The Perilous Journey of Patients With Primary CNS-HLH to Bone Marrow Transplant: A Case Report

Hemophagocytic lymphohistiocytosis (HLH) is a rare but life-threatening syndrome of immune dysregulation with an incidence of 1.2-1.5 cases per million children annually. Curative therapy for primary HLH requires hematopoietic stem cell transplantation (HSCT). A subset of patients develop central nervous system (CNS) involvement, which is associated with high morbidity and mortality yet remains poorly characterized. We describe two patients with genetically confirmed primary HLH (PRF1 mutations with impaired perforin activity) who developed CNS disease. Both presented to the emergency department with fever. Common features included pancytopenia, hepatosplenomegaly, cerebrospinal fluid pleocytosis, and absence of malignancy on bone marrow biopsy. Patient 1: Presented with fever, irritability, abnormal gait, abnormal eye movements, and significant abnormal MRI findings. Patient 2: Following RSV and streptococcal pharyngitis, developed fever, poor oral intake, and lethargy. Both patients received HLH-directed therapy (dexamethasone, etoposide, and emapalumab) plus intensive supportive care. Due to elevated neopterin and CNS disease, both underwent intrathecal chemotherapy to specifically target neuroinflammation. Outcomes diverged: Patient 1 developed refractory status epilepticus and died without transplantation, while Patient 2 successfully underwent HSCT and was discharged home. This case report highlights the heterogeneity of CNS involvement in primary HLH and its impact on outcomes. Elevated neopterin and neurologic manifestations may serve as critical early indicators of CNS disease. Despite advances in management strategies, timely recognition, aggressive treatment, and access to HSCT remain essential to survival. Broader clinical experience and collaborative studies are needed to optimize care strategies for CNS-HLH.