Copine-5-IgG-related autoimmune encephalitis: a novel paraneoplastic neurological syndrome with a strong melanoma association

BACKGROUND: Although significant progress has been made in identifying antigen targets in autoimmune encephalitis (AIE), in a substantial proportion of patients with presumed AIE no known autoantibodies can be detected. Herein, we describe a novel autoantibody reactivity, directed against copine-5 (CPNE5), in patients with AIE and melanoma. METHODS: Patients were identified through routine clinical testing for anti-neural autoantibodies by indirect immunofluorescence on neuronal tissue sections. The antigen was identified by immunoprecipitation and mass spectrometry and confirmed by recombinant protein assays. RESULTS: Serum and cerebrospinal fluid (CSF) immunoglobulin G (IgG) from four patients was found to exhibit distinct binding to cerebellar and hippocampal neurons. Copine-5 was identified as the target antigen. Clinical manifestations included cognitive decline, confusion/disorientation, psychosis, seizures and signs and symptoms compatible with basal ganglia involvement (movement disorders, including secondary parkinsonism, and/or abulia/akinetic mutism), alongside pain (including painful tonic spasms and focal allodynia), dysarthria, dysphagia, and abducens nerve palsy. Brain magnetic resonance imaging disclosed hyperintense lesions in the basal ganglia and the temporal lobe. CSF analysis revealed mild pleocytosis, intrathecal IgG synthesis, and blood/CSF barrier dysfunction. Of particular note, all four patients had melanoma, with an occult primary in three. In one patient, melanoma diagnosis and immunotherapy with the anti-PD-1 immune checkpoint inhibitor nivolumab preceded the onset of AIE by 9 months. Glucocorticoid treatment and/or intravenous immunoglobulins led to transient improvement in at least three patients; however, all relapsed and three progressed to hypoactive delirium or mutism. Plasma exchange and cyclophosphamide treatment were followed by clinical improvement and stabilization in one patient, but potentially contributed to fatal infectious complications. Copine-5-IgG belonged to the strongly complement-activating IgG1 subclass and was produced intrathecally. Serum titers ranged between 1:1000 and 1:100,000. CONCLUSIONS: Copine-5 is a novel autoantibody target in AIE. Testing for anti-copine-5 autoantibodies should be included in the diagnostic workup of patients with AIE, especially, but not exclusively, if associated with melanoma or positive melanoma-associated tumor markers. Further studies investigating the immunopathogenesis of copine-5-related autoimmunity and the potential significance of anti-copine-5 as a novel paraneoplastic serological marker and of copine-5 as a histopathological tumor marker in patients with suspected melanoma are highly warranted.