Acute Encephalopathy with Biphasic Seizures and Late Reduced Diffusion (AESD) has long been recognized as a rare but severe neurological disorder predominantly reported in Japan. Characterized by a distinctive clinical pattern involving biphasic seizures and radiological hallmarks visible on magnetic resonance imaging (MRI), AESD poses significant diagnostic and therapeutic challenges. Until recently, this condition was largely examined within Japanese cohorts, with limited acknowledgment of its global presence. However, a pioneering Italian case report combined with a comprehensive scoping review now illuminates AESD’s broader epidemiology, clinical manifestations, and potential etiological factors beyond Japan’s borders.
The Italian case involves a 3-year-old girl who developed classic features consistent with AESD, affirming that this neurological syndrome transcends geographic and ethnic confinements. Importantly, her clinical trajectory mirrored that of Japanese patients, including an initial seizure episode, followed by a latent period, and then a second devastating phase. MRI studies captured the hallmark late reduced diffusion in cerebral white matter, a cornerstone for AESD diagnosis. Such advanced imaging findings underscore the critical role of neuroimaging in identifying delayed biphasic neurologic deterioration that can otherwise be mistaken for other encephalopathies or infectious encephalitis.
AESD’s international recognition remains limited, with published reports outside of Japan accounting for only 29 cases until now. Despite the modest number, these cases share strikingly similar clinical and epidemiological characteristics with those documented in Japan. Patients generally present in early childhood, primarily under five years of age, and the gender ratio demonstrates a slight female preponderance. Most notably, the infectious triggers precipitating AESD show a geographic disparity: Human herpesvirus-6 (HHV-6), a predominant culprit in Japan, is scarcely found in cases reported elsewhere, suggesting that regional viral epidemiology and host-pathogen interactions contribute intricately to AESD pathogenesis.
This divergence in infectious agents emphasizes the potential influence of environmental and genetic factors in modulating disease susceptibility and clinical phenotypes. Japan’s relatively high AESD incidence, compared to the global rarity of reported cases, provokes compelling questions about ethnic predisposition, genetic polymorphisms, and possibly distinct viral strains engaging with the central nervous system. The present review advocates for extensive international multicenter collaborations to unravel these complex dimensions, which are crucial for developing universal diagnostic criteria and therapeutic guidelines.
Clinically, AESD evolves in a biphasic pattern: an initial prolonged seizure or cluster of seizures, often febrile but sometimes afebrile, followed by an apparently asymptomatic or minimally symptomatic interval. This silent window typically lasts several days before a second wave of seizures and neurological decline ensues, echoed by MRI evidence of late reduced diffusion in subcortical and periventricular white matter. The pathophysiological underpinnings are hypothesized to stem from delayed excitotoxic neuronal injury, inflammation, and energy metabolism disruption, culminating in irreversible cerebral damage if untreated.
Magnetic resonance imaging, particularly diffusion-weighted imaging (DWI), provides an invaluable diagnostic window into AESD. The temporal evolution of lesions visible on MRI delineates a specific pattern, with early images appearing near-normal and late images revealing widespread cytotoxic edema. These imaging dynamics not only corroborate the biphasic clinical course but also help distinguish AESD from other causes of pediatric encephalopathy, including metabolic disorders and viral encephalitis. The Italian case’s MRI findings reinforce the notion that serial imaging is indispensable for timely diagnosis, prognostication, and therapeutic decisions.
Despite the growing awareness of AESD, this pathological entity remains under-recognized worldwide, primarily due to low disease incidence, lack of standardized diagnostic protocols, and overlap with other pediatric neurologic disorders. The scoping review underscores that clinicians outside Japan often overlook AESD, attributing biphasic seizures to more common etiologies. This diagnostic gap may lead to underreporting, delayed or inappropriate interventions, and misclassification, effectively masking the true burden of AESD on a global scale.
The morbidity associated with AESD is profound, with many survivors experiencing persistent neurological deficits, including cognitive impairment, motor disabilities, and epilepsy. The long-term sequelae highlight the critical need for early identification and prompt intervention. However, therapeutic strategies remain empiric, centering on seizure control and supportive care. Immunomodulatory therapies, such as corticosteroids and intravenous immunoglobulin, have been used variably, though robust clinical trials validating their efficacy in AESD are lacking. Consequently, international consensus on management protocols is imperative.
Genetic studies exploring AESD susceptibility have revealed candidate polymorphisms in inflammatory cytokine genes and pathways regulating neuronal excitability. Nonetheless, the data remain preliminary and largely confined to Japanese cohorts. Expanding genomic research to encompass ethnically diverse populations, as represented by the Italian case, will be essential to delineate genetic contributions and to pave the way for personalized medicine approaches.
The role of infectious agents, notably HHV-6 in Japan, versus a broader spectrum of viruses elsewhere, underscores the interplay between environmental exposures and host responses. Understanding how different viral pathogens initiate or exacerbate the biphasic encephalopathy cascade could unlock novel antiviral or immunological interventions. Furthermore, investigating why HHV-6 hotspots coincide with higher AESD incidence in Japan could reveal viral genotypic variations influencing neurovirulence.
This scoping review serves as a clarion call to the global pediatric neurology community to recognize AESD as a worldwide entity rather than one confined to Japan. Collaborative, international surveillance and research are urgently needed to refine the epidemiological picture, harmonize diagnostic criteria, and develop evidence-based therapeutic guidelines. Such concerted efforts may ultimately reduce AESD’s burden and improve outcomes for affected children worldwide.
Educational initiatives must also be prioritized to inform clinicians globally about AESD’s distinctive presentation and imaging characteristics. Enhanced awareness will drive earlier diagnosis, facilitate appropriate management, and stimulate research engagement. Given the rapid neurological deterioration seen in AESD, time is of the essence, and thus, knowledge dissemination is a critical step toward mitigating this devastating syndrome.
Finally, this investigation into AESD exemplifies the broader challenges inherent in studying rare diseases with complex etiologies and variable phenotypes across populations. It highlights the necessity of integrating clinical acumen, cutting-edge imaging, molecular tools, and collaborative networks to unravel enigmatic conditions. As AESD transitions from a regional curiosity to a recognized global disorder, it also signifies progress in pediatric neurology’s capacity to confront rare, severe brain diseases on a worldwide stage.
Subject of Research: Acute Encephalopathy with Biphasic Seizures and Late Reduced Diffusion (AESD)
Article Title: Acute encephalopathy with biphasic seizures and late reduced diffusion (AESD): a scoping review.
Article References:
Lemieux, P.B., Calciano, F., Giacobbe, A. et al. Acute encephalopathy with biphasic seizures and late reduced diffusion (AESD): a scoping review. Pediatr Res (2025). https://doi.org/10.1038/s41390-025-04550-8
Image Credits: AI Generated
DOI: 04 December 2025
