Paraneoplastic Immune-Mediated Disorders (Continued)

The evolution of our understanding of paraneoplastic autoimmunity began with descriptions of particular syndromes associated with specific cancers and subsequent individual autoantibody identification. Antineuronal nuclear autoantibody type-1 (ANNA-1), also known as anti-Hu, was initially reported in patients with sensory neuronopathies related to small cell lung cancer (SCLC). Purkinje cell cytoplasmic autoantibody-type-1 (PCA-1), also known as anti-Yo, was first recognized in women with cerebellar ataxia and ovarian carcinoma. ANNA-2 (also known as anti-Ri) was initially reported in women with opsoclonus/myoclonus related to breast carcinoma. The antiamphiphysin antibody was first reported in women with “stiff-man” syndrome related to breast carcinoma.

In contrast, most paraneoplastic autoantibodies are associated with a multifocal, variable neurologic presentation involving multiple neuroaxis levels in most patients. Moreover, patterns of involvement vary significantly from one patient to another despite the presence of the same autoantibody or autoantibody profile. When tabulating the patterns of nervous system dysfunction by reported associated autoantibody, it becomes clear that although given antibodies are associated with specific syndromic presentations, these are not uniquely associated with the autoantibody, per se, nor is the expression of autoantibodies uniquely associated with one level of nervous system disease. However, when tabulating known autoantibodies by predictive value for identifying underlying neoplasms, the antibody or pattern of antibodies primarily predicts the cancer and not specific neurologic disorders. Understanding that the immune response to a tumor is highly complex, and that the expression of autoimmunity is related to dysregulation of immune function at any number of potential checkpoints, the complexity and range of neurologic autoimmunity for given patients with specific malignancies becomes easier to comprehend.

Cancers associated with paraneoplastic neurologic disorders are most often clinically asymptomatic and not defined, per se, until the appearance of the specific clinical syndrome dictates an evaluation for such, and that, per se, may not initially always lead to a diagnosis. Sometimes the cancer is not identified for months to years after the onset of the paraneoplastic neurologic syndrome. Taken together, the current appreciation of the pathophysiology of cancer-related autoimmunity, the understanding of autoantibodies as markers of a complex evolving immunoediting response, and knowledge that those antibodies are markers of the immune response to a specific cancer and not a specific neurologic syndrome, a diagnostic paradigm leading to a potentially specific diagnosis emerges. The specific neurologic disorder leads to an evaluation that includes a means to localize the disease, and exclude other diseases having a similar presentation. The suspicion of neurologic autoimmunity leads to testing for a panel of known paraneoplastic autoantibodies and search for an underlying cancer appropriate to age, sex, and risk factors such as tobacco abuse. Certain antibodies direct specific cancer investigations or, when unrevealing after an appropriately exhaustive search, a need for long-term surveillance. The need for immunotherapy is dictated by the severity of the underlying neurologic disorder, plans for treatment of the primary tumor, and previous experience with response to specific immunotherapeutic approaches for known conditions. There is always the inherent and paradoxical risk that initiation of immunomodulating therapy may suppress the body’s ability to fight the cancer, allowing it to appear sooner than it might have, barring this therapeutic intervention.

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