[Anti-NMDAR encephalitis associated with relapsing optic neuritis]. Belova A N,Grygorieva V N,Rasteryaeva M V,Ruina E A,Belova E M,Solovieva V S,Boyko A N Zhurnal nevrologii i psikhiatrii imeni S.S. Korsakova Autoimmune encephalitis with antibodies to NMDA receptors (anti-NMDAR encephalitis), is the most common form of autoimmune encephalitis. The disease is curable, however, the lack of timely therapy can lead to the disability of patients or to the death. Difficulties in the diagnosis of anti-NMDAR encephalitis are caused by the heterogeneity of its manifestations, a possible overlapping with other autoimmune diseases and insufficient awareness about this form of encephalitis. This article describes the case of anti-NMDAR encephalitis associated with recurrent optic neuritis which might be an atypical manifestation for this disease. Optic neuritis could not be explained by overlapping with multiple sclerosis or neuromyelitis optica spectrum disorders. 10.17116/jnevro2020120061105
    Anti-N-Methyl-D-Aspartate Receptor Antibody Mediated Neurologic Relapse Post Herpes Simplex Encephalitis: A Case Series. Geoghegan Sarah,Walsh Aoibhinn,King Mary D,Lynch Bryan,Webb David,Twomey Eilish,Ronan Leahy T,Butler Karina,Gavin Patrick The Pediatric infectious disease journal Despite the advent of antiviral therapy, herpes simplex encephalitis (HSE) remains a devastating condition with significant morbidity and mortality. Neurologic relapse after initial improvement is generally attributed to herpes simplex virus reactivation. In 2013, inflammation caused by anti-N-methyl-D-aspartate receptor antibodies was reported in association with cases of neurologic relapse after herpes simplex encephalitis. We present 3 such cases and discuss diagnostic and management dilemmas. 10.1097/INF.0000000000001205
    Repeated misdiagnosis of a relapsed atypical anti-NMDA receptor encephalitis without an associated ovarian teratoma. Zhang Weihe,Yan Li,Jiao Jinsong Neuroscience letters We present an atypical case of relapsed anti-NMDAR encephalitis in a young female patient without an associated ovarian teratoma. She presented with recurrent seizure attacks with muscle weakness, psychosis, dyskinesia, autonomic failure and insomnia. She was first misdiagnosed as mitochondrial encephalomyopathy with lactic acidosis and stroke-like episodes (MELAS) then Hashimoto's encephalopathy due to diffuse cerebral lesions, elevated serum lactic acid concentration, increased amount of thyroid peroxidase and thyroglobulin antibodies in serum and diffuse lesions of the thyroid gland. Her final diagnosis was delayed for 6 months with the detection of anti-NMDAR antibodies in her CSF. After treatment, she had poor recovery with serious sequelae at 10-month follow-up. Noteworthy, MELAS should be highlighted as a differential diagnosis of anti-NMDAR encephalitis. 10.1016/j.neulet.2016.11.057
    Pearls & Oy-sters: Relapse of anti-NMDA receptor encephalitis after prior first- and second-line immunotherapy. Chiang Sharon,Garg Tanu,Hu Austin,Amin Hitha,Davalos-Balderas Alfredo,Alfradique-Dunham Isabel,Goldsmith Corey E Neurology 10.1212/WNL.0000000000005517
    Anti-N-methyl-D-aspartate receptor encephalitis after Herpes simplex virus-associated encephalitis: an emerging disease with diagnosis and therapeutic challenges. Schein Flora,Gagneux-Brunon Amandine,Antoine Jean-Christophe,Lavernhe Sylvie,Pillet Sylvie,Paul Stéphane,Frésard Anne,Boutet Claire,Grange Rémi,Cazorla Céline,Lucht Frédéric,Botelho-Nevers Elisabeth Infection INTRODUCTION:Morbidity and mortality of Herpes simplex virus encephalitis (HSE) remain high. Relapses of neurological signs may occur after initial clinical improvement under acyclovir treatment. METHODS:We report here a case of post-HSE anti-N-methyl-d-aspartate receptor-mediated encephalitis in an adult and perform a systematic search on PubMed to identify other cases in adults. RESULTS:We identified 11 previously published cases, to discuss diagnostic and therapeutic management. Symptoms in adults are often inappropriate behaviors, confusion and agitation. Diagnosis of anti-NMDA-R encephalitis after HSE is often delayed. Treatment consists in steroids, plasma exchange, and rituximab. Prognosis is often favorable. CONCLUSION:Anti-NMDA-R antibodies should be searched in cerebrospinal fluid of patients with unexpected evolution of HSE. This emerging entity reopens the hot debate about steroids in HSE. 10.1007/s15010-016-0959-y
