基于“责任抗体”概念的自身免疫性脑炎诊断与治疗进展

自身免疫性脑炎是神经系统免疫性疾病的重要组成之一,存在靶向神经元表面蛋白、离子通道或突触表面受体的自身抗体,自身抗体检测对疾病的诊断、治疗及预后评估具有重要意义。确定责任抗体是解决同一例患者多种自身抗体共存的重要方法,本文基于新近提出的"责任抗体"概念对自身免疫性脑炎诊断与治疗进展进行综述。     

神经元自身抗体及其不同检测方法在自身免疫性脑炎中的价值研究进展

神经元自身抗体是自身免疫性脑炎诊断的关键,免疫组织化学法/间接免疫荧光法、啮齿类动物离体海马神经元的免疫细胞化学法、免疫印迹法等是目前常用的抗体检测方法,血清及脑脊液样本在不同亚型的自身免疫性脑炎中抗体检测的敏感性不同.神经元自身抗体滴度与肿瘤的发生相关,但与预后的相关性仍存在争议.近年来关于常见自身免疫性脑炎亚型相关...     

免疫性癫痫研究进展

癫痫是一种具有永久致痫倾向的慢性脑部疾病,同时具有一定的致残率和致死率。经过正规的抗癫痫治疗,临床上仍有近1/3的癫痫发展为耐药性癫痫,为抗癫痫药物治疗带来挑战。最新的研究证实,相当比例的耐药性癫痫为自身免疫性癫痫,免疫反应的异常激活参与其发病。免疫性癫痫是基于自身免疫性脑炎提出的概念,它是免疫介导的、通常伴有新发难治性癫痫发作、亚急性进行性认知衰退以及行为或精神功能障碍的自身免疫性疾病,此类患者脑脊液中可检测到神经元特异性相关抗体。早期免疫调节治疗除了能有效控制癫痫症状外,还可有效缓解某些癫痫综合征的发展。因此,早期进行免疫调控治疗可能成为未来免疫性癫痫治疗的关键。     

抗CASPR2抗体阳性的自身免疫性脑炎1例

本文报道了1例抗接触蛋白相关蛋白2(CASPR2)抗体阳性的自身免疫性脑炎老年患者,介绍了抗CASPR2抗体相关脑炎的常见表现和诊治过程,结合患者的临床症状和辅助检查结果,为老年患者以精神行为异常和认知功能下降为主要症状起病的自身免疫性脑炎的诊断提供思路,并提出老年患者患自身免疫性脑炎可能加剧脑血管病发生的可能性。     

对Lancet Neurol发表的自身免疫性脑炎诊断路径的思考

正临床发生的脑实质炎症反应致脑炎是神经科常见疾病之一,其致病因素可以分为感染性因素和非感染性因素两大类[1],在非感染性因素中,自身免疫性脑炎占据重要位置。随着抗细胞内抗原抗体和抗细胞表面抗原抗体的发现,临床明确诊断的自身免疫性脑炎病例数逐渐增加,目前,临床医师对此类疾病的诊断主要依靠自身抗体检测和试验性免疫调节治疗[2],故在很大程度上限制了早期治疗方案的选择。由于早期免疫调节治疗可以显著改     

抗体介导的自身免疫性脑炎患者的癫痫特点

越来越多的自身免疫性脑炎(Autoimmune encephalitis,AE)患者的资料显示,其临床表现和结局的特异性依赖于患者脑脊液、血清中特定抗原的抗体。这些特异性包括了癫痫相关的临床表现及对抗癫痫药物的反应。虽然学者们对这一类疾病的研究热情不断增加,且发现了新的抗体和相关的临床综合征,但仍有一些问题需要进一步解答。首先,鉴于每一种自身免疫性抗体介导的综合征的严重程度、患者特点、治疗时间不尽相同,治疗需要个体化;其次,缺乏随机对照试验是形成适当的免疫治疗策略的重大障碍。文章就一些已阐明的AE患者的癫痫诊断和治疗方面的新进展和挑战作一综述,并阐述在这一新兴领域中合理应用精确药物的原则。     

伴有精神症状的自身免疫性脑炎的临床特点分析

目的 分析不同抗体类型自身免疫性脑炎患者精神症状的特点.方法 回顾性研究了自身免疫性脑炎患者的临床特点.对自免脑患者的精神症状进行分析.对象:2019年9月到2020年12月就诊于中国医科大学附属第一医院神经内科确诊为自身免疫性脑炎的患者.结果 抗体阳性为20例,临床表现中最常见的依次是抽搐发作、精神症状、意识障碍、记...     

