Acute necrotising encephalopathy of childhood – A narrative review

Methods

Literature search was performed using the keywords’ Paediatric acute encephalopathy’ and ‘acute necrotising encephalopathy of childhood (ANEC)’ in PubMed and Google Scholar, and all relevant articles from 2001 to 2021 (including case reports) in the English language were reviewed. Prominent articles before 2001 were also reviewed. Herein, we review the aetiopathogenesis, clinical presentation, diagnosis, treatment, and prognosis of ANEC.

Introduction

ANEC is a potentially debilitating AE characterised by bilateral symmetric thalamic lesions and fever. Symptoms of ANE include rapidly progressing altered sensorium, seizures, tonic posturing, and vomiting. Liver dysfunction is commonly observed in affected individuals. CSF analysis typically shows increased protein without pleocytosis. ANE often exhibits high mortality and morbidity rates.^[2] Initially described in Japan, Taiwan, and Korea,^[3-5] cases are increasingly reported worldwide, including in India.^[6-9] ANE is relatively rare and can be mistaken for conditions such as febrile seizures and acute encephalitis syndrome, leading to delayed diagnosis.

The aetiopathogenesis of ANE is not fully understood, but many pathogens, particularly viruses, have been associated with the condition. Despite this, the exact pathomechanism remains unknown. ANEC has been etiologically associated with viruses such as Influenza A, influenza B, novel influenza A (H1N1), herpesvirus (HHV)-6, dengue, parainfluenza, varicella, HHV-6 and HHV-7, enterovirus, rotavirus, herpes simplex virus, rubella, and coxsackie A9.^[2,4,9-12] Recently, COVID-19 has been associated with ANEC.^[13] No difference has been noted with regard to aetiology except for more frequent brain stem lesions in ANEC secondary to influenza.^[14] Familial or recurrent ANEC due to mutations in the gene encoding the nuclear pore protein Ran Binding Protein 2 has also been reported, implying the role of host susceptibility.^[15] This gene accounts for 3/4^th of familial cases and has a dominant inheritance with incomplete penetrance. Human leukocyte antigen (HLA) DRB/HLA DQB genes might play a role in the pathogenesis of ANE.^[2] The most prevalent hypothesis is hypercytokinemia, commonly known as the ‘cytokine storm’. According to current understanding, an infection-induced aberrant immune response triggers an exaggerated production of cytokines, including tumour necrosis factor-alpha (TNF-α), interleukin (IL)-1 and IL-6, leading to brain and other organ injuries, such as liver dysfunction, acute renal failure, shock and disseminated intravascular coagulation (DIC). This abnormal immune response also results in altered vessel wall permeability, contributing to brain injury. In addition, high concentrations of IL-6 exhibit neurotoxic effects, while TNF-α can damage the endothelium of the CNS. Hypercytokinemia further disrupts the blood-brain barrier (BBB) through the action of trypsin and matrix metalloprotease-9, thereby increasing vessel wall permeability and resulting in cerebral oedema, haemorrhage, and necrosis.^[2]

Clinical presentation

Patients with ANE do not exhibit specific symptoms or typical neurological signs, and the disease’s clinical features have been consistent worldwide. Alongside prodromal symptoms due to viral infections, which may include fever, signs of upper respiratory tract infections, gastroenteritis, and erythema, ANE patients often present signs of SIRS such as shock, multiple organ dysfunction, and DIC. Neurological dysfunction in ANE manifests as seizures, rapidly progressing disturbance of consciousness, tonic posturing, and less commonly, focal neurological deficits.^[4]

Diagnosis

The diagnosis of ANEC is based on clinical symptoms, laboratory and neuroimaging findings, as proposed by Mizuguchi in 1995.^[4] In the diagnosis of ANE, bilateral symmetric lesions in thalami, particularly, are invaluable [Table 2]. Mizuguchi suggested the following diagnostic criteria for sporadic ANE:

AE is related to a febrile viral infection, characterised by rapid reduction of consciousness and seizures.

