From the Departments of Neurology (H.M., D.K., M.E., P.M.) and Immunology (J.H.), Second Faculty of Medicine Charles University and Motol University Hospital, Prague, Czech Republic; Institute of Clinical Chemistry (J.D., K.-P.W., F.L.), University Hospital Schleswig-Holstein, Kiel/Lübeck; and Neuroimmunology (F.L.), Department of Neurology, University Hospital Schleswig-Holstein Kiel, Germany.
Neurol Neuroimmunol Neuroinflamm. 2023 Oct 25;10(6). doi: 10.1212/NXI.0000000000200170. Print 2023 Nov.
Autoimmune encephalitis (AE) refers to a heterogenous group of inflammatory CNS diseases. Subgroups with specified neural autoantibodies are more homogeneous in presentation, trigger factors, outcome, and response to therapy. However, a considerable fraction of patients has AE features but does not harbor detectable autoantibodies and is referred to as antibody-negative AE. Our aim was to describe clinical features, trigger factors, treatments, and outcome of a cohort of comprehensively tested antibody-negative AE patients.
This retrospective monocentric study recruited adult patients whose serum and/or CSF was sent to our tertiary center for neural antibody testing between 2011 and 2020, who entered the diagnostic algorithm as possible antibody-negative AE and had the following: (1) probable antibody-negative AE, definite antibody-negative acute disseminated encephalomyelitis (ADEM), or definite autoimmune limbic encephalitis (LE) according to diagnostic criteria; (2) available data on MRI of the brain, CSF, and EEG; and (3) stored serum and/or CSF samples. These samples were reanalyzed using a comprehensive combination of cell-based and tissue-based assays.
Of 2,250 patients tested, 33 (1.5%) were classified as possible antibody-negative AE. Of these, 5 were found to have antibodies by comprehensive testing, 5 fulfilled the criteria of probable AE (3F:2M, median age 67, range 42-67), 4 of definite autoimmune LE (2F:2M, median age 45.5, range 27-60 years), one of definite antibody-negative ADEM, 2 of Hashimoto encephalopathy, one had no samples available for additional testing, and 15 had no further categorization. Of 10 probable/definite AE/LE/ADEM, one had a malignancy and none of them received an alternative diagnosis until the end of follow-up (median 18 months). In total, 80% (8/10) of patients received immunotherapy including corticosteroids, and 6/10 (60%) patients received rituximab, azathioprine, cyclophosphamide, plasma exchange, or IV immunoglobulins. Five (50%) patients improved, one (10%) stabilized, one (10%) worsened, and 3 (30%) died. All deaths were considered to be related to encephalitis. We did not observe differences of immunotherapy-treated patients in likelihood of improvement with or without nonsteroidal immunotherapy (with 2/6, without 1/2).
Antibody-negative AE should be diagnosed only after comprehensive testing. Diagnostic effort is important because many patients benefit from immunotherapy and some have malignancies.
自身免疫性脑炎（AE）是指一组异质性的中枢神经系统炎症性疾病。具有特定神经自身抗体的亚组在表现、触发因素、结局和治疗反应方面更为一致。然而，相当一部分患者具有 AE 特征，但未能检测到自身抗体，被称为抗体阴性 AE。我们的目的是描述一组经过全面检测的抗体阴性 AE 患者的临床特征、触发因素、治疗方法和结局。
这项回顾性单中心研究纳入了 2011 年至 2020 年期间血清和/或脑脊液被送到我们的三级中心进行神经抗体检测的成年患者，这些患者符合以下标准进入诊断算法：（1）根据诊断标准，可能为抗体阴性 AE、明确的抗体阴性急性播散性脑脊髓炎（ADEM）或明确的自身免疫性边缘性脑炎（LE）；（2）脑 MRI、CSF 和 EEG 检查数据可用；（3）有储存的血清和/或 CSF 样本。这些样本使用细胞和组织综合检测进行了重新分析。
在 2250 例接受检测的患者中，33 例（1.5%）被归类为可能的抗体阴性 AE。其中，5 例通过全面检测发现抗体，5 例符合可能的 AE 标准（3 例女性，2 例男性，中位年龄 67 岁，范围 42-67 岁），4 例符合明确的自身免疫性 LE（2 例女性，2 例男性，中位年龄 45.5 岁，范围 27-60 岁），1 例符合明确的抗体阴性 ADEM，2 例符合桥本脑病，1 例无样本可用于进一步检测，15 例无进一步分类。在 10 例可能/明确的 AE/LE/ADEM 患者中，有 1 例存在恶性肿瘤，在随访结束前（中位时间 18 个月），均未发现其他替代诊断。总的来说，80%（8/10）的患者接受了免疫治疗，包括皮质类固醇，6/10（60%）的患者接受了利妥昔单抗、阿扎胞苷、环磷酰胺、血浆置换或静脉注射免疫球蛋白。5 例（50%）患者病情改善，1 例（10%）病情稳定，1 例（10%）恶化，3 例（30%）死亡。所有死亡均被认为与脑炎有关。我们没有观察到接受免疫治疗的患者在有无非甾体免疫治疗的情况下（有 2/6 例，无 1/2 例）改善的可能性有差异。
只有在进行全面检测后，才能诊断抗体阴性 AE。进行诊断性检查非常重要，因为许多患者受益于免疫治疗，有些患者存在恶性肿瘤。
