7.  Back to cited text no. 9
    
10.
Wong AM, Simon EM, Zimmerman RA, Wang HS, Toh CH, Ng SH. Acute necrotizing encephalopathy of childhood: Correlation of MR findings and clinical outcome. AJNR Am J Neuroradiol 2006;27:1919-23.  Back to cited text no. 10
    
11.
Okumura A, Mizuguchi M, Kidokoro H, Tanaka M, Abe S, Hosoya M, et al. Outcome of acute necrotizing encephalopathy in relation to treatment with corticosteroids and gammaglobulin. Brain Dev 2009;31:221-7.  Back to cited text no. 11
    


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