    Anti-N-methyl-D-aspartate receptor encephalitis: A review of pathogenic mechanisms, treatment, prognosis. Huang Qianyi,Xie Yue,Hu Zhiping,Tang Xiangqi Brain research Anti-N-methyl-D-aspartate receptor (anti-NMDAR) encephalitis is a treatable autoimmune disorder characterized by prominent neuropsychiatric symptoms that predominantly affects children and young adults. In this review, we discuss the pathogenic mechanisms and immunologic triggers of anti-NMDAR encephalitis, and provide an overview of treatment and prognosis of this disorder, with specific focus on the management of common symptoms, complications, and patients during pregnancy. Most patients respond well to first-line treatment and surgical resection of tumors. When first-line immunotherapy fails, second-line immunotherapy can often improve outcomes. In addition, treatment with immunomodulators and tumor resection are effective treatment strategies for pregnant patients. Benzodiazepines are the preferred treatment for patients with catatonia, and electroconvulsive therapy (ECT) may be considered when pharmacological treatment is ineffective. Age, antibody titer, cerebellar atrophy, levels of biomarkers such as C-X-C motif chemokine 13 (CXCL13), cell-free mitochondrial (mt)DNA in cerebral serum fluid (CSF), and timing from symptom onset to treatment are the main prognostic factors. Patients without tumors or those who receive insufficient immunotherapy during the first episode are more likely to relapse. 10.1016/j.brainres.2019.146549
    Japanese encephalitis can trigger anti-N-methyl-D-aspartate receptor encephalitis. Ma Jiannan,Zhang Ting,Jiang Li Journal of neurology Japanese encephalitis (JE) is usually a monophasic disease; however, in rare cases, patients with JE may have an early relapse after a partial recovery, giving rise to a biphasic pattern for the disease. In this study, we report three pediatric cases in which post-JE relapse was characterized by movement disorder and/or behavioral problems, and was related to anti-N-methyl-D-aspartate receptor (NMDAR) immunoglobulin G (IgG). Serum and cerebrospinal fluid were examined for anti-NMDAR IgG in three patients who had confirmed JE and then developed relapsing symptoms which were similar to those of anti-NMDAR encephalitis. The main symptoms of the two young children were choreoathetosis, irritability, and sleep disorder; while for the teenager, agitation, mutism, rigidity, and sleep disorder were the main symptoms. Samples of cerebrospinal fluid from all patients were positive for anti-NMDAR IgG, and all patients gradually improved with immunotherapy. Testing for NMDAR antibodies is highly recommend in patients with JE, especially those with a relapsing syndrome involving movement disorder and/or behavioral problems, as these patients may benefit from immunotherapy. 10.1007/s00415-017-8501-4
    Relapse in herpes simplex virus encephalitis: It's not just about the virus. Bale James F,Du Pasquier Renaud Neurology 10.1212/WNL.0000000000002132
    Clinical characteristics and short-term prognosis of LGI1 antibody encephalitis: a retrospective case study. Li Weishuai,Wu Si,Meng Qingping,Zhang Xiaotian,Guo Yang,Cong Lin,Cong Shuyan,Zheng Dongming BMC neurology BACKGROUND:Recently, most reports of Leucine-rich glioma-inactivated 1 (LGI1) antibody encephalitis are from Europe and the US, while the short term outcome and clinical characteristics of Chinese patients are rarely reported,we study the clinical manifestations, laboratory results and brain magnetic resonance images (MRI) of eight patients who were recently diagnosed with LGI1 antibody encephalitis in our hospital to improve the awareness and knowledge of this disease. METHODS:Eight patients (five males and three females; mean age, 63.4) with LGI1 antibody encephalitis who were diagnosed and treated in the Department of Neurology of Shengjing Hospital of China Medical University from September 2016 to June 2017 were recruited for the current study. Their general information, clinical manifestations, treatment regimens, and short-term prognoses were retrospectively analyzed, as were the results from MRI and laboratory findings. RESULTS:Overall, patient symptoms included cognitive impairment, which manifested primarily as memory deficits (8/8), seizures (including faciobrachial dystonic seizure, (FBDS)) (8/8), psychiatric and behavioral disorders (7/8), sleep disorders (4/8), and autonomic abnormalities (3/8). Five patients also had abnormal findings on brain MRI, mainly involving the hippocampus, basal ganglia and insula. Hyponatremia occurred in six cases. All patients tested positive for LGI1 antibodies in their serum/cerebrospinal fluid (CSF)and patients were negative for tumors. Symptoms rapidly improved after treatment with immunoglobulin and/or steroid therapy. The patients were followed up for 4-13 months after discharge, and two patients relapsed. CONCLUSION:Primary symptoms of LGI1 antibody encephalitis include memory impairments, seizures, FBDS, and mental and behavioral abnormalities. Increased titers of LGI1 antibodies are also present in the serum/CSF of patients. Patients often have hyponatremia, and MRIs show abnormalities in various brain regions. Finally, immunotherapy shows good efficacy and positive benefits, although patients may relapse in the short-term. 10.1186/s12883-018-1099-z
