Japanese encephalitis-induced anti-N-methyl-d-aspartate receptor encephalitis: A hospital-based prospective study

ObjectivesA hospital-based prospective study was performed to determine: 1) whether Japanese encephalitis (JE) normally triggers anti-N-methyl-d-aspartate receptor (NMDAR) immunoglobulin G (IgG) synthesis, especially in monophasic JE patients; and 2) the incidence of JE-induced anti-NMDAR encephalitis in pediatric patients with JE.MethodsWe detected the level of anti-NMDAR IgG in the serum and cerebral spinal fluid (CSF) of JE patients within one week of onset. If patients relapsed during the convalescence phase, we detected JE virus RNA in the CSF and anti-NMDAR IgG in both the serum and CSF. For patients who did not relapse during the convalescence phase, serum was collected and anti-NMDAR IgG was detected during the 30–60-day course of the disease.ResultsWe enrolled 65 JE patients, who were negative for anti-NMDAR IgG in the serum and CSF during the acute phase, of which 63 patients were successfully followed up. Five patients relapsed during the convalescence phase, for whom JE virus RNA in the CSF was negative and excluded latent JE reactivation. The distinctive symptoms of four younger patients were choreoathetosis, whereas the psychiatric and behavioral manifestations were the distinctive symptoms experienced by the teenager. Anti-NMDAR IgG in the CSF of three patients was positive and they were diagnosed with anti-NMDAR encephalitis. The other two patients were negative for anti-NMDAR IgG in both the serum and CSF. For the 58 patients who did not relapse during the convalescence phase, anti-NMDAR IgG was negative in the serum of all patients at 30–60 days during the course of the disease.ConclusionsJE does not typically trigger anti-NMDAR IgG synthesis. Besides anti-NMDAR IgG, other unknown autoantibodies can also cause autoimmune encephalitis in the convalescence phase of JE. The incidence of JE-induced autoimmune encephalitis in pediatric patients with JE was 7.9%, and the incidence of JE-induced anti-NMDAR encephalitis was 4.7%.     

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。     

Autoimmune encephalitis: Recent updates and emerging challenges

The knowledge of immune dysregulation and autoimmunity in neurological disorders has expanded considerably in recent times. Recognition of clinical syndromes, reliable methods of diagnosis, and early targeted immunotherapy can lead to a favourable outcome in acute and subacute neurological disorders that may be associated with significant morbidity and mortality if left untreated. This review focuses on the rapidly expanding field of autoimmune encephalitis. We describe the differences between limbic encephalitis associated with antibodies targeting intracellular antigens, and neuronal surface antibody syndromes (NSAS) where the antigens are primarily receptors or synaptic proteins located on the neuronal cell surface. We chronologically highlight important developments in NSAS by focusing on voltage gated potassium channel complex-associated antibody mediated encephalitis, anti-N-methyl-d-aspartate receptor (anti-NMDAR) encephalitis, and anti-dopamine 2 receptor antibody-associated basal ganglia encephalitis. Contentious issues such as the complexities of using serum antibodies as biomarkers, the initiation of central nervous system autoimmunity, and possible pathogenic mechanisms of these antibodies will be reviewed. The therapeutic challenges that clinicians face such as the timing of therapy and the role of second-line therapy will be discussed, with crucial concepts highlighted in the form of clinical vignettes. Future directions will involve the identification of novel antigens and methods to establish their pathogenicity, as well as evaluation of the most efficacious therapeutic strategies in patients with established NSAS.     

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.     

