Abstract Immune checkpoint inhibitors (ICI) have revolutionized cancer therapy but can induce a broad spectrum of immune-related adverse events (irAE), including neurological syndromes. Among these, autoimmune encephalitis (AE) has been increasingly recognized. While several well-characterized antibodies—such as anti-NMDA receptor and anti-LGI1—are frequently linked to AE, the involvement of anti-titin antibodies is rare, with only a few cases reported to date. We present the case of a 74-year-old man with metastatic lung adenocarcinoma, involving the brain and paracardial lymph nodes (cT1bN3M1c), who experienced changes in his psychiatric symptoms and developed mild cognitive impairment following three cycles of treatment with cisplatin, pemetrexed, and pembrolizumab. On admission, akathisia was initially considered in the differential diagnosis of his behavioral impairments, but medication adjustment did not lead to improvement. Brain MRI showed multifocal T2-FLAIR hyperintensities in the white matter, in addition to the known brain metastases, consistent with demyelination. Cerebrospinal fluid analysis conducted later revealed no evidence of infection or malignant cells but was positive for anti-titin antibodies. Based on Graus’ diagnostic criteria, a diagnosis of autoimmune encephalitis was made. On hospital day 20, corticosteroid pulse therapy was initiated, resulting in marked improvement of his symptoms within a few days. After discharge, his clinical course remained favorable for several months while receiving pemetrexed monotherapy as an outpatient. This appears to be the first documented case of anti-titin positive AE in a patient with non-small cell lung cancer (NSCLC). However, the role of anti-titin antibodies remains poorly understood. Anti-titin antibodies are most commonly associated with myasthenia gravis and thymoma but have also been identified with various malignancies, including prostate, breast, and small cell lung cancers. Coexisting autoimmune disorders, such as Hashimoto’s disease, and additional autoantibodies, including anti-GABAA receptor and anti-GAD antibodies, have also been reported. These observations emphasize the need for broad autoantibody and malignancy screening when anti-titin antibodies are present. Moreover, previous studies have suggested that ICI therapy may disrupt immune homeostasis and unmask latent autoimmunity, which also seemed to occur in our case. Early initiation of immunotherapy may have contributed to better prognosis. This case highlights the importance of considering immune-mediated neurological complications during ICI treatment and the value of early antibody detection and prompt immunosuppressive therapy. Further studies are needed to clarify the role of anti-titin antibodies in autoimmune encephalitis, particularly in the context of ICI therapy. This abstract is funded by: None
Kanemoto et al. (Fri,) studied this question.