    [Clinical analysis of relapsing anti-N-methyl-D-aspartate receptor encephalitis]. Hongzhi Guan,Weize Kong,Bin Peng,Yan Huang,Qiang Lu,Yuan Jing,Qing Liu,Hang Shen,Haitao Ren,Yicheng Zhu,Dawei Sun,Liying Cui Zhonghua yi xue za zhi OBJECTIVE:With the discovery of more patients with anti-N-methyl-D-aspartate (anti- NMDAR) encephalitis, frequent clinical relapses pose a new challenge to neurologists. METHODS:Retrospective reviews were conducted for 16 hospitalized patients with relapsing anti-NMDAR encephalitis at our hospital from June 2011 until November 2014. Their clinical data including symptoms, cerebrospinal fluid (CSF) profiles, neuroimaging findings and relapsing treatment were compared with those initial episodes. RESULTS:There were 11 females and 5 males with a mean onset time of 21.2 (10-34) years. For initial episodes, the mean number of major symptoms was 5. 8 and the mean modified Rankin score (mRS) 4.56. And 7 (43.8%) cases were admitted into intensive care unit (ICU). All received first-line immunotherapy and only one case second-line immunotherapy. Ovarian teratoma was detected and resected in only one case of initial episode. Among 32 relapses, 8 cases (50% ) had multiple (2-4) relapses. There was a median delay of 5.0 (0.5-18) months for relapses. Relapses were common upon pausing or reducing immunotherapy, usually monotherapy with corticosteroids. Compared with initial episodes, relapses were less severe (mean mRS 2.69, mean number of symptom 2.59) and only 2 cases were admitted into ICU during relapses. Presentation of relapses were partial symptoms of initial episode. However, two patients had new symptoms of brain stem involvement. Brain magnetic resonance imaging (MRI) of 8 cases showed abnormality initially during initial episode and disappearance at relapses while new lesions appeared in 7 patients including 3 cases with CNS demyelinating features of central nervous system ( CNS) on MRI. The positivity rate of anti-NMDAR antibody was 100% in CSF and 53.1% in sera during relapses. Anti-AQP4 and NMO-Ig were positive in one case with brain stem involvement. All cases received first-line immunotherapy and 12 chronic second-line immunotherapy. Two cases of ovarian teratoma were detected on reassessment during relapse and then resected. CONCLUSION:Inadequacy of second-line and chronic immunotherapy, occult teratoma and potential demyelination may contribute to a relapse of anti-NMDAR encephalitis. And its proper management should follow the recommendations of guidelines.
    Anti-MOG encephalitis mimicking small vessel CNS vasculitis. Patterson Kristina,Iglesias Estibaliz,Nasrallah Maclean,González-Álvarez Verónica,Suñol Mariona,Anton Jordi,Saiz Albert,Lancaster Eric,Armangue Thaís Neurology(R) neuroimmunology & neuroinflammation Objective:To report 2 patients with anti-myelin oligodendrocyte glycoprotein (MOG)-associated encephalitis who were initially misdiagnosed with small vessel primary CNS vasculitis. Methods:Review of symptoms, MRI and neuropathologic features, and response to treatment. MOG antibodies were determined in serum and CSF using a cell-based assay. Results:Symptoms included fever, headache, and progressive mental status changes and focal neurologic deficits. CSF studies revealed lymphocytic pleocytosis, and both patients had abnormal brain MRIs. Brain biopsy samples showed prominent lymphocytic infiltration of the wall of small vessels; these findings initially suggested small vessel CNS vasculitis, and both patients were treated accordingly. Although 1 patient had a relapsing-remitting course not responsive to cyclophosphamide, the other one (also treated with cyclophosphamide) did not relapse. Retrospective assessment of serum and CSF demonstrated MOG antibodies in both cases, and review of biopsy specimens showed absence of fibrinoid necrosis (a pathologic requirement for small vessel CNS vasculitis). Conclusions:Anti-MOG-associated encephalitis can be mistaken for small vessel CNS vasculitis. This is important because the diagnosis of anti-MOG-associated encephalitis does not require brain biopsy and can be established with a serologic test. 10.1212/NXI.0000000000000538
