Diagnostic Complexity of Pediatric Hemophagocytic Lymphohistiocytosis With Central Nervous System Involvement

Hemophagocytic lymphohistiocytosis (HLH) is a hyperinflammatory syndrome frequently involving the central nervous system (CNS) and associated with poor outcomes. Neurological manifestations may precede or obscure systemic features, resulting in diagnostic challenges.

We retrospectively reviewed pediatric patients with HLH treated at Seoul National University Children's Hospital between 2000 and 2024. CNS involvement was defined by neurological symptoms and abnormal cerebrospinal fluid (CSF) findings and/or brain imaging abnormalities. Clinical features, neuroimaging findings, CSF profiles, genetic testing results, treatment, and outcomes were analyzed.

Among 136 screened patients with HLH, 20 met criteria for CNS involvement. Neurological symptoms were the initial manifestation in 6 of 20 patients (30%), and seizures were the most common symptom (14/20, 70%). Brain imaging abnormalities were observed in all patients who underwent neuroimaging (19/19), typically demonstrating multifocal parenchymal lesions with bilateral or multilobar involvement. CSF abnormalities were present in 13 of 18 patients (72%) but were nonspecific. More than half of the patients (11/20, 55%) were initially evaluated under alternative diagnostic considerations, contributing to delayed recognition of HLH. Genetic testing identified causative variants in 6 of 12 tested patients (50%), most commonly in UNC13D or STXBP2. Among the 19 patients with follow-up data, 7 (37%) survived.

Pediatric HLH with CNS involvement shows heterogeneous and often misleading initial presentations. Neurological-predominant manifestations may contribute to delayed recognition of HLH. Careful longitudinal assessment and consideration of genetic evaluation may facilitate earlier diagnosis in selected patients.