Hong Kong J Radiol. 2020;23:285-8 | https://doi.org/10.12809/hkjr2017177

CASE REPORT

Imaging Findings and Clinical Perspectives of Acute Necrotising : Report of Two Cases HL Wong, HY Lau, JCW Siu Department of Radiology, Tuen Mun Hospital, Tuen Mun, Hong Kong

INTRODUCTION contrast magnetic resonance imaging (MRI) revealed First coined by Mizuguchi1 in 1997, acute necrotising symmetrical T2 and fluid attenuated inversion recovery encephalopathy (ANE) is a severe, uncommon type of hyperintensities with restricted diffusion over bilateral encephalopathy with distinctive imaging and clinical thalami, white matter, and brain stem (Figure 1a-c). features and a global distribution. Despite ongoing Bilateral thalami were markedly swollen with central studies, the exact pathogenesis of ANE is yet to be hypo-enhancement (Figure 1d). Features were suggestive determined and is still classified as an idiopathic disorder. of ANE. It is hypothesised that the disease is an immune response to a prior, mostly viral, infection. With two illustrative The patient was started on intravenous pulse steroid cases, we showcase the current understanding of the but his neurological condition deteriorated rapidly. A pathogenesis, clinical and radiological presentation of follow-up computed tomography (CT) scan of the brain the disease as well as the latest treatment strategies. showed diffuse cerebral oedema with effacement of bilateral cerebral sulci and cisterns. Evidence of coning CASE 1 was also observed. An urgent bilateral craniotomy and A 2-year-old boy with good past health developed fever decompression were performed. Despite the surgical and upper respiratory symptoms for 1 day. His symptoms management, the patient’s condition remained poor. deteriorated overnight and he developed generalised Neurologically, the patient showed minimal brain . He was then urgently admitted to the Accident stem response and scored 4 (E1V1M2) in the Glasgow and Emergency Department where the seizure was Coma Scale. On day 5 after admission, the patient aborted with anticonvulsant therapy. He was transferred succumbed. to the paediatric intensive care unit for further care. CASE 2 A nasopharyngeal swab for rapid antigen test was A 6-year-old boy with good past health presented with positive for influenza A. Despite empirical treatment high fever, upper respiratory symptoms and transient with vancomycin, rocephin, acyclovir, and oseltamivir, episodes of confusion. An urgent CT scan of the brain the patient developed breakthrough seizure. An urgent performed on admission revealed no abnormality. A

Correspondence: Dr HL Wong, Department of Radiology, Tuen Mun Hospital, Tuen Mun, Hong Kong Email: [email protected]

Submitted: 2 Dec 2019; Accepted: 10 Dec 2019

Contributors: JCWS designed the study. HLW acquired and analysed the data, and drafted the manuscript. JCWS and HYL critically revised the manuscript for important intellectual content.

Conflicts of Interest: All authors have disclosed no conflicts of interest.

Funding/Support: This case report received no specific grant from any funding agency in the public, commercial, or not-for-profit sectors.

Ethics Approval: The patients were treated in accordance with the tenets of the Declaration of Helsinki. The patients provided written informed consent for all treatments and procedures.

© 2020 Hong Kong College of Radiologists. CC BY-NC-ND 4.0 285 Acute Necrotising Encephalopathy in Hong Kong

(a) (b) (c) (d)

Figure 1. A 2-year-old boy with acute necrotising encephalopathy. T2-weighted axial image showing abnormal hyperintensities at (a) bilateral cerebral white matter, (b) bilateral thalami, and (c) brain stem. (d) T1-weighted axial post-contrast image showing bilateral thalamic symmetrical hypoenhancing .

(a) (b) (c) (d)

Figure 2. A 6-year-old boy with acute necrotising encephalopathy. T2-weighted axial image showing hyperintensities and swelling at (a) bilateral cerebral white matter, (b) bilateral thalami, and (c) brain stem. (d) T1-weighted inversion recovery sagittal image showing significant swelling at the and with kinking of the cervicomedullary junction.