    Infectious and autoantibody-associated encephalitis: clinical features and long-term outcome. Pillai Sekhar C,Hacohen Yael,Tantsis Esther,Prelog Kristina,Merheb Vera,Kesson Alison,Barnes Elizabeth,Gill Deepak,Webster Richard,Menezes Manoj,Ardern-Holmes Simone,Gupta Sachin,Procopis Peter,Troedson Christopher,Antony Jayne,Ouvrier Robert A,Polfrit Yann,Davies Nicholas W S,Waters Patrick,Lang Bethan,Lim Ming J,Brilot Fabienne,Vincent Angela,Dale Russell C Pediatrics BACKGROUND AND OBJECTIVES:Pediatric encephalitis has a wide range of etiologies, clinical presentations, and outcomes. This study seeks to classify and characterize infectious, immune-mediated/autoantibody-associated and unknown forms of encephalitis, including relative frequencies, clinical and radiologic phenotypes, and long-term outcome. METHODS:By using consensus definitions and a retrospective single-center cohort of 164 Australian children, we performed clinical and radiologic phenotyping blinded to etiology and outcomes, and we tested archived acute sera for autoantibodies to N-methyl-D-aspartate receptor, voltage-gated potassium channel complex, and other neuronal antigens. Through telephone interviews, we defined outcomes by using the Liverpool Outcome Score (for encephalitis). RESULTS:An infectious encephalitis occurred in 30%, infection-associated encephalopathy in 8%, immune-mediated/autoantibody-associated encephalitis in 34%, and unknown encephalitis in 28%. In descending order of frequency, the larger subgroups were acute disseminated encephalomyelitis (21%), enterovirus (12%), Mycoplasma pneumoniae (7%), N-methyl-D-aspartate receptor antibody (6%), herpes simplex virus (5%), and voltage-gated potassium channel complex antibody (4%). Movement disorders, psychiatric symptoms, agitation, speech dysfunction, cerebrospinal fluid oligoclonal bands, MRI limbic encephalitis, and clinical relapse were more common in patients with autoantibodies. An abnormal outcome occurred in 49% of patients after a median follow-up of 5.8 years. Herpes simplex virus and unknown forms had the worst outcomes. According to our multivariate analysis, an abnormal outcome was more common in patients with status epilepticus, magnetic resonance diffusion restriction, and ICU admission. CONCLUSIONS:We have defined clinical and radiologic phenotypes of infectious and immune-mediated/autoantibody-associated encephalitis. In this resource-rich cohort, immune-mediated/autoantibody-associated etiologies are common, and the recognition and treatment of these entities should be a clinical priority. 10.1542/peds.2014-2702
    A Case of Recurrent Insomnia: Extending the Spectrum of Autoimmune Encephalitis. Sabharwal Priyanka,Mahmoudi Mandana,Berberi Nisida,Vasquez Blanca A,Friedman Daniel,Kothare Sanjeev V Journal of clinical sleep medicine : JCSM : official publication of the American Academy of Sleep Medicine ABSTRACT:Recurrent insomnia is an uncommon manifestation that is encountered rarely in a sleep clinic. We report a woman with recurrent insomnia due to an autoimmune process that resolved after a course of immunotherapy. 10.5664/jcsm.5814
    Viral triggering of anti-NMDA receptor encephalitis in a child - an important cause for disease relapse. Wickström Ronny,Fowler Asa,Cooray Gerald,Karlsson-Parra Alex,Grillner Pernilla European journal of paediatric neurology : EJPN : official journal of the European Paediatric Neurology Society Herpes simplex encephalitis (HSE) in children is a potentially devastating condition which is occasionally complicated by a clinical relapse. An autoimmune component has long been suspected in these relapses and recent findings suggest that antibodies against N-methyl-D-aspartate receptors (NMDARs) may be part of this mechanism. We here report an 11 months old girl with acute HSE and with negative NMDAR antibody serology at presentation who after an initial response to antiviral treatment deteriorated with seizures, abnormal movements, focal neurologic deficits and psychiatric symptoms. We show that this relapse occurred as production of NMDAR antibodies developed and that clinical improvement followed immunotherapy with a concomitant decrease in NMDAR antibody titers in CSF. She also developed a characteristic 15-20 Hz activity over both hemispheres which has been previously described as an electroencephalographic presentation of anti-NMDAR encephalitis. We conclude that relapse or persisting symptoms in HSE in children may represent an immune-mediated mechanism rather than a viral reactivation and that NMDAR antibodies should be analyzed as this may be of importance for the choice of therapy. 10.1016/j.ejpn.2014.03.011
    Anti-N-Methyl-D-aspartate Receptor Encephalitis: A Severe, Potentially Reversible Autoimmune Encephalitis. Liu Cai-Yun,Zhu Jie,Zheng Xiang-Yu,Ma Chi,Wang Xu Mediators of inflammation Anti-N-methyl-D-aspartate receptor (NMDAR) encephalitis is potentially lethal, but it is also a treatable autoimmune disorder characterized by prominent psychiatric and neurologic symptoms. It is often accompanied with teratoma or other neoplasm, especially in female patients. Anti-NMDAR antibodies in cerebrospinal fluid (CSF) and serum are characteristic features of the disease, thereby suggesting a pathogenic role in the disease. Here, we summarize recent studies that have clearly documented that both clinical manifestations and the antibodies may contribute to early diagnosis and multidisciplinary care. The clinical course of the disorder is reversible and the relapse could occur in some patients. Anti-NMDAR encephalitis coexisting with demyelinating disorders makes the diagnosis more complex; thus, clinicians should be aware of the overlapping diseases. 10.1155/2017/6361479
