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Table of Contents    
Year : 2021  |  Volume : 69  |  Issue : 2  |  Page : 466-469

Acute Leucoencephalopathy with Restricted Diffusion in Children – A case series

1 Professor of Pediatrics and In.Charge Child Development Centre, KAHER University's J N Medical College, Belgaum, Karnataka, India
2 Senior resident, Child Development Centre, KLE Prabhakar Kore Hospital, Belgaum, Karnataka, India
3 Professor of Radiology, KAHER University's J N Medical College, Belgaum, Karnataka, India

Date of Submission07-Aug-2018
Date of Decision24-Jul-2019
Date of Acceptance12-Nov-2019
Date of Web Publication24-Apr-2021

Correspondence Address:
Dr. Mahesh Kamate
Division of Pediatric Neurology, Professor of Paediatrics, KAHER University's J N Medical College, Belgaum - 590 010, Karnataka
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Source of Support: None, Conflict of Interest: None

DOI: 10.4103/0028-3886.314577

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 » Abstract 

Objective: To study the clinico-radiological profile of children with acute leukoencephalopathy with restricted diffusion.
Methods: A retrospective chart review of children with acute leukoencephalopathy with restricted diffusion was done from July 2015 to July 2018. The clinical details, neuroimaging findings, sequelae, and the final outcome on modified Rankin Score were analyzed.
Results: Sixteen children with a mean age of 4.4 years were diagnosed with acute leukoencephalopathy with restricted diffusion. All, except one, had fever, seizure, and altered sensorium. The median duration of hospital stay was 3 weeks. Only one out of 16, had biphasic clinical picture that is characteristic of acute encephalopathy with biphasic seizures and restricted diffusion. Magnetic resonance imaging showed restriction diffusion in all. While it was symmetric in 13 children, in 3 children it was asymmetric, and in 2 children there was patchy involvement. Seven children (43.7%) had post-encephalopathic epilepsy. While complete neurological recovery was seen in 2 children, behavioral problems like hyperactivity in 10 (62.5%), speech problems in 8 (50%), and cognitive delay in 3 (18.8%) children were noted.
Conclusion: Acute leukoencephalopathy with restricted diffusion is emerging as an important cause of acute encephalopathy in children with a protracted course and long-term sequelae such as cognitive impairment and refractory postencephalopathic epilepsy.

Keywords: Acute encephalopathy with biphasic seizures and restricted diffusion, acute leukoencephalopathy with restricted diffusion, neuroimaging, post-encephalopathic epilepsy
Key Message: Acute leucoencephalopathy with restricted diffusion is an important cause of post or para-infectious acute encephalopathy that has characteristic neuroimaging findings. Unlike other causes, it has a protracted clinical course, high incidence of long term sequelae and low mortality rate.

How to cite this article:
Kamate M, Detroja M, Hattiholi V. Acute Leucoencephalopathy with Restricted Diffusion in Children – A case series. Neurol India 2021;69:466-9

How to cite this URL:
Kamate M, Detroja M, Hattiholi V. Acute Leucoencephalopathy with Restricted Diffusion in Children – A case series. Neurol India [serial online] 2021 [cited 2021 May 11];69:466-9. Available from:

Acute encephalopathy as a presentation of common viral and bacterial infections often affects young children and causes death or severe neurological sequelae.[1] An early, prompt diagnosis helps in the institution of appropriate treatment and most importantly prognosis. In the last decade, a new viral-associated encephalopathy, acute leukoencephalopathy with restricted diffusion (ALERD) (also known as acute encephalopathy with biphasic seizures and restricted diffusion [AESD]) has been described mainly from the Asian continent.[2] It is characterized by seizures with fever, altered sensorium for 1–4 weeks, and magnetic resonance imaging (MRI) showing areas of restricted diffusion. Depending on the MRI findings, two types of ALERD are described: diffuse ALERD and central sparing ALERD. The central sparing ALERD refers to the previously well-described AESD. There have been no publications from India and hence decreased awareness about this entity among pediatricians, intensivists, and neurologists. We present our experience with ALERD in the last 3 years.

