Paraneoplastic and Other Autoimmune Encephalitides: Antineuronal Antibodies, T Lymphocytes, and Questions of Pathogenesis

Abstract

Autoimmune and paraneoplastic encephalitides represent an increasingly recognized cause of devastating human illness as well as an emerging area of neurological injury associated with immune checkpoint inhibitors. Two groups of antibodies have been detected in affected patients. Antibodies in the first group are directed against neuronal cell surface membrane proteins and are exemplified by antibodies directed against the N-methyl-D-aspartate receptor (anti-NMDAR), found in patients with autoimmune encephalitis, and antibodies directed against the leucine-rich glioma-inactivated 1 protein (anti-LGI1), associated with faciobrachial dystonic seizures and limbic encephalitis. Antibodies in this group produce non-lethal neuronal dysfunction, and their associated conditions often respond to treatment. Antibodies in the second group, as exemplified by anti-Yo antibody, found in patients with rapidly progressive cerebellar syndrome, and anti-Hu antibody, associated with encephalomyelitis, react with intracellular neuronal antigens. These antibodies are characteristically found in patients with underlying malignancy, and neurological impairment is the result of neuronal death. Within the last few years, major advances have been made in understanding the pathogenesis of neurological disorders associated with antibodies against neuronal cell surface antigens. In contrast, the events that lead to neuronal death in conditions associated with antibodies directed against intracellular antigens, such as anti-Yo and anti-Hu, remain poorly understood, and the respective roles of antibodies and T lymphocytes in causing neuronal injury have not been defined in an animal model. In this review, we discuss current knowledge of these two groups of antibodies in terms of their discovery, how they arise, the interaction of both types of antibodies with their molecular targets, and the attempts that have been made to reproduce human neuronal injury in tissue culture models and experimental animals. We then discuss the emerging area of autoimmune neuronal injury associated with immune checkpoint inhibitors and the implications of current research for the treatment of affected patients.

Progressive Global Ataxia With Sensory Changes as a Paraneoplastic Syndrome in a Patient With Chromophobe Renal Cell Carcinoma

“…To our knowledge, there are no large, randomized trials evaluating its role in PNS and the majority of literature for use in this context comes from observational studies. Due to its suppressive effect on the immune system, rituximab can cause hepatitis B reactivation, hypogammaglobulinemia, infusion reactions, and progressive multifocal leukoencephalopathy, among others [ 24 ]. In the era of COVID-19, it is not inconceivable that anti-CD20 therapy, such as rituximab, may worsen disease course and prognosis, especially given lower vaccine immunogenicity [ 25 ].…”

PET-CT in Clinical Adult Oncology—V. Head and Neck and Neuro Oncology

“…It is important that imaging professionals and referring providers be aware of these conditions, which can mimic brain tumors or signal the presence of an underlying systemic malignancy with paraneoplastic neural manifestations [ 108 ]. Encephalitis is a devastating condition that can be seen with either paraneoplastic and autoimmune conditions as well as patients treated with check-point inhibitors [ 109 ]. The pathogenesis of these conditions may involve antibodies directed against neuronal components, such as those against the N-methyl-D-aspartate receptor (anti-NMDAR).…”

“…Again, MRI is critical in excluding this diagnosis. Immunotherapy and check point inhibitor therapy can result in encephalitis as well as hypophysitis, the latter showing increased uptake on FDG PET-CT in the pituitary gland [ 108 , 109 , 111 ]. Incidental note of uptake in the pituitary is most frequently due to either a micro adenoma (<1 cm diameter), or a macro adenoma (>1 cm in diameter) ( Figure 39 ).…”

Trial of cytotoxic T cell induction in mice as an ex vivo model of paraneoplastic neurologic syndrome with anti‐Hu antibodies

“…Moreover, they bind to relevant tumors and neuronal tissues, which indicate a close relationship with the pathogenesis of paraneoplastic neurologic syndromes. Several studies have assessed the direct role of antibodies in neuronal damage 6 . However, the results were controversial, and whether these antibodies, which recognize intracellular antigens such as anti‐Hu and anti‐Yo, damage the neurons remains unclear 7–10 .…”