Kon Chu

Teratoma pathology and genomics in anti‐NMDA receptor encephalitis

AbstractIntroductionOvarian teratoma is a common occurrence in patients with anti‐NMDA receptor encephalitis (NMDARe), and its removal is crucial for a favorable prognosis. However, the initial pathogenesis of autoimmunity in the encephalitic teratoma remains unclear. In this study, we aimed to investigate the genomic landscape and microscopic findings by comparing NMDARe‐associated teratomas and non‐encephalitic control teratomas.Materials and MethodsA prospective consecutive cohort of 84 patients with NMDARe was recruited from January 2014 to April 2020, and among them, patients who received teratoma removal surgery at Seoul National University Hospital were enrolled. We conducted a comparison of whole‐exome sequencing data and pathologic findings between NMDARe‐associated teratomas and control teratomas.ResultsWe found 18 NMDARe‐associated teratomas from 15 patients and compared them with 17 non‐encephalitic control teratomas. Interestingly, the genomic analysis revealed no significant differences in mutations between encephalitic and non‐encephalitic teratomas. Pathologic analysis showed no discrepancies in terms of the presence of neuronal tissue and lymphocytic infiltration between the encephalitic teratomas (n = 14) and non‐encephalitic teratomas (n = 18). However, rituximab‐naïve encephalitic teratomas exhibited a higher frequency of germinal center formation compared to non‐encephalitic teratomas (80% vs. 16.7%, P = 0.017). Additionally, rituximab‐treated encephalitic teratomas demonstrated a reduced number of CD20+ cells and germinal centers in comparison to rituximab‐naïve encephalitic teratomas (P = 0.048 and 0.023, respectively).DiscussionThese results suggest that the initiation of immunopathogenesis in NMDARe‐associated teratoma is not primarily attributed to intrinsic tumor mutations, but rather to immune factors present in the encephalitic patient group, ultimately leading to germinal center formation within the teratoma.

Teratoma Removal, Steroid, IVIG, Rituximab and Tocilizumab (T-SIRT) in Anti-NMDAR Encephalitis

In anti-N-methyl-D-aspartate receptor (NMDAR) encephalitis, we analysed the efficacy of a combined immunotherapy protocol consisting of teratoma removal, steroid, intravenous immunoglobulin (IVIG), rituximab and tocilizumab (T-SIRT). This cohort study included seventy-eight consecutive patients treated for anti-NMDAR encephalitis between Jan 2014 and Oct 2019 in a national referral hospital. Detailed 2-year disease time course was analysed using Clinical Assessment Scale for Autoimmune Encephalitis (CASE) scores at every 2 weeks for 12 weeks from baseline, every month for the next 3 months and then every 3 months. Treatment regimens at each time point were categorized as SI, SIR, or SIRT with/without teratoma removal (T). Adverse events were classified according to the Common Terminology Criteria for Adverse-Events (CTCAE v5.0), where a severe adverse event was defined as an adverse event with CATAE grade 4. In a linear mixed model analysis, using the SIRT regimen was more effective than SIR or SI regimens in lowering CASE scores (P < 0.001 and P = 0.001, respectively). The presence of teratoma (P = 0.001), refractory status epilepticus (P < 0.001) and a higher CASE score at baseline (P < 0.001) predicted a higher CASE score at each time point. Completion of the (T)-SIRT regimen within 1 month of onset resulted in better 1-year improvements in CASE score (P < 0.001) and modified Rankin scale scores (P = 0.001), compared to those of using other regimens within 1 month or delaying teratoma removal for more than 1 month. Pneumonia was a frequent adverse event (52/78, 66.7%) in the whole study population and neutropenia was frequent during SIRT (11/52, 21.2%), but the regimen was well tolerated in most patients. We concluded that the early application of combined immunotherapy consisting of T-SIRT had better efficacy than was found for delayed or partial application of this combination in anti-NMDAR encephalitis.