 » Material and Methods Top

Retrospective chart review of all children with a diagnosis of ALERD from July 2015 to July 2018 was done. Children with acute encephalopathy and MRI showing predominantly restricted diffusion with inversion on apparent diffusion coefficient maps were labeled as ALERD. When it followed the use of drugs/toxins it was labeled as toxic ALERD, otherwise, it was named as post/para-infectious ALERD.[2],[3] The clinical presentation, duration of illness, hospital stay, investigation, treatment taken, and the follow-up data (outcome on modified Rankin score (mRS) and sequelae such as cognitive deficits, epilepsy, and behavioral disturbances) was entered in excel sheet and analyzed using SPSS software.

 » Results Top

A total of 16 children (9 males) had a diagnosis of ALERD. The key findings are summarized in [Table 1]. The mean and median age was 4.4 and 3.5 years, respectively. All except one, presented with fever, seizures, and altered sensorium. The child without fever had a head injury due to a fall from a height of 2 m on the day of presentation. While, one child developed ALERD following the use of methotrexate for hemophagocytic lymphohistiocytosis (toxic ALERD), another child developed ALERD on the 6th postoperative day (anorectal malformation repair). The biphasic nature of the disease (onset marked by a prolonged seizure that usually lasts for >30 min with fever followed by improved consciousness and clustered seizures, signs of frontal lobe dysfunction, and worsening of consciousness becoming apparent at 3–4 days after onset) that is characteristic of AESD was seen in only one child [Figure 1]a and [Figure 1]b. The seizures were focal, generalized, or both. The seizures during the acute phase were recurrent and required 2–3 antiepileptic drugs (AEDs) to control, but generally subsided in a weeks' time (average 6 days; range: 3–9 days). None of them had signs of meningeal irritation. The worst mean and median Glasgow coma scale (GCS) during the course of illness was 7.1 and 7.0, respectively. The altered sensorium took around 2–3 weeks to improve. The mean and median duration of hospital stay was 28.2 and 20 days, respectively. The cerebrospinal fluid examination was normal in all children (none had >10 cells). Two of them were tested for autoimmune antibodies (NMDAR) and were found to be negative. Blood and cerebrospinal fluid culture examinations showed no growth in all children. MRI of brain showed restricted diffusion in all children [Figure 1]. While it was symmetric in 13 children, in 3 children it was asymmetric [Figure 1]d and [Figure 1]e. The child with toxic ALERD had involvement of the occipital lobes [Figure 1]f. Two of them had bilateral but patchy involvement. The involvement of deep gray matter was seen in six patients.
Table 1: Summary of clinical and radiological findings of children with ALERD

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Figure 1: (a and b) Diffusion-weighted images (DWI) of patient 7 showing diffusion restriction in bilateral cerebral hemispheres with sparing of the central sulcus with reversal on apparent diffusion coefficient (ADC) map (b). (c) DWI of patient 3 showing bilateral diffuse white matter involvement. (d-f) DWI of patients 9, 11, and 16 respectively, showing patchy, asymmetric, and isolated posterior restriction. (g-i) DWI of patient 10 on day 2 and 7 showing restriction in the parietal region initially and later on evolving to involve both hemispheres; On day 60, fluid-attenuated inversion recovery (FLAIR) image (i) with biparietal white-matter hyperintensities and diffuse cerebral atrophy