CSF examination showed a normal cell count and increased protein concentration.

The presence of symmetrical and multiple brain lesions on head CT and/or MRI, with bilateral thalamic lesions being consistently observed. Symmetric lesions may also be found in the periventricular white matter, internal capsule, putamen, upper brainstem tegmentum, and cerebellum and increased serum transaminase levels without elevation in serum ammonia levels.

ANE radiology

In addition, to diffuse brain oedema, there are bilateral symmetric, oedematous/necrotic lesions in specific brain regions, esp. the thalami. The classical neuroimaging of ANE has a concentric structure.^[2,8] This typical manifestation is more obvious on ADC of MRI where the centre of the lesion presents a slightly high signal with a low signal in the surrounding of the lesion(cytotoxic oedema) and again high signal in its periphery (vasogenic oedema). DWI shows increased diffusion (necrosis and perivascular haemorrhage) in the centre of the thalamic lesion, restricted diffusion in the surrounding zone, and increased diffusion in the periphery [Figure 1]. Thalamic lesions show hypodensities on CT. In the acute stage, the lesions show low T1, high T2 intensity, and decreased diffusion. In the early subacute stage, the thalamic lesions are concentric due to central T1 hyperintensity indicating haemorrhagic changes.^[1] In the late subacute stage, there is progressive cerebral atrophy, and shrinkage or disappearance of thalamic lesions. Gadolinium-contrast MRI has been reported to identify lesions at an early stage of ANE (alteration of the BBB permeability) when conventional CT, MRI, and even DWI and ADC may show no abnormalities.^[2] The gadolinium-contrast MRI may, therefore, help in early diagnosis and enable the initiation of prompt treatment to alleviate neurological sequelae in ANE. However, enhancement on gadolinium-contrast MRI is not always seen; therefore, this needs to be interpreted with caution. Magnetic resonance spectroscopy (MRS) may provide additional information, though it may not be consistent or specific. Transient lipid-lactate complex peak and glutamate/ glutamine complex peak on MRS have been reported in patients with ANE. The glutamate/glutamine complex peak on MRS might depend on the severity of the disease.^[2] Spinal cord involvement may occasionally be noted. The hippocampus/ amygdala is more often involved in familial ANEC.

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Figure 1:

(a) Axial diffusion-weighted image shows restricted diffusion in bilateral thalami. (b) Axial T1 post-contrast image shows enhancement in thalami R>L. (c and d) Axial T2-weighted and T2 fluid-attenuated inversion recovery images show hyperintensities in bilateral thalami from a child with good recovery without any deficits. (e) Axial image of non-contrast computed tomography head shows bilateral thalamic hypodensities. (f) Axial T1-weighted image shows thalamic hyperintensities. (g and h) Axial gradient echo image shows hyperintensities in bilateral thalami and deep white matter in a child with mild to moderate disability-learning disability, squint, epilepsy. (i) Axial apparent diffusion coefficient maps suggest restricted diffusion in bilateral thalami and periventricular white matter. (j) Axial diffusion-weighted restricted diffusion in bilateral deep white matter. (k) Axial susceptibility-weighted images suggest haemorrhage in the central part of bilateral deep white matter lesions. (l) Sagittal T2-weighted image shows hyperintensities in cerebral and cerebellar white matter from a child with severe disability-wheel chair bound. (m and n) Axial non-contrast computed tomography (CT) head shows hypodensities in midbrain, subthalamic nucleus and bilateral thalami at admission. (o and p) Axial non-contrast CT head a day later shows hypodensities in thalami with effacement of sulcal spaces, blurring of grey-white junction and intraventricular bleed in a child who succumbed to acute necrotising encephalopathy of childhood.

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Other than ANE, conditions like ADEM and AE with biphasic seizures and late reduced diffusion (AESD) may also exhibit thalamic lesions. In addition, symmetrical brain lesions may be observed in the cerebral and/or cerebellar white matter and brain stem tegmentum in ANE. Unlike ADEM, the white matter lesions in ANE are generally located in the internal capsule and deep white matter and are not asymmetric. Furthermore, ANE does not involve the subcortical white matter, as seen in AESD (bright tree appearance).