    Investigations on CXCL13 in anti-N-methyl-D-aspartate receptor encephalitis: a potential biomarker of treatment response. Leypoldt Frank,Höftberger Romana,Titulaer Maarten J,Armangue Thaís,Gresa-Arribas Nuria,Jahn Holger,Rostásy Kevin,Schlumberger Wolfgang,Meyer Thomas,Wandinger Klaus-Peter,Rosenfeld Myrna R,Graus Francesc,Dalmau Josep JAMA neurology IMPORTANCE:Anti-N-methyl-D-aspartate receptor (NMDAR) encephalitis is a severe but treatable autoimmune encephalitis affecting mainly young adults and children. The lack of suitable biomarkers of disease activity makes treatment decisions and identification of relapses challenging. OBJECTIVE:To determine the levels of the B-cell-attracting C-X-C motif chemokine 13 (CXCL13) in serum samples and cerebrospinal fluid (CSF) of patients with anti-NMDAR encephalitis and whether they can be used as biomarkers of treatment response and outcome. DESIGN, SETTINGS, AND PARTICIPANTS:Retrospective cohort study of 167 patients consecutively diagnosed as having anti-NMDAR encephalitis between May 1, 2008, and January 31, 2013. Concentration of CXCL13 was determined with enzyme-linked immunosorbent assay in all available patients' samples (272 CSF and 55 serum samples). Samples from 25 patients with noninflammatory neurological disorders and 9 with neuroborreliosis served as controls. Expression of CXCL13 in the brain biopsy of a patient with anti-NMDAR encephalitis was determined by immunohistochemistry. MAIN OUTCOMES AND MEASURES:Percentage of patients with anti-NMDAR encephalitis and elevated CXCL13 in CSF. RESULTS:Compared with control individuals, 70% of patients with early-stage anti-NMDAR encephalitis had increased CXCL13 in CSF (>7 pg/mL; P < .001) but none in serum samples (>1047 pg/mL; P > .99). High concentration of CSF CXCL13 was associated with the presence of prodromal fever or headache (P = .01), limited response to therapy (P = .003), clinical relapses (P = .03), and intrathecal NMDAR-antibody synthesis (P < .001). Among patients with monophasic disease assessed 2 to 6 months after starting treatment, 10 of 15 with limited treatment response vs 0 of 13 with favorable response had increased CSF CXCL13 (specificity, 100%; 95% CI, 75-100 and sensitivity, 67%; 95% CI, 38-88; P = .02). Six of 12 patients had elevated CSF CXCL13 at relapse including 3 with previously normal levels. In brain, abundant mononuclear cells in perivascular infiltrates and scattered intraparenchymal microglia expressed CXCL13. CONCLUSIONS AND RELEVANCE:Seventy percent of patients with early-stage anti-NMDAR encephalitis had increased CSF CXCL13 concentration that correlated with intrathecal NMDAR-antibody synthesis. Prolonged or secondary elevation of CXCL13 was associated with limited response to treatment and relapses. CXCL13 is a potentially useful biomarker of treatment response and outcome in anti-NMDAR encephalitis. 10.1001/jamaneurol.2014.2956
    TLR3 deficiency in herpes simplex encephalitis: high allelic heterogeneity and recurrence risk. Lim Hye Kyung,Seppänen Mikko,Hautala Timo,Ciancanelli Michael J,Itan Yuval,Lafaille Fabien G,Dell William,Lorenzo Lazaro,Byun Minji,Pauwels Elodie,Rönnelid Ylva,Cai Xin,Boucherit Soraya,Jouanguy Emmanuelle,Paetau Anders,Lebon Pierre,Rozenberg Flore,Tardieu Marc,Abel Laurent,Yildiran Alisan,Vergison Anne,Roivainen Reina,Etzioni Amos,Tienari Pentti J,Casanova Jean-Laurent,Zhang Shen-Ying Neurology OBJECTIVE:To determine the proportion of children with herpes simplex encephalitis (HSE) displaying TLR3 deficiency, the extent of TLR3 allelic heterogeneity, and the specific clinical features of TLR3 deficiency. METHODS:We determined the sequence of all exons of TLR3 in 110 of the 120 patients with HSE enrolled in our study who do not carry any of the previously described HSE-predisposing mutations of TLR3 pathway genes (TLR3, UNC93B1, TRIF, TRAF3, and TBK1). All the new mutant TLR3 alleles detected were characterized experimentally in-depth to establish the causal relationship between the genotype and phenotype. RESULTS:In addition to the 3 previously reported TLR3-deficient patients from the same cohort, 6 other children or young adults with HSE carry 1 of 5 unique or extremely rare (minor allele frequency <0.001) missense TLR3 alleles. Two alleles (M374T, D592N) heterozygous in 3 patients are not deleterious in vitro. The other 3 are deleterious via different mechanisms: G743D+R811I and L360P heterozygous in 2 patients are loss-of-function due to low levels of expression and lack of cleavage, respectively, and R867Q homozygous in 1 patient is hypomorphic. The 3 patients' fibroblasts display impaired TLR3 responses and enhanced herpes simplex virus 1 susceptibility. Overall, TLR3 