Clinical manifestations,treatment outcomes,and prognostic factors of pediatric anti-NMDAR encephalitis in tertiary care hospitals: A multicenter retrospective/prospective cohort study

ObjectiveAnti-NMDAR encephalitis is an acute autoimmune neurological disorder that is increasingly recognized in pediatric populations. Several studies of the disorder have been conducted worldwide but there are few publications in Thailand. Here, we describe the clinical manifestations, treatment outcomes, and prognostic factors in children with anti-NMDAR encephalitis.MethodsBetween January 2007 and September 2017, we conducted a retrospective/prospective cohort study of children diagnosed with anti-NMDAR encephalitis from three tertiary care hospitals in Thailand: King Chulalongkorn Memorial Hospital, Chonburi Hospital, and Prapokklao Hospital. We assessed the Modified Rankin Score (mRS) score for each participant to measure severity of disease and treatment outcome at baseline, 12, and 24 months.ResultsWe recruited 14 participants (1–13 years with median age 8.4 years). Participants were followed up for a median of 20.5 months. Clinical manifestations included behavioral dysfunction (100%), movement disorder (93%), speech disorder (79%), sleep disorder (79%), and seizures (79%). All patients received first-line immunotherapy (corticosteroids: 100%, intravenous immunoglobulin: 79%, plasma exchange: 21%). Second-line immunotherapy (cyclophosphamide) was administered to 57% of patients. During the first 12 months, 8 patients (62%) achieved a good outcome (mRS ≤ 2). At 24 months, 9 patients (81%) had achieved a good outcome. Altered consciousness and central hypoventilation were predictors of poor outcome. (p < 0.05).ConclusionsWe observed similar clinical manifestation of anti-NMDAR encephalitis in Thai children to those reported in other countries. Furthermore, the percentage of patients with good outcomes in our study was comparable with previous studies. Further studies are required to investigate other populations in other regions of Thailand.     

Anti-N-methyl-D-aspartate receptor encephalitis associated with hepatic neuroendocrine carcinoma: A case report

Anti-N-methyl-D-aspartate receptor (Anti-NMDAR) encephalitis can present with and without tumor. Tumor associations are less common in older patients. We report a 65-year-old gentleman who presented with one week history of cough, chills, rigor and altered behavior, followed by florid visual and auditory hallucinations. Mini mental status examination score was 16/30. Both cerebrospinal fluid and plasma anti-NMDA receptor antibodies were detected. A course of intravenous methylprednisolone was given with partial symptom improvement. A hepatic neuroendocrine carcinoma was detected and confirmed on biopsy. Unfortunately, he developed several medical complications: non-ST elevation myocardial infarction, infected foot gangrene and peripheral vascular disease, which made him unsuitable for both surgery and chemotherapy. He passed away 6 months later due to the progression of the malignancy. This case illustrated that NMDAR encephalitis may be associated with an uncommon hepatic neuroendocrine carcinoma in an older person, which is responsive to early treatment.     

抗NMDAR脑炎血清抗NMDAR抗体阴性患者临床分析

目的 探讨血清抗N-甲基-D-天冬氨酸受体(NMDAR)抗体阴性的抗NMDAR脑炎患者的临床表现特征、治疗及其预后特点.方法 收集郑州大学第一附属医院2013-09—2019-12确诊为抗NMDAR脑炎的60例患者,根据其血清中抗NMDAR抗体的情况分为血清抗体阴性组和阳性组,分析2组临床表现特征、辅助检查、治疗及预后...     

Suppression of synaptic plasticity by cerebrospinal fluid from anti-NMDA receptor encephalitis patients

The functional effects of cerebrospinal fluid (CSF) from patients with anti-NMDA receptor (NMDAR) encephalitis on the NMDAR-mediated synaptic plasticity were evaluated by using mouse hippocampus slices. Anti-NMDAR antibody detection system was established by immunostaining recombinant NMDAR heteromers expressed in HEK cell culture as well as native NMDARs in cultured hippocampal neurons. Under a complete blind manner for the clinical information, CSF and sera collected from 36 pre-diagnosed patients were tested for anti-NMDAR antibodies. With this test, thirteen patients were diagnosed as anti-NMDAR encephalitis. CSF positive for anti-NMDAR antibodies suppressed induction of long-term potentiation (LTP) at Schaffer collateral-CA1 synapses in mouse hippocampal slices. LTP induction was not suppressed by CSF collected from herpes simplex virus (HSV) encephalitis or non-encephalitis control patients. Antibody absorption with NMDAR-expressing HEK cell culture reversed the suppression of LTP by anti-NMDAR encephalitis patients' CSF, confirming that anti-NMDAR antibodies suppressed LTP. The present experiments firmly support the proposal that the anti-NMDAR encephalitis autoantibody is responsible for cognitive disorders like amnesia accompanying this disease.     