合并多种抗体阳性自身免疫性脑炎临床分析

目的总结自身免疫性脑炎合并多种抗神经元抗体阳性患者的临床特点及意义。方法回顾性分析郑州大学第一附属医院2015-01-2019-05确诊的7例合并多种抗神经元抗体阳性自身免疫性脑炎患者的临床表现、实验影像学检查及治疗效果,并进行相关文献复习。结果255例自身免疫性脑炎患者仅出现7例合并多抗体阳性患者,其中4例抗NMDAR抗体阳性患者分别合并抗LGI1抗体、抗-Ma2、抗-Yo抗体阳性,2例抗GABABR脑炎分别合并抗Hu、抗amphiphsin阳性,1例抗LGI1脑炎合并抗Hu阳性。6例免疫治疗有效好转,1例对症治疗后好转,其中2例患者病情严重并于治疗后半年死亡,余5例均明显好转。结论多种抗神经元抗体阳性的自身免疫性脑炎并不多见,临床表现更复杂多样,极易引起误诊或漏诊。潜在肿瘤风险更大,合并的肿瘤类型可能更广泛,加重病情、增加复发率及病死率,需引起高度重视,全面的实验室检查及定期复查是必要的。     

伴癫痫发作的自身免疫性脑炎临床特征分析

目的 分析不同类型自身免疫性脑炎病程中癫痫发作特征,筛查具有早期诊断价值的标志物。方法 收集2014年8月至2021年1月于华中科技大学同济医学院附属同济医院就诊的91例自身免疫性脑炎伴癫痫发作患者的社会人口学资料、发病特点、脑电图与影像学特征、治疗与预后等临床资料。结果 （1）抗N-甲基-D-天冬氨酸受体（NMDAR）脑炎（58例）、抗γ-氨基丁酸B型受体（GABABR）抗体相关脑炎（12例）和抗富亮氨酸胶质瘤失活蛋白1(LGI1)抗体相关脑炎（12例）是自身免疫性脑炎的常见类型。（2）快速进展性痴呆[79.12%(72/91)]、睡眠障碍[79.12%(72/91)]和精神障碍[75.82%(69/91)]为主要非癫痫症状,而情绪障碍或言语障碍少见。（3）脑炎病程中76.92%(70/91)患者出现全面性强直-阵挛发作,为抗GABABR抗体相关脑炎（12/12）的特征性发作类型;而面-臂肌张力障碍发作则是抗LGI1抗体相关脑炎[4.40%(4/91)]的特征性发作类型。（4）视频脑电图主要表现为背景慢波[37.88%(25/66)]、慢波合并痫样放电[27.27%(18/66)]或...     

应重视无菌性脑膜炎及抗体阴性的自身免疫性脑炎的诊断

随着对自身免疫相关脑膜脑炎的认识和诊断技术的提高,其诊断与治疗水平显著提高,然而对于未找到明确病原体且自身免疫抗体呈阴性的患者,常过度诊断为抗体阴性的自身免疫性脑炎,忽视无菌性脑膜炎的诊断,延误治疗。本文从不同视角对无菌性脑膜炎与抗体阴性的自身免疫性脑炎的发病机制、临床症状、诊断与治疗、预后等方面进行阐述,以期提高临床鉴别诊断能力。     

Characterisation of a syndrome of autoimmune adult onset focal epilepsy and encephalitis

