[Anti-Ma2-associated encephalitis and paraneoplastic limbic encephalitis]

Abstract

Anti-Ma2-associated encephalitis (or anti-Ma2 encephalitis) is a paraneoplastic neurological syndrome (PNS) characterized by isolated or combined limbic, diencephalic, or brainstem dysfunction. Anti-Ma2 antibodies detected in the serum or cerebrospinal fluid of patients are highly specific for this disease entity and belong to a group of well-characterized onconeuronal antibodies (or classical antibodies). The corresponding antigen, Ma2 is selectively expressed intracellularly in neurons and tumors as is the case with other onconeuronal antigens targeted by classical antibodies. However, in most cases the clinical pictures are different from those of classical PNS and this creates a potential risk of underdiagnosis. Although limbic dysfunction is the most common manifestation in patients with anti-Ma2 encephalitis which is one of the major causes of paraneoplastic limbic encephalitis (LE), it has been reported that less than 30% of the patients with anti-Ma2 LE exhibit clinical presentations typical of the classical description of LE. Of the remaining, many exhibit excessive daytime sleepiness, vertical ophthalmoparesis, or both associated with LE, because of frequent involvement of the diencephalon and/or upper brainstem. Anti-Ma2 LE can also be manifested as a pure psychiatric disturbance such as obsessive-compulsive disorder in a few cases. Some patients develop mesodiencephalic encephalitis with minor involvement of the limbic system, and some may manifest severe hypokinesis. About 40% of the patients with anti-Ma2 antibodies also have antibodies against different epitopes on Ma1, a homologue of Ma2. These patients may have predominant cerebellar and/or brainstem dysfunctions due to more extensive involvement of subtentorial structures. Anti-Ma2 encephalitis is outstanding among other PNS associated with classical antibodies in that the response rate to treatment is relatively high. While it can cause severe neurological deficits or death in a substantial proportion of the patients, approximately one-third show neurological improvement and another 20 - 40% stabilize in response to treatment, including immunotherapy and/or tumor treatment. Patients who have limited CNS involvement and testicular tumors with complete response to therapy are more likely to show neurological improvement. This fact emphasizes the importance of early diagnosis and prompt initiation of therapy. However, it should be noted that even carcinoma in situ, which is difficult to detect can cause severe neurological disorders. In this respect, it is useful to highlight that anti-Ma2 encephalitis is almost always associated with testicular germ cell tumors in men younger than 50 years. We experienced a 40-year-old patient with severe hypokinesis caused by anti-Ma2 encephalitis associated with bilateral intratubular germ-cell neoplasm of the testes. In older men and women, non-small-cell lung cancer is most common but various types of cancers are reported to be associated. In this study,in addition to reviewing the above case we have reviewed the significance of anti-Ma2 antibodies in the diagnosis of anti-Ma2 encephalitis and the clinical features of this disease.