Paraneoplastic neurological syndromes: clinical presentations and management

Abstract

We provide an overview of the varied presentations of paraneoplastic neurological syndromes. We also review the onconeural antibodies and their particular oncological and neurological associations. Recognition of these syndromes and their oncological associations is crucial, as early diagnosis and management has been associated with better patient outcomes. Specific management strategies and prognosis vary widely depending on the underlying etiology. An understanding of the relevant clinical details, imaging findings, and other diagnostic information can help tailor treatment approaches. We provide an outline of the diagnostic evaluation and treatment of various paraneoplastic neurological disorders, presenting with central and/or peripheral nervous system involvement. We briefly discuss neurologic immune checkpoint inhibitor-related adverse events, which can occasionally present with paraneoplastic neurological syndrome phenotypes.

Keywords: Paraneoplastic neurological syndrome; immune checkpoint inhibitor; onconeural antibodies; paraneoplastic neurological disorder.

Figure 1.

Pathophysiological mechanisms for paraneoplastic neurological disorders. Tumor-targeted immune responses are initiated by proteins expressed in the plasma membrane, nucleus, cytoplasm, or nucleolus of certain cancer cells (A). These antigens are also expressed in neurons or glial cells and thus are coincidental targets. Intracellular antigens are not accessible to immune attack in situ, but peptides derived from intracellular proteins are displayed on upregulated MHC class I molecules after breakdown in the proteasome and in turn are targeted by peptide-specific cytotoxic T cells (B). Antibodies (e.g. anti-Hu or ANNA-1) targeting these intracellular antigens are not pathogenic but serve as diagnostic markers in clinical practice of a T-cell-predominant immune response. In contrast, antibodies directed at neural cell surface antigens (e.g. N-methyl-D-Aspartate [NMDA] receptors) are effectors through multiple mechanisms (C). (Reprinted by permission from Springer Nature, H. Mitoma, M. Manto (eds.), Neuroimmune Diseases, Contemporary Clinical Neuroscience. Shelly S, Narayan R, Dubey D. Autoimmune Limbic Encephalitis. 4750161436477).

Figure 2.

Unique indirect immunofluorescence assay on mouse brain with antihuman IgG staining. Key: ANNA-1, anti-neuronal nuclear antibody type-1 (anti-Hu); CRMP5, collapsin response-mediator protein-5; GM, gastric mucosa; KLHL11, Kelch-like Protein 11; MP, myentric plexus; WM, white matter.