AMPAR is a subtype of glutamate receptor that mediates most of the fast excitatory neurotransmission in the brain. The majority of AMPAR are tetramers composed of GluR1, 2, 3 or 4 subunits. A high level of GluR1/2 and GluR2/3 receptors is found in the synaptic CA3-CA1 areas of the hippocampus followed by the subiculum, cerebellum, caudate-putamen, and cerebral cortex (7).
The thymus is a central organ for the development of the immune system, particularly for the selection of T cells with appropriate self-tolerance (8). It is not surprising that thymoma is considered to be a possible initiator for most paraneoplastic neurological disease, such as AE (8). In 2009, Lai (7) first reported three patients with anti-AMPAR encephalitis, and thymoma were identified among 109 cases of limbic encephalitis. To date, eleven cases of thymoma-associated anti-AMPAR2 encephalitis have been described in six publications (Table) (6, 7, 9-12). In most cases, thymoma was detected in oncological screening with the first episode of encephalitis, though a malignant thymoma treated with radiotherapy and chemotherapy six years prior to encephalitis was found in one case (9). Our case was unique in that the patient initiated with the symptom of myasthenia gravis and thymoma two years prior to AE, and a complete thymectomy was performed before AE onset without recurrence of the thymoma when AE occurred. Recently, a patient with anti-AMPAR encephalitis who was reported to be in remission for 34 months showed clinical relapse three months after the detection of recurrent thymoma (11). Our case raises the questions of whether the autoantigens could be expressed by the thymus after thymectomy, and how these autoantigens from thymic tumors could trigger immune disorders. It is probable that these autoantigens were expressed by the thymus at an early stage before thymectomy and existed in the central nervous system or blood circulatory system and that AE was caused by these autoantigens due to virus infection or over-fatigue.
Anti-AMPAR encephalitis has been reported to be associated with other autoimmune antibodies, such as antibodies against ANA, dsDNA, cardiolipin, glutamic acid decarboxylase (GAD), CV2/CRMP5 and AChR (5, 6). AChR Ab is also positive in our patient; however, the immune relationships between these antibodies and AMPAR Ab has not been thoroughly elucidated to date.
Fourteen cases in 22 patients with anti-AMPAR encephalitis had tumors, such as lung cancer, thymoma, breast cancer, or ovarian teratoma, indicating that paraneoplastic autoimmunity plays a key role in the pathogenic mechanisms of anti-AMPAR encephalitis (10). However, that no tumor has been identified in eight cases of 22 patients with anti-AMPAR encephalitis implies that other mechanisms may exist in addition to paraneoplastic autoimmunity (10).
Based on the clinical outcome of our patient and review of the published literature, tumor removal with or without chemotherapy and radiotherapy may be applied to anti-AMPAR encephalitis with thymic tumors, and immunotherapy including corticosteroids, IVIg and plasma exchange during presentation or relapse and chronic treatment with rituximab or azathioprine may prevent relapse and improve outcomes. In patients with anti-AMPAR encephalitis, oncological screening is mandatory with a particular focus on the thymus, lung and breast (12).
There are several limitations to our study. A more intense oncological screening and long-term follow-up is needed to determine whether the patient has other tumors or metastatic tumors in addition to thymoma.
In conclusion, we presented a case in which a thymectomy was applied in a myasthenia gravis patient with thymoma two years prior to the onset of anti-AMPAR2 encephalitis. This case highlights the complexity of autoimmune encephalitis associated with thymoma.