rapid antigen test on nasopharyngeal swab was positive DISCUSSION for influenza A. Pathogenesis and Aetiology of Acute Necrotising Encephalopathy The patient’s level of consciousness deteriorated rapidly: The most widely accepted cause of ANE is Glasgow Coma Scale score dropped from 15 to 4 over 7 hypercytokinaemia.2 Patients with ANE mount hours. MRI performed 12 hours after admission revealed an exaggerated immune response to infection by bilateral symmetrical T2 hyperintensities in the thalamus releasing a high level of cytokines. There is evidence and brain stem (Figure 2a and b). Associated bilateral that the level of various inflammatory mediators, cerebral and cerebellar white matter hyperintensities including different interleukins (IL-6, IL-15, IL-1β, were also observed (Figure 2c). Features were suggestive IL-10), tumour factor-α as well as interferon-γ,2-4 of ANE. There was significant swelling at the thalamus is raised in the serum as well as the . and brain stem with kinking of the cervicomedullary This causes multiple system failure.1 junction (Figure 2d). Crowding of the foramen magnum was evident. Both environmental and host factors seem to play a role in a predisposition to ANE. A neurosurgical opinion was sought and the boy was deemed too ill to benefit from surgery. He remained A number of different infections are associated with comatose with no obvious return of any brainstem ANE and different pathogens have been reported, function despite all medical support. The patient was including viruses and bacteria.2,5 Influenza virus is the certified dead on day 12 after admission. most common culprit.

286 Hong Kong J Radiol. 2020;23:285-8 HL Wong, HY Lau, JCW Siu

There have been some recurrent cases reported within the lesions will have a low T1 signal and high T2 signal. certain families, suggesting a genetic predisposition.5 There will also be fluid restriction on diffusion-weighted In recurrent cases, missense in Ran-binding imaging and apparent diffusion coefficient.5 protein 2 were identified as the susceptibility alleles.5 As the disease progresses, imaging features change. Clinical Presentation of Acute Necrotising Oedema will subside and features of petechial Encephalopathy haemorrhage and necrosis may appear. On CT, this will In general, the clinical presentation of ANE can be appear as new heterogeneous hyperdense foci within the classified into three stages: the prodromal stage, the previously seen hypodensities.1,5 On MRI T1-weighted acute encephalopathy stage, and the recovery stage. image, there will be new hyperintensities within the pre-existing hypointense lesions, while on T2-weighted The presentation in the prodromal stage is highly image they will show up as a hypointense centre variable, due to the wide range of antecedent pathogens surrounded by a high signal rim.5 Susceptibility weight possible. Symptoms may include fever, upper respiratory images and T2* gradient echo imaging are more able symptoms, gastroenteritis, or skin rashes. Patients with to show the petechial haemorrhage that will appear as ANE may also present with more severe symptoms low signal foci with blooming artefact.5 The classically including shock, disseminated intravascular coagulation described ANE imaging features of concentric structures, and even multiple organ failure.5 tricolour pattern, or target-like appearance can be seen on apparent diffusion coefficient images. The centre As the disease progresses, the acute encephalopathy of the shows high signal with a hypointense rim stage ensues during which neurological symptoms suggesting cytotoxic oedema. A further outer rim of will manifest rapidly. , an altered level of hyperintensity suggests vasogenic oedema.5,6 consciousness and focal neurological deficits may occur. The patient usually requires intensive care With specific imaging features of ANE and a rapid support. neurological decline, the imaging differential diagnoses of ANE are limited. Entities that need to be considered Although majority of the cases result in high morbidity include acute disseminated , Reye’s and mortality, milder forms with recovery have also syndrome and Leigh’s syndrome. Acute disseminated been reported.5 encephalomyelitis is associated with multiple bilateral brain lesions bilaterally. Nonetheless the lesions do Radiological Findings and Imaging not typically affect the brain symmetrically as in ANE. Differential Diagnoses of Acute Necrotising Although Reye’s syndrome and Leigh’s syndrome may Encephalopathy present with symmetrical brain lesions, both entities are Contrary to the highly non-specific clinical presentations, characterised by the presence of . imaging features of ANE can usually help to narrow down the differential diagnosis.5 The list of differential In both of our cases, the later imaging features were diagnoses is limited when rapid neurological deterioration not well demonstrated due to the rapid clinical course. is taken into account. Unfortunately both patients succumbed before follow- up imaging was available. However, the typical early The typical imaging presentation of ANE is multiple imaging features of ANE were well demonstrated. symmetrical lesions with supra- and infra-tentorial brain involvement. The thalami, brain stem, cerebral white Diagnostic Criteria of Acute Necrotising matter, and cerebellum1,2 are typical sites of involvement. Encephalopathy involvement is also occasionally reported.5 Diagnosis of ANE is made if both clinical and imaging Among them, bilateral thalami involvement is the most findings are present and when similar-presenting distinctive feature of ANE.1 diseases have been excluded. Mizuguchi1 have outlined the diagnostic criteria (Table). It is also common for imaging features of ANE to change over the clinical course.1,5 Significant oedema is seen Management and Prognosis of Acute in the early phase. On CT, the lesions will show up as Necrotising Encephalopathy symmetrical hypodense foci with mass effect. On MRI, There is no definitive recommended treatment for