N-methyl D-aspartate receptor encephalitis: A new addition to the spectrum of autoimmune encephalitis

A large proportion of “encephalitis” is caused by unknown agents. Of late, a new category of disorders, “autoimmune encephalitis,” has been described, which present with features similar to viral encephalitides. A well-delineated and common entity among this group is the recently described anti-NMDAR encephalitis (NMDARE). Although this entity was initially described in young women harboring ovarian teratomas, it is now characterised as well in children and men. Approximately 60% of the patients have an underlying tumor, usually an ovarian teratoma. In 40% of the patients, no cause can be found (idiopathic NMDARE). NMDARE typically presents with psychiatric features followed by altered level of consciousness, severe dysautonomia, hyperkinetic movement disorders, seizures and central hypoventilation. Orofacial dyskinesias resulting in lip and tongue mutilation are quite common. Seizures, are common and may be difficult to treat. The disease can be confirmed by serum and cerebrospinal fluid anti-NMDAR antibodies. Titers of these antibodies can also guide response to treatment. Tumor removal is necessary if identified, followed by immunological treatment. Intravenous methylprednisolone and immunoglobulins aim to suppress/modulate immune response while plasma exchange attempts to remove antibodies and other inflammatory cytokines. Rituximab and cyclophosphamide aim to suppress antibody production. Recovery is slow and often with neurological deficits if treatment is delayed. With many distinctive clinical features, a specific antibody that aids diagnosis, and early effective treatment with commonly available drugs leading to good outcomes, NMDARE is a diagnosis that should be considered early in any case of “unexplained encephalitis.”     

抗GABA_B受体脑炎5例报道及文献复习

目的探讨抗γ-氨基丁酸受体(GABA_BR)脑炎的临床特点及诊治。方法对5例抗GABA_BR脑炎患者临床表现、辅助检查等进行回顾性分析及文献回顾。结果 5例抗GABA_B抗体阳性患者均亚急性起病,表现为难治性癫痫,其中1例以性格改变、2例以抽搐、2例以记忆减退为首发症状。3例患者头部MRI显示边缘系统异常高信号,3例脑电图显示异常,2例脑脊液检查合并其它自身免疫抗体,2例肺部CT或PET-CT扫描提示肺部占位。经给予丙球或激素治疗明显好转。结论 (1)抗GABA_B受体脑炎首发症状多样,主要表现为难治性癫痫。(2)对于怀疑边缘性脑炎(LE)患者应筛查抗GABA_B受体抗体。(3)对抗GABA_B受体抗体阳性的患者应该积极进行肿瘤的筛查。     

抗NMDA受体脑炎1例报道并文献复习

目的探讨抗NMDA受体脑炎的发病机制、临床表现、辅助检查、及治疗方法。方法报道本院确诊的1例患者的临床资料并复习国内外相关文献。结果本例患者以发热为首发症状,后出现癫癎、精神行为异常、意识障碍、口-面-舌部的异常运动,经脑脊液和血液检测出抗NMDAR抗体,确诊为抗NMDA受体脑炎,经激素及丙种球蛋白治疗后患者基本恢复正常。结论抗NMDA受体脑炎是一种少见的新型自身免疫性脑炎,好发于青年女性,主要表现为癫癎、精神症状、意识障碍、口-面-舌的异常运动等,脑脊液抗NMDAR抗体检测阳性可确诊本病,激素、丙种球蛋白、血浆置换为该病的一线治疗,早诊断、早治疗后大多患者预后良好。     

