Tocilizumab as a key therapeutic option in high-risk pediatric acute necrotizing encephalopathy

Article information

Clin Exp Pediatr. 2026;69(2):114-116

Publication date (electronic) : 2026 January 26

doi : https://doi.org/10.3345/cep.2026.00073

Jon Soo Kim, MD, PhD

Department of Pediatrics, Chungbuk National University Hospital, College of Medicine, Cheongju, Korea

Corresponding author: Jon Soo Kim, MD, PhD. Division of Pediatric Neurology, Department of Pediatrics, Chungbuk National University Hospital, 776 Sunhwan-1-ro, Seowon-gu, Cheongju 28644, Korea Email: pedkjs79@gmail.com

Received 2026 January 9; Revised 2026 January 18; Accepted 2026 January 23.

Key message

Acute necrotizing encephalopathy (ANE) is a rare but catastrophic neurological emergency that primarily affects children [1]. ANE is characterized by abrupt disturbances of consciousness, seizures, and symmetrical necrosis with hemorrhagic involvement of the thalami and brainstem [1-3]. Although ANE is distinct from classical autoimmune encephalitis (AE), in which immune responses are directed against specific neuronal antigens, accumulating evidence suggests important overlap in their underlying mechanisms [1]. ANE is increasingly recognized as an infection-triggered, autoimmune-like disorder driven by an overwhelming cytokine response following viral illnesses such as influenza, Severe acute respiratory syndrome coronavirus 2 and human herpesvirus-6 infection [2,4]. Accordingly, the prompt initiation of immunomodulatory therapy—similar to the treatment strategies used in AE—is critical to limiting excessive inflammation and preventing irreversible brain injury. Without timely intervention, clinical outcomes are frequently poor [5]. Thus, ANE can be conceptualized as a fulminant form of encephalitis mediated predominantly by cytokine-driven immune dysregulation. From this perspective, the study entitled “High-dose methylprednisolone and tocilizumab improve survival of patients with high-risk pediatric acute necrotizing encephalopathy” published in Clinical and Experimental Pediatrics by Fan et al. [2], provides important clinical evidence that targeting cytokine-driven immune dysregulation—particularly through interleukin-6 (IL-6) receptor blockade with tocilizumab—can significantly improve survival in pediatric ANE.

The precise pathophysiology of ANE remains incompletely elucidated; however, current hypotheses implicate both viral neuroinvasion and an exaggerated host immune response [1,3]. Viruses reportedly access the central nervous system through several routes, including translocation across the nasal mucosa and lamina cribrosa to the olfactory bulb, or via retrograde axonal transport (Fig. 1) [1-3]. Once triggered, this process induces a profound systemic cytokine storm characterized by marked elevation of proinflammatory cytokines, particularly IL-6. Importantly, recent studies demonstrated significantly elevated IL-6 levels in the serum and cerebrospinal fluid of patients with ANE, providing direct evidence of intrathecal cytokine activation and central nervous system involvement [6]. The ensuing inflammatory and prothrombotic cascade results in endothelial injury, disruption of the blood-brain barrier, and subsequent development of the characteristic symmetric edema, necrosis, and hemorrhage affecting the thalamus and other vulnerable brain regions. These findings emphasize that immune-mediated injury, rather than direct viral cytotoxicity, plays a central role in the pathogenesis of ANE [4].

Fig. 1.

Pathogenesis of acute necrotizing encephalopathy and immunomodulatory treatment. Figure created using bioRender (https://www.biorender.com). IL-6, interleukin-6; IVIG, intravenous immunoglobulin.

Despite the high rates of mortality and long-term neurological sequelae associated with ANE, standardized evidence-based treatment guidelines are lacking [1-3]. Current therapeutic approaches rely largely on empiric immunomodulation, reflecting the presumed immune-driven nature of ANE (Fig. 1). The early administration of high-dose intravenous methylprednisolone is widely considered the cornerstone of treatment and should ideally be initiated within 24 hours of symptom onset to maximize the neurological recovery [1,2]. A meta-analysis of 158 patients demonstrated a significant benefit of early corticosteroid therapy, with therapeutic efficacy declining when treatment was delayed beyond the first 24 hours [7]. The commonly recommended regimen consists of intravenous methylprednisolone at 30 mg/kg/day (maximum 1 g/day) for 3–5 consecutive days. Adjunctive therapies such as intravenous immunoglobulin may be considered, although their clinical benefit remains uncertain [1,8]. Plasma exchange is generally reserved for patients who fail to respond to first-line immunotherapy within 48–72 hours. Other immunomodulatory strategies, including anakinra or intrathecal corticosteroid administration, remain experimental and require further validation in larger studies [1].

Tocilizumab, a monoclonal antibody targeting the IL-6 receptor, recently emerged as a promising off-label adjunctive treatment for severe ANE, particularly in high-risk pediatric populations [9]. In patients exhibiting rapid neurological deterioration or hemorrhagic brain lesions, its early administration (8–12 mg/kg intravenously, maximum 800 mg) within 18–32 hours of encephalopathy onset may be strongly considered [1]. Available evidence suggests that combination therapy with high-dose corticosteroids and tocilizumab may be more effective than corticosteroids alone at reducing mortality and severe neurological disability.

Notably, Fan et al. [2] provided compelling evidence that the addition of tocilizumab to high-dose methylprednisolone significantly improves the survival of pediatric patients with high-risk ANE. In the absence of formal treatment guidelines, however, therapeutic decisions for ANE have historically relied on limited case series and institutional experience. The findings reported by Fan et al. [2] represent a meaningful advance in the field, demonstrating superior survival outcomes in patients receiving combined immunotherapy versus corticosteroids alone, particularly among those with severe clinical manifestations. These results constitute the strongest clinical evidence to date of the efficacy of tocilizumab as an adjunctive immunomodulatory agent in pediatric ANE.

Consistent with these observations, recent case reports and small series have reported favorable outcomes with early combined high-dose methylprednisolone and tocilizumab [2,8,9]. Emerging data indicate that an earlier initiation of tocilizumab during the encephalopathy course may be associated with improved neurological outcomes. In clinical practice, the decision to administer tocilizumab is often guided by disease severity, rapid clinical progression, elevated inflammatory biomarkers, or a high score on established ANE severity scales.