Anti-Ma2-Associated Limbic Encephalitis after Termination of Immune Checkpoint Inhibitor Therapy for Malignant Pleural Mesothelioma

Neurological adverse events of immune checkpoint inhibitor (ICI) therapy mostly develop within 3 months after initiation of ICI treatment. An 82-year-old male with malignant pleural mesothelioma developed anti-Ma2-associated limbic encephalitis at a delay of 18 months after the start of nivolumab therapy (3 months after termination of a 15-month course of ICI treatment). Immunotherapy with steroids and immunoglobulins resulted in moderate neurological improvement. Over the next year, malignant pleural mesothelioma gradually worsened, while the anti-Ma2 antibody test remained positive. Anti-Ma2 paraneoplastic encephalitis may occur after a delay following the discontinuation of ICI therapy.

Autoimmune encephalitis: proposed best practice recommendations for diagnosis and acute management

The objective of this paper is to evaluate available evidence for each step in autoimmune encephalitis management and provide expert opinion when evidence is lacking. The paper approaches autoimmune encephalitis as a broad category rather than focusing on individual antibody syndromes. Core authors from the Autoimmune Encephalitis Alliance Clinicians Network reviewed literature and developed the first draft. Where evidence was lacking or controversial, an electronic survey was distributed to all members to solicit individual responses. Sixty-eight members from 17 countries answered the survey. Corticosteroids alone or combined with other agents (intravenous IG or plasmapheresis) were selected as a first-line therapy by 84% of responders for patients with a general presentation, 74% for patients presenting with faciobrachial dystonic seizures, 63% for NMDAR-IgG encephalitis and 48.5% for classical paraneoplastic encephalitis. Half the responders indicated they would add a second-line agent only if there was no response to more than one first-line agent, 32% indicated adding a second-line agent if there was no response to one first-line agent, while only 15% indicated using a second-line agent in all patients. As for the preferred second-line agent, 80% of responders chose rituximab while only 10% chose cyclophosphamide in a clinical scenario with unknown antibodies. Detailed survey results are presented in the manuscript and a summary of the diagnostic and therapeutic recommendations is presented at the conclusion.

The contribution of thymic tolerance to central nervous system autoimmunity

Autoimmune diseases of the central nervous system (CNS) are associated with high levels of morbidity and economic cost. Research efforts have previously focused on the contribution of the peripheral adaptive and innate immune systems to CNS autoimmunity. However, a failure of thymic negative selection is a necessary step in CNS-reactive T cells escaping into the periphery. Even with defective thymic or peripheral tolerance, the development of CNS inflammation is rare. The reasons underlying this are currently poorly understood. In this review, we examine evidence implicating thymic selection in the pathogenesis of CNS autoimmunity. Animal models suggest that thymic negative selection is an important factor in determining susceptibility to and severity of CNS inflammation. There are indirect clinical data that suggest thymic function is also important in human CNS autoimmune diseases. Specifically, the association between thymoma and paraneoplastic encephalitis and changes in T cell receptor excision circles in multiple sclerosis implicate thymic tolerance in these diseases. We identify potential associations between CNS autoimmunity susceptibility factors and thymic tolerance. The therapeutic manipulation of thymopoiesis has the potential to open up new treatment modalities, but a better understanding of thymic tolerance in CNS autoimmunity is required before this can be realised.