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Table. Proposed diagnostic criteria for acute necrotising Therapeutic hypothermia has also been mentioned as a by Mizuguchi.1 supportive treatment.5 1. Acute encephalopathy present with rapid consciousness deterioration and convulsion followed by a viral febrile illness 2. Elevated protein level without increase in lymphocyte count in Despite treatment, ANE has a grave prognosis. The cerebrospinal fluid mortality rate is reported to be about 30%. Complete 3. Elevation of serum aminotransferase level without neurological recovery is observed in fewer than 10% increase ammonia level 4. Neurological findings compatible with bilateral thalami, cerebral of patients and many survivors develop long-term periventricular white matter, internal capsule, putamen, upper neurological sequelae.1,5 brain stem tegmentum, and cerebellar medulla involvement Exclusion of similar illness A. Clinical CONCLUSION • Toxic shock syndrome Acute necrotising encephalitis is a severe neurological • Haemolytic uraemic syndrome complication of a common infection. The exact • pathogenesis is incompletely understood. The prognosis • Haemorrhagic shock • Heat of ANE is generally poor, although recent studies have B. Imaging shown that starting treatment early may have a great • Leigh encephalopathy impact on the final outcome. Prompt diagnosis is vital to • Glutaric acidaemia • Methyl malonic aciduria ensure early treatment. The diagnosis of ANE is mainly • Infantile bilateral striatal necrosis based on clinical and radiological features after exclusion • of other diseases with similar presentation. • Acute disseminated encephalomyelitis • Acute haemorrhagic leukoencephalitis • Severe hypoxia The two cases we describe had typical imaging findings • Toxins resulting in symmetric bilateral necrosis, and clinical presentation. One important limitation of our including: case sharing is a lack of radio-pathological correlation.  Carbon monoxide, methanol  1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine In both patients, the cause of death was stated as ANE  Cyanide and autopsy was waived in the absence of any other  Manfanese, carbon disulphide suspected cause.  Tegretol • Other diseases with symmetric bilateral basal ganglia involvement, including: REFERENCES  Osmotic myelinolysis 1. Mizuguchi M. Acute necrotizing encephalopathy of childhood: a  Canavan disease novel form of acute encephalopathy prevalent in Japan and Taiwan.  Methylmalonic acidaemia Brain Dev. 1997;19:81-92.  Wilson disease 2. Munakata M, Kato R, Yokoyama H, Haginoya K, Tanaka Y,  Juvenile Huntington disease Kayaba J, et al. Combined therapy with hypothermia and  Hallervorden–Spatz syndrome anticytokine agents in influenza A encephalopathy. Brain Dev 2000;22:373-7. 3. Tabarki B, Thabet F, Al Shafi S, Al Adwani N, Chehab M, Al Shahwan S. Acute necrotizing encephalopathy associated with enterovirus infection. Brain Dev. 2013;35:454-7. 4. Vargas WS, Merchant S, Solomon G. Favorable outcomes in acute ANE. The mainstay of treatment is intensive care and necrotizing encephalopathy in a child treated with hypothermia. symptomatic treatment. Pediatr Neurol. 2012;46:387-9. 5. Wu X, Wu W, Pan W, Wu L, Liiu K, Zhang HL. Acute necrotizing encephalopathy: an underrecognized clinicoradiologic disorder. Theoretically, intravenous steroids, immunoglobulin, Mediators Inflam. 2015;2015:792578. and plasmapheresis should be effective in view of the 6. Ohsaka M, Houkin K, Takigami M, Koyanagi I. Acute necrotizing postulated immunological aetiology.5,7 High-dose encephalopathy associated with human herpesvirus-6 infection. steroid is the most widely documented treatment. Pediatr Neurol. 2006;34:160-3. 7. Skelton BW, Hollingshead MC, Sledd AT, Philips CD, Castillo M. Administration of steroids within 24 hours of symptom Acute necrotizing encephalopathy of childhood: typical findings in 5 onset is proposed to be related to an improved outcome. an atypical disease. Pediatr Radiol. 2008;38:810-3.

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