We retrieved previously reported cases and identified 66 cases of anti-AMPAR encephalitis associated with tumors [1, 4,5,6,7,8,9,10,11,12,13,14,15]. Among these cases, thymic tumors (n = 30, median age 45 year, including 16 patients with thymoma, 13 patients with thymic carcinoma, and one patient with thymic carcinoid) were the most common, followed by lung cancer (n = 17, median age 65 year, including 11 patients with small cell lung cancer, two patients with non-small cell lung cancer, and four patients with undefined lung cancer), ovarian tumors (n = 8, median age 42 year, including two patients with ovarian adenocarcinoma and six patients with teratoma), breast cancer (n = 7, median age 61 year), medullary thyroid cancer (n = 1, age 69 year), melanoma (n = 1, age 61 year), Ewing sarcoma (n = 1, age 19 year), and seminoma (n = 1, age 36 year). The clinical manifestations varied among different tumor types. (Table 1)

Table 1 Clinical characteristics, treatment, and outcomes in anti-AMPAR encephalitis patients with tumors

AMPAR antibody titers in the serum or CSF were reported in 14 patients (Table 2). Notably, the CSF titer of several patients was negative; thus, acquiring paired serum and CSF samples of patients suspected of anti-AMPAR encephalitis is essential [16, 17]. The AMPAR antibody would decrease after immunotherapy [3, 18,19,20]. In our reported case, however, we did not obtain the patient’s antibody titer after immunotherapy because her relatives refused lumbar puncture. Severe symptoms such as consciousness and autonomic dysfunction are thought to be related to higher titers of AE antibodies. However, from the previous cases, we observed some patients presenting mild symptoms but with high titers in serum and/or CSF and some patients being in fatal status but had relatively lower titers [17, 20,21,22]. We supposed that the inconsistency was due to the concurrent onconeural antibodies, and the tumor itself might also have an impact on the severity of symptoms.

Table 2 Anti-AMPAR antibody titer, clinical manifestations, ICU admission, and outcomes in anti-AMPAR encephalitis patients with tumors

For patients with paraneoplastic anti-AMPAR encephalitis, both immunotherapies and tumor treatment are warranted. Almost all patients (87.5%) diagnosed with anti-AMPAR encephalitis associated with ovarian tumors received second-line immunotherapy, exceeding other tumors. ICU admission was also more likely to be reported in patients with ovarian tumors (85.7%), indicating anti-AMPAR encephalitis associated with ovarian tumors could deteriorate rapidly, and patients are more likely to suffer from fatal situations such as severe autonomic dysfunction and consciousness dysfunction. Thus, the first-line immunotherapies did not bring significant effects (Table 1). Furthermore, we supposed that the limited clinical improvement was also due to the clinical course specificity of the patient. For autoimmune encephalitis patients treated in our hospital and in cases reported previously, we found that the course of the disease varied in patients; some had a course several years long [3, 4, 9, 23]. For patients with a long disease course, treatments such as IVIG and plasmapheresis could not improve their symptoms in the short phase. For this group of patients, a second-line agent was applied. Due to its low toxicity and direct effects on B cells, rituximab is more commonly prescribed as the second-line agent by clinicians to improve patients’ outcomes. Moreover, some clinicians believe that adding second-line immunotherapy can also prevent the early relapse of AE [1]. However, there is no consensus for the treatment of autoimmune encephalitis except pediatric NMDAR encephalitis [24]. A multi-institutional observational study found that for patients who had no improvements within four weeks with first-line therapy, those who received second-line therapy had better outcomes than those who received either continued first-line treatment or discontinued therapy [25]. The result could be explained by the opinion that the second-line therapy should be initiated if patients do not respond to the first-line therapy within 4 weeks. Due to the mechanisms of rituximab and cyclophosphamide, the above result could be interpreted that for this group of patients, rituximab and/or cyclophosphamide should be applied as the first-line therapy [26]. A recent meta-analysis found that therapeutic apheresis alone or combined first-line therapy (corticosteroids and IVIG; corticosteroids, IVIG, and therapeutic apheresis) indicated good outcomes, providing evidence for first-line therapy selection. The study also concluded that timely initiation of second-line therapy was associated with better outcomes [27]. Since anti-AMPAR encephalitis patients associated with ovarian tumors were more likely to be in a fatal state, it is urgent to identify this patient group and initiate immunotherapy and vital support as early as possible.