We report a series of patients with a clinical syndrome characterised by the explosive onset in adulthood of recurrent focal seizures of frontotemporal onset and features suggestive of autoimmune encephalitis. We propose that this presentation of “autoimmune adult onset focal epilepsy and encephalitis” is a recognisable clinical syndrome, and provide evidence it may be associated with heterogeneous immunological targets. Between 2008 and 2011 we encountered six patients with new-onset epilepsy in whom we suspected an autoimmune aetiology. We first characterised the clinical, electroencephalographic, cerebrospinal fluid (CSF), imaging, and pathological findings of this syndrome. We subsequently tested them for antibodies against both intracellular and neuronal cell surface antigens. All patients presented with recurrent seizures with focal frontotemporal onset, refractory to multiple anticonvulsants. Four had focal T2-weighted hyperintensities on MRI. CSF mononuclear cells were variably elevated with positive oligoclonal bands in four. Brain biopsy in one patient demonstrated perivascular lymphocytic infiltration. Two were treated with immunosuppression and went on to achieve complete seizure control and return to baseline cognition. Three of four patients who received only pulsed steroids or no treatment had ongoing frequent seizures, with two dying of sudden unexpected death in epilepsy. Subsequently, three had antibodies identified against neuronal cell surface antigens including N-methyl-d-aspartate receptor and leucine-rich glioma inactivated 1. We suggest that patients with such a presentation should be carefully evaluated for a suspected autoimmune aetiology targeting cell surface antigens and have a therapeutic trial of immunosuppression as this may improve their long-term outcome.     

Seizure specificities in patients with antibody‐mediated autoimmune encephalitis

Accumulating data on patients with autoimmune encephalitis have shed light on specificities concerning clinical presentation and outcomes, which are dependent on the antigen targeted by the autoantibodies found in the patients’ cerebrospinal fluid or sera. Such specificities include seizure‐related clinical manifestations as well as the responsiveness to antiepileptic drugs. Although increased enthusiasm accompanies the discovery of novel antibodies and their associated clinical syndromes, several issues remain unsettled. First, it appears that therapy needs to be personalized in the view of the severity of each antibody‐mediated syndrome, patient‐related characteristics, and timing of treatment. Second, the lack of randomized controlled trials is a major drawback in the formulation of an appropriate immunotherapeutic strategy. In this review, we discuss the novel developments and challenges for the diagnosis and treatment of epilepsy in patients with well‐characterized autoimmune encephalitis, and delineate the principles for a rational approach toward precision medicine in this emerging field.     

Seizures in autoimmune encephalitis: Kindling the fire

Epilepsy is a common neurological disorder that increases the risk of morbidity and mortality. Autoimmune epilepsy is a subset of epilepsy that occurs in the setting of autoimmunity, such as in autoimmune encephalitis (AIE). AIE is an autoimmune disorder characterized by immune-mediated neuroinflammation resulting in a variety of neurological symptoms, including psychiatric disturbance, cognitive dysfunction, and seizures. Seizures in AIE are thought to be a result of antibodies directed against neuronal cell-surface proteins involved in synaptic transmission. The role of blood-brain barrier dysfunction, myeloid cell infiltration, and the initiation of proinflammatory cascades in epileptogenesis has been shown to be important in animal models and human patients with epilepsy. Epileptogenesis in AIE is likely to arise from the synergistic effect of both innately driven neuroinflammation and antibody-induced hyperexcitability. Together, these processes produce persistent drug-resistant seizures that contribute to the morbidity seen in AIE. Understanding the proinflammatory pathways involved in this process may improve diagnostics and provide alternative treatment targets in AIE.     

What is autoimmune encephalitis-associated epilepsy? Proposal of a practical definition

Seizures resulting from cerebral autoimmunity are either acutely symptomatic in the context of autoimmune encephalitis (AIE) with neural surface antibodies, or they are indicative of an enduring predisposition to seizures, that is, epilepsy. Here, we propose a practical definition for autoimmune encephalitis-associated epilepsy (AEAE): Seizures associated with antibodies against glutamic acid decarboxylase, paraneoplastic syndromes, or Rasmussen encephalitis are classified as AEAE. AEAE secondary to AIE with antibodies against the N-methyl-D-aspartate receptor, leucine-rich glioma inactivated protein 1, contactin-associated protein-2, or γ-aminobutyric acid-B receptor can be diagnosed if the following criteria are met: seizures persist for at least 2 years after immunotherapy initiation; no signs of encephalitis on magnetic resonance imaging and no fluorodeoxyglucose positron emission tomography hypermetabolism; normal cerebrospinal fluid cell count; and a substantial decrease in antibody titers. This classification corresponds to different disease mechanisms. While AIE results from the pathogenic effects of neural antibodies, AEAE is probably the consequence of encephalitis-related tissue damage and thereby mainly structurally mediated. The distinction between AIE and AEAE also has practical consequences: In AIE, immunotherapy is usually highly beneficial, whereas anti-seizure medication has little effect. In AEAE, immunotherapy is less promising and the usual anti-seizure interventions are preferable. In addition, the diagnosis of AEAE has social consequences in terms of driving and professional limitations.     