8例自身免疫性脑炎的病例分析并文献复习

目的探讨自身免疫性脑炎的临床表现、磁共振(MRI)图像、脑脊液特点及治疗转归。方法回顾性分析我院8例(自2012年1月-2016年1月)自身免疫性脑炎患者的临床资料。结果 8例患者平均发病年龄为44岁,其中有4例抗NMDA受体脑炎,3例LGI1蛋白抗体阳性边缘系统脑炎,1例抗GABABR脑炎,所有患者(100%)均有认知功能损害和精神症状;5例(62%)出现癫痫发作;3例(37%)出现不自主运动和自主神经功能障碍。4例(50%)患者脑电图存在异常;4例(50%)患者有磁共振检查异常信号;1例发现肺癌。结论以认知功能损害、精神行为异常、癫痫发作为主要表现的患者,要警惕自身免疫性脑炎的可能,以免误漏诊。     

抗N-甲基-D-天冬氨酸受体脑炎患者临床特点分析

目的 探讨抗N-甲基-D-天冬氨酸受体(N-methyl- D-aspartate receptor,NMDAR)脑炎的临床特征与抗NMDAR抗体在诊断该病中的意义.方法 选择62例各种病因的脑炎、脑病及其他中枢神经系统疾病患者,采用转染细胞间接免疫荧光法检测其血清及脑脊液抗NMDAR抗体,同时对该病的临床表现、实验室检查、治疗及预后进行分析.结果 28％(9/32)的临床诊断脑炎病例组患者血清或脑脊液抗NMDAR抗体为阳性.脑脊液抗体的阳性率高于血清,其中5例抗体滴度较高的患者伴有血脑屏障破坏.这些患者均未发现肿瘤,临床上以发热、精神异常、癫痫、肌张力障碍与自主神经功能障碍表现突出,并有头颅MRI与脑电图异常,早期免疫治疗有效.结论 脑脊液及血清中抗NMDAR抗体检测有助于自身免疫性抗NMDAR脑炎患者的早期诊断与治疗.     

Validity and prognostic utility of clinical assessment scale for autoimmune encephalitis (CASE) score in children with autoimmune encephalitis

IntroductionThe clinical assessment scale for autoimmune encephalitis (CASE) is a recently developed and validated scale to rate the severity of autoimmune encephalitis (AE) in adults. But it is yet to be validated in pediatric AE cases.MethodsIn a prospective observational study, we determined the validity and prognostic utility of CASE in the pediatric population with a diagnosis of probable or definite AE. We also determined clinical, neuroimaging, or laboratory-based prognostic factors for favorable clinical outcomes at 3 months after presentation. We used weighted kappa statistics and the intra-class correlation coefficient of individual item scores and total scores for determining inter-observer and intra-observer reliability respectively.ResultsWe enrolled a total of 54 patients (28 girls, probable [45%] or definite [55%] AE). Functional status score (FSS), CASE score, and other scores showed significant improvement at the time of discharge and 3-months, as compared to baseline (p < 0.0001). The intra-observer and interobserver reliability of the total scores was excellent (k = 0.94 and 0.95 respectively). CASE was also found to have good internal consistency (Cronbach-α = 0.83). The corrected item-total correlations of all items were >0.40. The correlation between the total CASE score and FSS score at admission, at discharge, and at 3 months was strong (r = 0.90, 0.92, and 0.94, p < 0.001). In multivariate analysis, only seropositivity or definite AE and CASE score at baseline was found to be significant predictive factors for functional status at 3 months (p = 0.03, 0.01).ConclusionCASE score can be used for monitoring the severity of pediatric AE patients. It also has prognostic usefulness for predicting functional independence on follow-up.