We report the first case of anti-AMPAR encephalitis developed in an HGSOC patient after cytoreduction surgery. Cytoreduction surgery followed by platinum-based chemotherapy represents the standard treatment for epithelial ovarian cancer (EOC). Recently, new therapeutic strategies have proved to be effective. Adding bevacizumab to standard first-line platinum-based chemotherapy and to second-line therapy has demonstrated better survival outcomes in EOC patients. Although bevacizumab showed promising data in feasibility and safety as a neoadjuvant agent, it warrants further investigation in terms of administration timing considering the complications [28]. Poly (ADP-ribose) polymerase (PARP) inhibitors (PARP inhibitors) are emerging as the first-line maintenance treatment after platinum-based chemotherapy in newly diagnosed and as a maintenance treatment for relapse patients with BRCA mutated or HRD-positive settings [29]. Cytoreduction surgery refers to the curative treatment for peritoneal carcinoma. Its procedures include thorough surgical exploration and total omentectomy, with peritonectomy and organ(s) resection if suspecting carcinomas involvement [30]. Considering some patients’ encephalitis initiation began after cytoreduction surgery, we suggest cytoreduction surgery might be a trigger for AE. The tumor is considered a trigger for AE, our case and others reported GluA1/GluA2 expressions on the tumor tissue [1]. Surgical procedure might make it easier for the antigens on tumor tissue enter into circulation system, inducing the AMPAR antibodies production and encephalitis initiation. However, it is still unclear whether cytoreduction surgery or even tumor resection is related to the initiation of AE [1, 15, 31].

Of the previously reported anti-AMPAR encephalitis associated with ovarian tumors, one patient developed cognitive deficits following the surgery for ovarian adenocarcinoma [6, 9, 32]. Notably, we identified three cases in which patients developed encephalitis symptoms only a few days after tumor resection: two patients with breast cancer and another with thymoma [14, 15, 33]. Generally, patients with paraneoplastic AE develop encephalitis before detecting concurrent tumors or suggesting recurrent tumors [34,35,36,37,38,39]. However, some patients developed acute or subacute encephalitis symptoms after tumor resection [13,14,15, 33, 40]. For this group of patients, symptoms such as short-term memory loss and behavior change would develop in the non-neurology department and are easily neglected. Patients were discharged and readmitted in several weeks in our case and previously reported ones. If the possibility of AE could be suspected earlier, the earlier immunotherapy initiation might improve their outcomes. As a result, clinicians should consider AE as a differentiation diagnosis when postoperative patients with tumors develop acute/subacute symptoms indicating multifocal brain inflammation.

Here, we present an approach to detecting probable AE patients in the gynecology department. (Fig. S2) Perioperative diseases (including pulmonary embolism, ischemic stroke, and electrocyte abnormalities), neurological diseases (including cranial hemorrhage, infectious encephalitis, Hashimoto encephalitis, and brain metastases related to ovarian cancer), and postoperative delirium and cognitive dysfunction should be considered as differential diagnosis [41,42,43,44,45].

Anti-AMPAR encephalitis is rare, with various acute or subacute onset symptoms, including cognitive deficits, psychosis, and decreased consciousness. Most patients can respond to immunotherapy. Some of them, however, might experience life-threatening occasions. As a result, early diagnosis and quick initiation of immunotherapy, and mature basic life support techniques are required. The disease might develop postoperatively if the tumor is a trigger of AE, and cytoreduction surgery might further stimulate the antigens into the circulation system; thus, surgeons should keep alarmed at patients’ cognitive and consciousness conditions, especially those who undertake surgeries for breast cancer, thymoma, or ovarian cancer.

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