Paraneoplastic Neurologic Disease

The term paraneoplastic neurologic disease (PND) encompasses several degenerative central or peripheral nervous system disorders that result from indirect effects of systemic cancer on elements of the nervous system. By definition, the dysfunction does not result from invasion or metastasis by tumor. The concept of a remote or indirect effect of cancer on the nervous system arose in the latter nineteenth century by empiric association between peripheral neuropathy and lung cancer (Oppenheim, 1888). During the first half of the twentieth century, the term paraneoplastic disease was applied to nearly any neurologic dysfunction in a cancer patient for which an etiology was not readily apparent. As a result, the category included a variety of metabolic, nutritional, vascular, and infectious disorders. In the latter half of the twentieth century, the autoimmune etiology of many paraneoplastic disorders evolved, beginning with the discovery of antineuronal antibodies in patients with small cell lung cancer (SCLC) (Croft and Wilkinson, 1965). Several different serum autoantibody markers have now been associated with the paraneoplastic neurologic clinical syndromes, which has allowed the clinician to confirm the diagnosis in suspect cases. However, the pathogenetic relationship between PND antibodies, clinical syndromes, and neuropathologic abnormalities has not been entirely clarified. Furthermore, not all patients with such autoantibodies have syndromes consistent with PND. Additional etiologies may be involved, such as infectious or parainfectious processes, nutritional deficiencies, or direct neurotoxicity from proteins and other substances elaborated by the tumor. Nonetheless, the description of specific autoantibodies in PND has resulted in separation of a group of patients with PND from others without antibodies. Many PND autoantibodies have now been associated with specific tumors, particularly those from lung, breast, gynecologic, and testicular neoplasms. In some circumstances, this has allowed the clinician to expedite the discovery of the primary cancer in suspect patients and designate the complicated neurologic illness in given patients as a paraneoplastic condition. A major future challenge still remains—the identification of effective therapies for these largely unresponsive conditions. Such therapies are likely to result from elucidation of the pathogenetic mechanisms involved in the production of these disorders.