deficiency is therefore found in 6 (5%) of the 120 patients studied. There is high allelic heterogeneity, with 3 forms of autosomal dominant partial defect by negative dominance or haploinsufficiency, and 2 forms of autosomal recessive defect with complete or partial deficiency. Finally, 4 (66%) of the 6 TLR3-deficient patients had at least 1 late relapse of HSE, whereas relapse occurred in only 12 (10%) of the total cohort of 120 patients. CONCLUSIONS:Childhood-onset HSE is due to TLR3 deficiency in a traceable fraction of patients, in particular the ones with HSE recurrence. Mutations in TLR3 and TLR3 pathway genes should be searched and experimentally studied in children with HSE, and patients with proven TLR3 deficiency should be followed carefully. 10.1212/WNL.0000000000000999
    Ovarian teratoma development after anti-NMDA receptor encephalitis treatment. Omata Taku,Kodama Kazuo,Watanabe Yoshimi,Iida Yukiko,Furusawa Yoshiaki,Takashima Akiko,Takahashi Yukitoshi,Sakuma Hiroshi,Tanaka Keiko,Fujii Katsunori,Shimojo Naoki Brain & development BACKGROUND:Anti-NMDA-R receptor encephalitis occurs predominantly in younger women and is often comorbid with ovarian teratoma, a feature that is often absent in children. Here, we report our experience with two pediatric patients, in whom no tumors were present during treatment for encephalitis, but in whom ovarian teratomas developed without encephalitis relapse after treatment was completed. CASES:Patient 1 was a 14-year-old girl who was diagnosed due to characteristic symptoms and anti-NMDA-R antibody. MRI scanning during treatment revealed no ovarian tumors, but a tumor developed in the right ovary 10months after onset. Another tumor developed in the left ovary 3years after onset, and a mature ovarian teratoma was confirmed after bilateral partial ovariectomy. Patient 2 was an 11-year old girl who was also diagnosed due to characteristic symptoms and anti-NMDA-R antibody. Imaging during treatment revealed no ovarian tumors, but a 2.5-cm tumor mass was found in the left ovary 10months after onset, and a mature ovarian teratoma was confirmed after partial ovariectomy. DISCUSSION:This case report suggests the need for regular tumor screening after treatment for anti-NMDA receptor encephalitis because of potential subsequent tumor development, even in pediatric patients who initially present with no comorbid tumors. No analysis of relapse risk has yet been reported in cases of tumor development after treatment, and at this point, whether or not resection is needed to prevent relapse remains unclear. However, because teratomas usually grow, have an associated risk of torsion, and can be malignant, tumor removal should be considered. 10.1016/j.braindev.2016.12.003
    Herpes simplex encephalitis relapse associated with positive N-methyl-D-aspartate receptor antibodies. Boangher Sabina,Mespouille Pascal,Goffette Sophie,van Pesch Vincent,Cuciureanu Dan Acta neurologica Belgica 10.1007/s13760-018-0897-9
    Anti-N-methyl-D-aspartate receptor encephalitis during relapse of herpes simplex encephalitis in a young boy: A brief review of literature. Patil Varsha A,Kulkarni Shilpa D,Udwadia-Hegde Anaita,Sayed Rafat J,Garg Meenal Neurology India 10.4103/neuroindia.NI_1218_15
    Limbic encephalitis as a relapse of Whipple's disease with digestive involvement and spondylodiscitis. Brönnimann Didier,Vareil Marc-Olivier,Sibon Igor,Lagier Jean-Christophe,Lepidi Hubert,Puges Mathilde,Haneche Fatiha,Raoult Didier,Desclaux Arnaud,Neau Didier,Cazanave Charles Infection INTRODUCTION:Many clinical manifestations can be related to Tropheryma whipplei infection. CASE REPORT:We report a Tropheryma whipplei limbic encephalitis developed as a relapse of classical Whipple's disease. DISCUSSION:This case is to the best of our knowledge the first proof of the effective brain-blood barrier crossing of both doxycycline and hydroxychloroquine as demonstrated by direct concentration monitoring on brain biopsy. 10.1007/s15010-018-1173-x
    Autoimmune encephalitis epidemiology and a comparison to infectious encephalitis. Dubey Divyanshu,Pittock Sean J,Kelly Cecilia R,McKeon Andrew,Lopez-Chiriboga Alfonso Sebastian,Lennon Vanda A,Gadoth Avi,Smith Carin Y,Bryant Sandra C,Klein Christopher J,Aksamit Allen J,Toledano Michel,Boeve Bradley F,Tillema Jan-Mendelt,Flanagan Eoin P Annals of neurology OBJECTIVE:To evaluate the incidence and prevalence of autoimmune encephalitis and compare it to that of infectious encephalitis. METHODS:We performed a population-based comparative study of the incidence and prevalence of autoimmune and infectious encephalitis in Olmsted County, Minnesota. Autoimmune encephalitis diagnosis and subgroups were defined by 2016 diagnostic criteria, and infectious encephalitis diagnosis required a confirmed infectious pathogen. Age- and sex-adjusted prevalence and incidence rates