Fulminant immune checkpoint inhibitor encephalitis associated with nivolumab: Case report and review of the literature

Abstract Introduction: Immune checkpoint inhibitors (ICIs) are increasingly used in oncologic clinical practice, and have significantly improved progression-free survival (PFS) and overall survival (OS) in a number of malignancies, including Hodgkin lymphoma. However, this has also led to a corresponding rise in immune-related adverse events (irAEs). Rarely, these events are associated with death, known as fulminant irAEs. Nivolumab, an ICI that inhibits programmed death-1 (PD-1) protein on T-cells, has been shown to have favorable PFS and OS in patients with relapsed/refractory Hodgkin lymphoma, and is now a recommended treatment option in this setting by the guidelines of the National Comprehensive Cancer Network. With this background, we report a case of fulminant ICI-associated encephalitis after a single administration of nivolumab, in a patient with recurrent Hodgkin lymphoma. Case Presentation: Within 24 hours of initiating nivolumab combined with brentuximab (an antibody-drug conjugate), a White male in his 70s with recurrent Hodgkin lymphoma and history of cutaneous T-cell lymphoma presented with altered mental status, status epilepticus, and abnormal signal in the bilateral temporal lobes on brain magnetic resonance imaging (MRI). Despite minor elevation in protein on lumbar puncture, there was no evidence of abnormal autoantibodies or pathogenic infection. Following multidisciplinary consultation, the patient was ultimately diagnosed with ICI-encephalitis and begun on empiric treatment with intravenous methylprednisolone dosed 1 g/day for 5 days, followed by 5 days of intravenous immunoglobulin (IVIG). The patient experienced resolution of electrographic seizures and gradual improvement of mental status toward baseline, but had persistent short-term memory loss and did not experience complete brain MRI recovery. Ultimately, hospice placement was pursued after goals of care discussions with the patient spouse, and the patient expired within one month of discharge.Discussion: Fulminant irAE has previously been reported in patients receiving nivolumab. In a multicenter analysis of 21 patients with fatal irAEs, the median time to onset following treatment initiation was 15 days, with the earliest occurring 3 days after treatment initiation. Fourteen of these patients were treated with PD-1 inhibitors (9 monotherapy, 5 combined PD-1/CTLA-4 blockade). Like our patient, 19 of the patients in the analysis also had a history of skin cancer, and median age of presentation was 72 years old. Aligning with previous reports, hyperintense signals in the bitemporal regions on T2/FLAIR sequences are the most prevalent MRI finding of fulminant ICI-associated encephalitis, with our patient demonstrating these characteristic MRI findings. However, the rapidity of our patient presentation has not been previously described in literature. Conclusion: This case serves as a safety signal for fulminant irAE following nivolumab administration. According to available literature, this represents the most rapidly-presenting case of fulminant irAE following administration of an ICI.