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The children were given supportive care with antiepileptic drugs. After the infection was ruled out, pulse methylprednisolone was given for 5 days. Antiepileptic drugs were continued at discharge for 3–6 months. In those without seizure recurrence and normal EEG at 6 months, AEDs were tapered and stopped. No deaths were seen in our group. The mean duration of follow-up was 13.9 months. Children who had seizure recurrence or new types of seizures occurring after 3 months were labeled as post-encephalopathic epilepsy (PEE). Seven children (43.7%) had PEE and all were refractory to medical treatment (three had auditory myoclonus). EEG of these children showed multifocal epilepsy. While complete neurological recovery was seen in two children, behavioral problems such as hyperactivity in 10 (62.5%), speech problems in 8 (50%), and cognitive delay in 3 (18.8%) children were noted. One child with asymmetric ALERD had residual hemiparesis at follow-up. The mean and median mRS at follow-up after >6 months (data from 12 children; one lost to follow-up, 3 had not completed 6-months follow-up) was 2.0 (range: 0–5) and 2.0 (range: 0–5), respectively. The only child with poor mRS of 5 had sustained secondary hypoxic injury during the hospital stay. The follow-up MRI after 6–12 months showed diffuse cerebral atrophy in those with diffuse ALERD with resolution of white matter restriction on diffusion-weighted images (DWI). Laminar necrosis and increased signal intensities in the subcortical white matter on T2-weighted images in three.

 » Discussion Top

ALERD is a clinico-radiological syndrome and is one of the infection-associated encephalopathy syndromes seen in childhood.[2] It has been reported mainly from East Asia. In a series of 44 patients from Nagoya University, Japan, causative pathogens isolated were human herpes virus-6, adenovirus, rotavirus, influenza, Mycoplasma pneumoniae, enterovirus type coxsackie virus-A6, and Escherichia coli O157:H7.[4] At times, it can be a presentation of bacterial septic encephalopathy like Streptococcus pneumonia.[5] In the current study, because of the lack of facilities, specific aetiological workup was not done.

In the present study, there was no gender difference noted and ALERD-affected children were of all ages from 1 to 13 years. The presenting features in all except one included fever, seizures, and altered sensorium which is common to most acute encephalopathies in children. The seizures in ALERD can be focal, generalized, or both. The seizures during the acute phase are recurrent and may require 2–3 drugs to control, but generally settle in a weeks' time unlike fever-induced refractory epilepsy syndrome, where seizures continue for weeks together. The altered sensorium and the speech take a longer time to recover. However, the protracted course (mean duration of altered sensorium: 3 weeks) was a pointer toward ALERD. This fact should help to suspect ALERD, differentiating it from other causes of acute encephalopathy, and it is important to counsel the parents about this fact when we make a diagnosis of ALERD.

The biphasic nature of the disease (fever with a seizure at presentation followed by improvement and worsening of consciousness with seizure recurrence at 3–4 days later) that is a characteristic of AESD was seen in only one child. Hence, the term ALERD is more appropriate for these children than AESD. The diffuse type of ALERD was the most common type seen in our study. The pattern that we see here is probably different than that seen in the East-Asian countries. While one child had a history of head injury, another developed ALERD on the 6th postoperative day. Events such as trauma and surgery might have triggered the occurrence of ALERD. However, this needs to be looked at in future studies on ALERD.

MRI showed restricted diffusion in all children giving the “bright tree appearance.”[1] Signal changes on the DWI that revert on the apparent diffusion coefficient maps are characteristic of ALERD. When changes are marked or when the scan is done late into the disease, the signal changes may be seen on T2 weighted and fluid-attenuated inversion recovery sequences. However, the changes would be more marked in the DWI sequences. It is important to note that when the scan is done early, the changes may be subtle and a repeat scan after a week may show characteristic changes. Hence, when the suspicion of ALERD is strong and the initial imaging is normal, it is worthwhile to repeat imaging. While the literature has mentioned symmetric changes, three children in the present study had asymmetric involvement in the current study. Two of them had symmetric patchy involvement resembling rotaviral encephalitis.[6] This pattern has not been reported earlier in the literature. If this pattern is specific to rotavirus infection it needs to be studied in future studies. Published case series on AESD have reported hyperintensities in the caudate nucleus in some patients but sparing of basal ganglia, thalami, and corpus callosum.[1],[7] However, in the present study, thalamic involvement was seen in four, putaminal involvement in three, and corpus callosal involvement in one child. There is a need to collect more neuroimaging data to know the exact involvement of various brain structures in ALERD.

