Immune checkpoint inhibitor‐associated central nervous system autoimmunity

Abstract

Background and purpose Outcome and rechallenge data on central nervous system (CNS) autoimmunity triggered by immune checkpoint inhibitors (ICIs) are limited. We aim to describe a large series of patients with ICI‐triggered CNS autoimmunity, and to compare these patients with spontaneous paraneoplastic syndromes (PNS). Methods We retrospectively reviewed Mayo Clinic patients with ICI‐triggered CNS autoimmunity (February 2015–June 2021). Clinical characteristics were compared to spontaneous PNS patients (with antineuronal nuclear antibody [ANNA]‐1 or anti‐Hu neurological autoimmunity, and/or neuroendocrine tumors [NET]) evaluated within the same period. Results Thirty‐one patients were included (55% female, median age = 63 years, range = 39–76). Median time from ICI initiation was 3.65 months (range = 0.8–44.5). The most common associated malignancies were melanoma and small cell lung cancer. CNS manifestations included encephalitis (n = 16), meningoencephalitis (n = 8), cerebellar ataxia (n = 4), demyelinating syndrome (n = 2), and myelopathy (n = 1). Magnetic resonance imaging was abnormal in 62%. Cerebrospinal fluid was inflammatory in 70%. Neural autoantibodies were identified in 47%, more frequently in patients with NET (p = 0.046). ICI was discontinued in 97%; 90% received immunosuppressive treatment. After median 6.8 months follow‐up (range = 0.7–46), 39% had unfavorable outcomes (grade ≥ 3). This was associated with higher severity degree at onset, shorter period from ICI to neurological symptom onset, and encephalitis. Four patients were rechallenged with ICI, and one relapsed. Patients with NET and with ANNA‐1 ICI‐triggered CNS autoimmunity had associated peripheral nervous system manifestations more frequently than their spontaneous counterparts (p = 0.007 and p = 0.028, respectively). Conclusions One third of ICI‐related CNS autoimmunity patients have unfavorable outcomes. Relapses may occur after ICI rechallenge. Neural autoantibodies are often present, more commonly in patients with NET.

Autoimmune Encephalitis Following Check Point Inhibitor Therapy in a Patient with Metastatic Melanoma in Complete Remission

“…The majority of these patients received immunosuppressive treatment and ICIs was discontinued in 97%. The unfavorable outcome was described in 39% of the entire reported series, and it was associated with higher severity degree at onset, shorter period from ICIs to the onset of neurological symptoms [18].…”

Immune-Related Adverse Events Due to Cancer Immunotherapy: Immune Mechanisms and Clinical Manifestations

“…Focal encephalitis is the most frequent CNS N-irAE, occurring in more than 50% of cases [159,171]. Several phenotypes have been described, but most patients present a well-defined limbic or brainstem encephalitis, whereas isolated cerebellar syndromes are less common [159,172].…”

“…Meningitis and meningoencephalitis are less common and usually present with fever, meningeal signs with or without encephalopathy [171,172]. In some cases, anti-GFAP Abs may be detected [172].…”

Neurological Immune-Related Adverse Events Induced by Immune Checkpoint Inhibitors

“…Brain MRI is unrevealing in up to 50% of cases; however, leptomeningeal contrast enhancement and brain parenchymal T2 hyperintensities have been seen in a subgroup of cases [ 65 , 66 ]. Paraneoplastic antineuronal antibodies are usually absent; however, glial fibrillary acidic protein (GFAP) antibodies have been detected in a few cases [ 62 , 67 ]. Despite disease severity at the peak of clinical symptoms, the prognosis is usually favorable following ICI withdrawal and immunosuppressive treatment initiation [ 66 ].…”