The Multifactorial Nature of Acute Leukoencephalopathy with Restricted Diffusion Requires a Comprehensive Work-Up

We read with interest the article by Jayaramu and Doddamani on a retrospective study of clinical and radiological findings in 48 pediatric patients with acute leukoencephalopathy with restricted diffusion (ALERD), defined as impaired consciousness with/without other neurological abnormalities lasting >24 hours in pediatric patients with infectious diseases (fever, cough, or diarrhea), and subcortical white matter lesions (WMLs) lasting longer than 24 hours.[ 1 ] It was found that one-fifth of patients met the criteria for ALERD and that the WMLs were either diffuse or centrally spared.[ 1 ] It was concluded that ALERD represents a distinct clinical-radiological syndrome with characteristic diffusion-weighted imaging patterns.[ 1 ] The study is impressive, but some points should be discussed. First, it would be interesting to know whether there were differences between previous results and those of the index study with regard to the distinction between diffuse ALERD and centrally sparing ALERD, which is well established and widely recognized in the literature.[ 2 ] Centrally sparing ALERD affects the subcortical white matter but spares the central cerebral regions, is typically milder than diffuse ALERD, commonly features a biphasic course with initially prolonged febrile seizures followed by a second wave of seizures a few days later, is associated with milder laboratory abnormalities, and has an overall better outcome than diffuse ALERD.[ 3 ] [ 4 ] Second, the underlying cause of ALERD was not determined in the nine reported patients. The etiological investigation for infectious, autoimmune, metabolic, and vascular causes of ALERD was attempted but could be more comprehensive. The study could benefit from including EEG (electroencephalogram) data since seizure-related cases were included, from cerebrospinal fluid (CSF) examinations, and from more results of multimodal magnetic resonance imaging and magnetic resonance angiography (MRA) details if performed.[ 1 ] By MRA, vasculitis, spasms, or dissection could have been ruled out and T1 images with contrast could document whether the WMLs enhanced or not. The CSF could have been tested for neurotropic viruses, including SARS-CoV-2 (severe acute respiratory syndrome coronavirus 2), since patients were recruited during the pandemic, and for specific immunological parameters if accessible.[ 1 ] EEG recordings could document epileptiform discharges and nonconvulsive status epilepticus. In addition, acute disseminated encephalomyelitis, electrolyte disturbances, sepsis, and ischemic stroke should have been considered.[ 1 ] Third, there is a discrepancy between the objectives in the summary, where patients with acute leukoencephalopathy, seizures, and fever were examined, and the methodology section, where patients with and without seizures were analyzed. It should be clearly stated whether seizures were an inclusion criterion or not. Fourth, it should be taken into account that fever does not necessarily mean infection. Fever can also be due to a structural or functional lesion of the central nervous system, an immunological or endocrine disorder, medications, or a malignancy. It should be explained how causes of fever other than infection were excluded. Finally, we should know how many patients had somnolence, how many had sopor, and how many were comatose. Regarding outcomes, it should be reported how many recovered completely, how many partially, how many were disabled, and how many died. Overall, the study could benefit from the inclusion of cerebrovascular findings, CSF findings, and EEG results regarding the identification of the underlying cause of ALERD, and from reporting treatment outcomes for the enrolled patients. Including these details could elucidate the cause of ALERD and lead to more targeted treatment of this condition. Future studies should consider the importance of multimodal imaging, EEG, and CSF analysis and initiate the investigation of infectious, immunological, metabolic, and vascular causes in patients with suspected ALERD. Publication History Article published online: 13 August 2026 © 2026. Indian Radiological Association. This is an open access article published by Thieme under the terms of the Creative Commons Attribution-NonDerivative-NonCommercial License, permitting copying and reproduction so long as the original work is given appropriate credit. Contents may not be used for commercial purposes, or adapted, remixed, transformed or built upon. (https://creativecommons.org/licenses/by-nc-nd/4.0/) Thieme Medical and Scientific Publishers Private Limited A-13A, Graphix Tower 1, 6th floor, Sector 62, Noida 201309, Uttar Pradesh, India