IV pulse steroids and intravenous immunoglobulin (IVIG) have been used in ALERD after neuroinfections have been ruled out.[1] Currently, there is no evidence for the use of steroids/IVIG in ALERD and hence there is a need to collect cases of ALERD and conduct randomized studies for a definitive answer. As the proposed pathogenesis for ALERD is an excitotoxic injury with delayed neuronal death, there have been some case reports with combination therapy of N-methyl-D-aspartate (NMDA) receptor antagonist, dextromethorphan, and apoptosis inhibitor, cyclosporine A.[8] A study on four patients with ALERD showed favorable results. However, in the current study, none of the patients were put on these drugs.

PEE was seen in 43.7% of children in contrast to 23% reported in the literature.[4] Seizures that are induced by sudden unexpected sounds were seen in three children and was drug refractory. Most of them are refractory to treatment. Sequelae in the form of cognitive impairment, behavioral problems, and speech impairment alone and/or in combination was seen in 14 (87.5%) children in contrast to 55.5% in Okumara's study.[1]

This study is the first case series on AESD/ALERD from India. Sixteen children were diagnosed over 3 years from one center. This shows that many cases are being missed in our country. The major limitations of our study were the retrospective nature of data collection and the lack of etiological workup.

In conclusion, ALERD is emerging as an important cause of acute encephalopathy in children with a protracted course. MRI of the brain shows restricted diffusion and the illness is prolonged and lasts for 2–3 weeks. Diffuse ALERD is more common in our set up and more than 75% children have cognitive or speech delays with hyperactivity while almost 50% of them have postencephalopathic epilepsy.

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 » References Top

Okumura A, Kidokoro H, Tsuji T, Suzuki M, Kubota T, Kato T, et al. Differences of clinical manifestations according to the patterns of brain lesions in acute encephalopathy with reduced diffusion in the bilateral hemispheres. AJNR Am J Neuroradiol 30:825-30.  Back to cited text no. 1
Kamate M. Acute leukoencephalopathy with restricted diffusion. Indian J Crit Care Med 2018;22:519-23.  Back to cited text no. 2
[PUBMED]  [Full text]  
Singh V, Tomar V, Kumar A, Phadke RV. Acute leucoencephalopathy with restriction of diffusion—a case report. East J Med 2012;17:149-52.  Back to cited text no. 3
Ito Y, Natsume J, Kidokoro H, Ishihara N, Azuma Y, Tsuji Y, et al. Seizure characteristics of epilepsy in childhood after acute encephalopathy with biphasic seizures and late reduced diffusion. Epilepsia 2015;56:1286-93.  Back to cited text no. 4
Yamaguchi H, Tanaka T, Maruyama A, Nagase H. Septic encephalopathy characterized by acute encephalopathy with biphasic seizures and late reduced diffusion and early nonconvulsive status epilepticus. Case Rep Neurol Med 2016;2016:7528238.  Back to cited text no. 5
Kamate M, Naik S, Torse S, Hattiholi V. Neonatal rotaviral encephalitis. Indian J Pediatr 2017;84:865-6.  Back to cited text no. 6
Takanashi J, Oba H, Barkovich AJ, Tada H, Tanabe Y, Yamanouchi H, et al. Diffusion MRI abnormalities after prolonged febrile seizures with encephalopathy. Neurology 2006;66:1304-9.  Back to cited text no. 7
Matsuo M, Maeda T, Ono N, Sugihara S, Kobayashi I, Koga D, et al. Efficacy of dextromethorphan and cyclosporine a for acute encephalopathy. Pediatr Neurol 2013;48:200-5.  Back to cited text no. 8


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