Hemophagocytic lymphohistiocytosis (HLH) is a rare and severe inflammatory syndrome characterized by hyperactivity of macrophages and lymphocytes. Although not part of diagnostic criteria, neurological involvement is common and can range from meningeal inflammation with normal MRI to parenchymal lesions. Prompt diagnosis and treatment is imperative to prevent neurological sequela but demands a high degree of clinical suspicion. 

A 78-year-old woman with hypertension, type 2 diabetes mellitus, and hyperlipidemia presented with acute on chronic lower back pain and confusion. Laboratory workup was significant for severe transaminitis, along with pancytopenia, and soon after she developed fevers up to 39^oC. Neuroimaging was unrevealing and cerebrospinal fluid (CSF) studies only showed mild hyperproteinemia (42 mg/dL) and lymphocyte-predominant pleocytosis (12/µL). CSF cultures and autoimmune encephalitis antibodies were negative, and patient had no electrolyte abnormalities or use of delirium-causing medications. Vitamins B12 and B1, urea, and ammonia levels were normal. Further workup revealed elevated ferritin (11,963.1 ng/mL), hypertriglyceridemia (183 mg/dL) and soluble Interleukin-2 receptor (38,695.5 pg/mL) with normal fibrinogen level (184 mg/dL). Given the concern for HLH (HScore of 210), liver and bone marrow biopsies were obtained and confirmed histiocytic infiltrative disease. Genetic studies demonstrated loss of D20S108 (20q12) and mutations on SF3B1, TP53 and RUNX1, typical of hematological malignancies and HLH. Treatment with etoposide and dexamethasone per HLH-94 protocol was initiated with initial improvement of hepatic function but persistent encephalopathy. Eventually, the decision was made per family wishes to defer oncological treatment and the patient was transitioned to hospice care.

This is case demonstrated an unusual path of encephalopathy leading to the diagnosis of HLH. Despite neurological manifestations being common, HLH remains rare and low clinical suspicion for this condition can severely delay diagnosis and treatment.