were calculated. Patients with encephalitis of uncertain etiology were excluded. RESULTS:The prevalence of autoimmune encephalitis on January 1, 2014 of 13.7/100,000 was not significantly different from that of all infectious encephalitides (11.6/100,000; p = 0.63) or the viral subcategory (8.3/100,000; p = 0.17). The incidence rates (1995-2015) of autoimmune and infectious encephalitis were 0.8/100,000 and 1.0/100,000 person-years, respectively (p = 0.58). The number of relapses or recurrent hospitalizations was higher for autoimmune than infectious encephalitis (p = 0.03). The incidence of autoimmune encephalitis increased over time from 0.4/100,000 person-years (1995-2005) to 1.2/100,000 person-years (2006-2015; p = 0.02), attributable to increased detection of autoantibody-positive cases. The incidence (2.8 vs 0.7/100,000 person-years, p = 0.01) and prevalence (38.3 vs 13.7/100,000, p = 0.04) of autoimmune encephalitis was higher among African Americans than Caucasians. The prevalence of specific neural autoantibodies was as follows: myelin oligodendrocyte glycoprotein, 1.9/100,000; glutamic acid decarboxylase 65, 1.9/100,000; unclassified neural autoantibody, 1.4/100,000; leucine-rich glioma-inactivated protein 1, 0.7/100,000; collapsin response-mediator protein 5, 0.7/100,000; N-methyl-D-aspartate receptor, 0.6/100,000; antineuronal nuclear antibody type 2, 0.6/100,000; and glial fibrillary acidic protein α, 0.6/100,000. INTERPRETATION:This study shows that the prevalence and incidence of autoimmune encephalitis are comparable to infectious encephalitis, and its detection is increasing over time. Ann Neurol 2018;83:166-177. 10.1002/ana.25131
    Severe relapse of anti-NMDA receptor encephalitis 5 years after initial symptom onset. Nakajima Hideto,Unoda Kiichi,Hara Makoto eNeurologicalSci Anti-NMDAR encephalitis is characterized by abnormal behavior, cognitive dysfunction, seizures, disturbance of consciousness, central hypoventilation, and movement disorders, with a tendency to occur in younger women. Immunotherapy and tumor removal, where applicable, are effective for this disorder. However, previous papers have shown neurological relapse in 12-24% of cases. We present a case of anti-NMDAR encephalitis relapse 5 years after the initial episode. Although the relapse was much more severe than the initial episode, she recovered with aggressive therapy using first- and second-line immunotherapies. Anti- NMDAR encephalitis could relapse with a more severe clinical course after several years. Aggressive immunotherapy including cyclophosphamide must be necessary even for recurrent cases of anti-NMDAR encephalitis. 10.1016/j.ensci.2019.100199
    Role of Autoantibodies to N-Methyl-d-Aspartate (NMDA) Receptor in Relapsing Herpes Simplex Encephalitis: A Retrospective, One-Center Experience. Sutcu Murat,Akturk Hacer,Somer Ayper,Tatli Burak,Torun Selda Hancerli,Yıldız Edibe Pembegul,Şık Guntulu,Citak Agop,Agacfidan Ali,Salman Nuran Journal of child neurology Post-herpes simplex virus encephalitis relapses have been recently associated with autoimmunity driven by autoantibodies against N-methyl-d-aspartate (NMDA) receptors. Because it offers different treatment options, determination of this condition is important. Between 2011 and 2014, 7 children with proven diagnosis of herpes simplex virus encephalitis were identified in a university hospital of Istanbul. Two patients had neurologic relapse characterized mainly by movement disorders 2 to 3 weeks after initial encephalitis. The first patient received a second 14 days of acyclovir treatment together with antiepileptic drugs and left with severe neurologic sequelae. The second patient was found to be NMDA receptors antibody positive in the cerebrospinal fluid. She was treated with intravenous immunoglobulin and prednisolone. She showed substantial improvement, gradually regaining lost neurologic abilities. Post-herpes simplex virus encephalitis relapses may frequently be immune-mediated rather than a viral reactivation, particularly in children displaying movement disorders like choreoathetosis. Immunotherapy may provide benefit for this potentially devastating condition, like the case described in this report. 10.1177/0883073815595079
