Paraneoplastic Neurologic Disorders

Epidemiology

Overall, paraneoplastic neurologic disorders are rare; they are present in up to 0.01% of the cancer patients; exceptions exist, for example myasthenia gravis (MG) is seen in 30%–40% of patients with thymoma. The commonest cancers associated with paraneoplastic neurologic disorder include SCLC, adenocarcinoma of the breast and ovary, and thymoma.

Pathogenesis

Paraneoplastic autoimmunity is initiated by onconeural proteins expressed in the plasma membrane, cytoplasm, nucleus, or nucleolus of certain tumor cells; neural cell populations are coincidental targets. Depending on the location of antigen, cell surface versus intracellular, the consequent neural damage and response to immunotherapy may differ. It is thought that antibodies directed toward intracellular antigens are probably not causative of neural injury, because the antibodies do not come in direct contact with the intracellular epitopes. The immune response in these disorders with intracellular antigens involves cytotoxic T cell–mediated cytotoxicity. In contrast, antibodies against cell surface antigens have access to epitopes on cell surfaces resulting in immune-mediated attack on the function and structure of neurons; these disorders are usually more amenable to immunotherapy treatments ( Table 51.1 ).

Diagnostic Principles

• Key indicators of paraneoplastic autoimmunity-related neurologic disorders include acute to subacute course of disease, multifocal and broad range of neurologic signs and symptoms, and positive family and/or personal history of autoimmunity.

• Identification of specific antibodies in serum and/or cerebrospinal fluid (CSF) targeting neural (neuronal and glial) cells may provide clues to the specific cancer type; however, one cannot extrapolate definitively from these data to the neurologic presentation, because one specific antibody may be associated with different phenotypes, and different antibodies may cause the same clinical syndrome.

• It is not unusual to find more than one serum antibody on testing for paraneoplastic syndromes, because cancer cells often express multiple antigens with resulting activation of an immune response. These antibody clusters allow prediction of the associated cancer. For example, thymoma is present in 85% of patients, younger than 50 years, who have a combination of muscarinic acetylcholine receptor (AChR) antibody and striational antibody.

• Antibody testing should be done both in CSF and serum, where indicated, because this will increase the diagnostic yield. CSF has higher sensitivity compared with serum in detection of N -methyl- d -aspartate receptor (NMDAR) antibodies; in contrast, serum is more sensitive for detection of aquaporin-4 (AQP4) IgG.

• Low titers of paraneoplastic antibodies may be seen in patients with autoimmune disorders, and these may not be pathogenic. Patients prone to autoimmunity may show incidental seropositivity for voltage-gated potassium channel (VGKC) complex or ganglionic AChR without evidence of corresponding neurologic disorders. Therefore the clinical syndrome must match the disease profile of the detected antibody; if it does not, then alternative causes should be sought for the patient's symptoms.

• Monitoring for relapses primarily consists of serial clinical assessment. Usually, antibody titers are not monitored. In some instances, significant elevation in antibody titers may portend return of the underlying cancer.

• CSF analysis in paraneoplastic neurologic disorders may show additional abnormalities such as elevated protein, pleocytosis, oligoclonal bands, elevated IgG, IgG index, and/or kappa chains.