Case Presentation: An elderly man was diagnosed with clear cell renal cell carcinoma in 1987, and treated with left nephrectomy, though developed multi-organ metastatic disease in 2015. After he did not tolerate initial treatment with sunitinib, he received 15 cycles of NKTR-214 and nivolumab as part of a phase I/II study. Three months after his final cycle he presented to the hospital with one week of fevers and progressive lethargy. He demonstrated expressive aphasia, but no other focal neurologic deficits. He was febrile and tachycardic. MR brain imaging showed mild diffuse FLAIR hyperintensity. Providers started empiric broad spectrum antibiotics, acyclovir, and fosphenytoin. Lumbar puncture revealed CSF with lymphocytic pleocytosis of 65 and an elevated protein of 126 mg/dL. Viral encephalitis panel and meningitis-encephalitis PCR panels were negative. Video EEG showed no epileptiform activity. The patient remained febrile with worsening encephalopathy and decreased arousal over the following days. Out of concern for immune-related encephalitis, despite three months passing since his last immunotherapy, providers cautiously decided to initiate empiric treatment with high dose intravenous steroids. The day of his first dose of steroids, the patient demonstrated dramatic improvement in his mental status. Antibiotics and antivirals were discontinued. He was discharged to acute rehabilitation and subsequently returned home the following week with near complete resolution of his presenting symptoms. After discharge, CSF autoimmune and paraneoplastic encephalitis studies resulted as negative.
Discussion: The development of immune checkpoint inhibitors (ICPis) has transformed the field of cancer treatment. The drug in question, nivolumab, inhibits programmed cell death protein 1 (PD-1) to mediate anti-tumor response, and has been approved to treat a variety of malignancies. Despite their increasingly recognized clinical benefit, ICPis have been linked to significant and unique adverse events, the scope of which continue to be elucidated. ICPi-associated neurologic toxicities, including encephalitis, are common though heterogenous, and affect up to 6% of people taking PD-1 inhibitors. If suspected, PD-1 inhibitor associated encephalitis workup should include brain MRI, lumbar puncture, EEG, and basic lab tests to rule out other causes of encephalopathy. Surprisingly, as demonstrated in this case, ICPi-related adverse reactions can occur months after cessation of therapy. Because of limited general awareness of such delayed reactions, our hospitalist team was initially apprehensive about treating him with the recommended pulse-dose steroids for immune-related encephalitis before all infectious and non-infectious etiologies of his altered mental status had been definitively ruled out. However, early consideration and timely treatment of delayed immune-related encephalitis spared this patient further devastating non-traumatic brain injury and prolonged hospitalization.
Conclusions: We add this case to a limited but growing literature describing severe delayed ICPi-related adverse reactions that can occur months after cessation of immunotherapy. An awareness of delayed reactions, and understanding of workup and treatment considerations, is of vital importance to hospitalists who care for a growing population of patients treated with ICPis.