Laboratory findings

Laboratory findings may vary between patients, while some could be used to support the diagnosis of ANE, such as abnormalities of liver function without hyperammonemia.^[4] Increased protein levels of CSF and low platelet count could be a predictor of the prognosis of the disease. The protein levels in CSF are elevated in two-thirds of patients, possibly due to the extravasated plasma proteins and the disintegrated neural proteins (myelin basic protein).^[2]

Treatment

There have been limited reports on specific treatments for ANE. In a retrospective study conducted in Japan, corticosteroids (such as pulsed steroid therapy or intravenous dexamethasone) administered within 24 h after symptom onset were associated with better outcomes in ANE patients without brainstem lesions.^[17] Although there is insufficient evidence for its use in ANE, early pulse steroid therapy is recommended shortly after symptom onset.^[1] The role of intravenous immunoglobulin has not been conclusively proven, and while some authors have reported good outcomes with plasmapheresis, further research is needed. Therapeutic hypothermia, utilised as an anti-cytokine therapy, may hold the potential to improve outcomes in children with ANE, particularly if initiated within 12 h after onset.^[2] There have also been anecdotal reports of successful use of tocilizumab.^[18]

Presently, effective treatment for ANE has not been firmly established, but early pulse steroid therapy is recommended. The efficacy of intravenous immunoglobulin or hypothermia in treating ANE remains unproven.^[1] The management of ANE faces challenges due to the lack of a standardised treatment protocol, the need for intensive care during the acute phase and the requirement for rehabilitation services during the post-hospitalisation phase, with outcomes varying among individuals.

Outcome and prognosis

Outcomes in ANE are potentially devastating but variable.^[19,20] The ANE Severity Score (ANE-SS) is determined by considering clinical and laboratory parameters, which include the presence of shock (3 points), brain stem lesions or age over 48 months (2 points each), and platelet count <100,000/uL or CSF protein above 60 mg/dL (1 point each).^[21] The total score can range from 0 to 9 points, and patients are categorised into low-risk (ANE-SS 0–1 points), medium-risk (ANE-SS 2–4 points) or high-risk (ANE-SS 5–9 points) groups. High-risk ANE-SS has been associated with increased mortality and severe morbidity. Wong et al. devised an MRI scoring system that considers the presence of haemorrhage, cavitation and lesion location (brain stem and/or white matter – cerebral, cerebellar, or both).^[22] One point is assigned for each of these features, and the composite score correlates with neurological outcomes. Serial disability scoring is valuable for assessing the progress of ANEC patients during follow-up, and evaluation at one month after diagnosis can aid in predicting long-term outcomes.^[19]

Continued neurologic recovery at follow-up has been described.^[9,19] Although patients with ANE may eventually have a good outcome, the recovery is gradual; hence, at discharge, many children may have significant neurologic problems. The reason for the good outcome in some reports may be, firstly, due to increased recognition of the mild form based on the clinical symptoms and radiologic findings and secondly, to prompt and appropriate treatment after early diagnosis of the disease.

Future directions

ANEC is a relatively uncommon but important cause of acute febrile encephalopathy with diagnostic neuroimaging findings. Increasing awareness about ANE is needed to promote early diagnosis and enable appropriate treatment. On 31 July, ANE awareness day can be utilised by running educational campaigns about the disease. Standard institutional protocols will facilitate timely treatment. Multicentre studies are needed to establish the role of immunotherapy, including steroids and hypothermia, in improving outcomes in this ANE. Rehabilitation needs to be emphasised as these children tend to recover gradually.

Clinical significance

Infection-associated AE syndromes are an important cause of AE. Recognition of specific syndromes is crucial for management. Among them, ‘ANE has distinctive neuroimaging findings that can aid in the early diagnosis and prompt administration of specific treatment to improve outcomes’.