自身免疫性癫痫的临床研究进展

许多研究表明,药物难治性癫痫的发生可能与自身免疫炎性机制相关,神经元特异性细胞内或细胞膜抗体通过不同途径促使癫痫发作。癫痫发作的症状学、神经元特异性抗体、炎性脑脊液、磁共振成像和脑电图等,均有助于诊断自身免疫性癫痫。免疫治疗有望成为有效治疗自身免疫机制介导的药物难治性癫痫的新手段。免疫治疗药物包括糖皮质激素、静脉用免疫球蛋白、环磷酰胺、利妥昔单抗和硫唑嘌呤等。近年来的研究发现,环孢霉素A、他克莫司和雷帕霉素这3种免疫抑制剂对自身免疫性癫痫有效。此外,血浆置换也是急性期的治疗选择之一。自身免疫性癫痫患者接受急性期早期免疫治疗与稳定期维持治疗后,有望获得较好的预后。本文对自身免疫性癫痫的发病机制、临床特征、诊断和治疗的研究进展进行综述。     

Recent advances in pathogenic concepts and therapeutic strategies in Rasmussen's encephalitis

Rasmussen's encephalitis (RE) is a rare inflammatory brain disease mainly affecting children and characterised by intractable epilepsy involving a single hemisphere that undergoes progressive atrophy. RE is characterized by refractory focal seizures, often associated with epilepsia partialis continua, progressive unilateral motor defect, slow EEG activity over the entire contralateral hemisphere, with focal white matter hyperintensity and insular cortical atrophy on neuroimaging. Surgical exclusion of the affected hemisphere is the only treatment that interrupts progression of the disease. Pathogenic concepts have considered viruses, autoimmune antibodies and autoimmune cytotoxic T lymphocytes that might contribute to the initiating or perpetuating events in the central nervous system. Based on these concepts, different therapeutic strategies have been pursued, such as antiviral agents, plasmapheresis, immuno-adsorption, immunosuppression or immunomodulation with intravenous immunoglobulins. However, due to the lack of large studies, to date there is no established therapeutic strategy for this devastating condition. In this review, we give an overview of the current state of immunopathogenic concepts for Rasmussen's encephalitis and discuss the different therapeutic options for future perspectives.     

Effect of tacrolimus in a case of autoimmune encephalitis

We report a 17-year-old boy who was diagnosed as autoimmune encephalitis with various neurological complications such as hemiplegia, aphasia and seizures. An autoimmune process was considered to be responsible for the repeated episodes of encephalitis because the symptoms were highly responsive to steroids and anti-glutamate receptor antibodies were detected in the CSF. After administration of the immunosuppressant tacrolimus, we could taper the steroid dosage. He has had no relapse for three years to date. We demonstrated the possibility of steroid-sparing treatment with tacrolimus for a patient with steroid-responsive encephalitis. There were few reports describing tacrolimus therapy for encephalitis. Tacrolimus may be effective for selected patients with recurrent encephalitis in which an autoimmune mechanism is considered as the pathogenesis.     

GAD65 antibody‐associated autoimmune epilepsy with unique independent bitemporal‐onset ictal asystole

Antibodies against the 65‐kDa isoform of the intracellular enzyme, glutamate decarboxylase (GAD65), have been found in patients with limbic encephalitis and drug‐resistant autoimmune epilepsy. We report a 22‐year‐old female who presented with new‐onset seizures and neuropsychiatric symptoms. Video‐EEG captured unique, independent bitemporal‐onset focal seizures with impaired awareness and ictal asystole. An autoimmune epilepsy panel revealed elevated GAD65 antibodies in the serum (225 nmol/l) and CSF (2.78 nmol/l), while [¹⁸F]‐fluoro‐deoxy‐glucose positron emission tomography showed bitemporal hypometabolism (left > right). The patient was diagnosed with GAD65 antibody‐associated autoimmune epilepsy. Our observation adds to the spectrum of neurocardiac syndromes associated with autoimmune epilepsy.