    Surgical outcomes in patients with anti-N-methyl D-aspartate receptor encephalitis with ovarian teratoma. Dai Yi,Zhang Junji,Ren Haitao,Zhou Xingnan,Chen Juan,Cui Liying,Lang Jinghe,Guan Hongzhi,Sun Dawei American journal of obstetrics and gynecology BACKGROUND:Anti-N-methyl-D-aspartate receptor encephalitis is an autoimmune encephalitis mediated by anti-N-methyl-D-aspartate receptor antibodies. Ovarian teratoma is closely related to anti-N-methyl-D-aspartate receptor encephalitis. However, the optimal treatment remains unknown, and strategies used for the diagnosis and therapy, including surgical intervention of ovarian teratoma, are debatable. OBJECTIVE:The objective of the study was to study the clinical features of anti-N-methyl-D-aspartate receptor encephalitis with ovarian teratoma to further understand the disease. STUDY DESIGN:This single-center prospective study included patients with anti-NMDAR encephalitis with ovarian teratoma from 2011 to 2016 who were admitted to Peking Union Medical College Hospital, Beijing, and discussed the clinical characteristics, treatment, and prognosis of the disease. The diagnosis of anti-N-methyl-D-aspartate receptor encephalitis was established preoperatively by identifying anti-N-methyl-D-aspartate receptor antibodies in the cerebrospinal fluid. Ovarian teratomas were suspected preoperatively by pelvic ultrasound and were diagnosed pathologically after laparoscopic detection and ovarian tumor resection. All patients were treated with first-line immunotherapy (steroids, intravenous immunoglobulin, and plasmapheresis), and when the therapy failed, they were treated with second-line immunotherapy (cyclophosphamide and rituximab). All patients were followed up regularly, and N-methyl-D-aspartate receptor antibodies, pelvic ultrasound, and neurological condition were monitored. Neurological symptoms were assessed using the modified Rankin Scale. RESULTS:A total of 108 female patients with anti-N-methyl-D-aspartate receptor encephalitis were screened, of whom, 29 patients (26.9% of 108; mean age ± SD, 23.14 ± 6.59 years) had pathologically confirmed ovarian teratoma. The incidence of fever, decreased consciousness, arrhythmia, central hypoventilation, ventilator-assisted respiration, and intensive unit care (75.9%, 65.5%, 27.6%, 55.2%, 55.2%, and 58.6%, respectively) were significantly higher in patients with ovarian teratoma than in those without ovarian teratoma. The modified Rankin Scale at the acute onset in those 29 patients was 4.11 ± 1.20, which was also much higher than that in patients without ovarian teratoma (3.58 ± 1.08). Of the 29 patients with ovarian teratoma, 22 (75.9%) underwent laparoscopy during the acute onset of neurological symptoms. The mean diameter of the tumor was 4.61 ± 3.41 cm (SD), and the smallest tumor was only 1 cm in the unilateral ovary. All other cysts, except 4 bilateral cysts (13.8%), were unilateral. Only 1 patient was diagnosed pathologically with immature ovarian teratoma, while others had benign ovarian teratomas. In all, 28 patients (96.5%) had a good outcome (modified Rankin Scale ≤2) and 1 died. In the follow-up visit (mean duration, 37.69 months), the relapse rate of encephalitis in patients with ovarian teratoma undergoing laparoscopic cystectomy was 14.6%, whereas for those without ovarian teratoma, the relapse rate was 33.3%. The removal of ovarian teratoma was associated with reduced risk of relapse. CONCLUSION:Patients having anti-N-methyl-D-aspartate receptor encephalitis with ovarian teratomas tend to present more severe neurological conditions. The diameter of the tumor in these patients is not very large and could be as small as 1 cm, and thus, careful exploration should be considered during surgery. Most of the ovarian teratomas in patients with anti-N-methyl-D-aspartate receptor encephalitis are mature. Early operative treatment is safe and effective because it is associated with reduced risk of relapse and complete recovery. 10.1016/j.ajog.2019.05.026
    N-methyl-D-aspartate receptor antibodies in post-herpes simplex virus encephalitis neurological relapse. Hacohen Yael,Deiva Kumaran,Pettingill Phillipa,Waters Patrick,Siddiqui Ata,Chretien Pascale,Menson Esse,Lin Jean-Pierre,Tardieu Marc,Vincent Angela,Lim Ming J Movement disorders : official journal of the Movement Disorder Society Herpes simplex virus encephalitis (HSVE) is a devastating condition that relapses, often with a chorea in children, despite adequate antiviral treatment. At relapse, evidence of viral replication is frequently absent, suggesting that the relapse may be immune-mediated. Seven children who had a neurological relapse following their initial encephalitis, identified from 20 cases of pediatric HSVE, were studied. Serum and/or cerebrospinal fluid (CSF) were tested for N-methyl-D-aspartate receptor (NMDAR) and other antibodies previously reported in central nervous system autoimmunity. Five of the 7 relapsing children had choreoathetosis; 2 of these were NMDAR antibody-positive, 2 were negative (1 with HSV-positive CSF), and 1 was not available for testing. An additional patient, who relapsed with cognitive regression but with no movement disorder, was also NMDAR antibody-positive. In 2 of the NMDAR antibody-positive patients who were treated at relapse and in 1 who was treated only after 10 years of having a relapsing encephalopathy, a beneficial response was observed. Neurological relapses after HSVE may frequently be immune-mediated, particularly in children with chorea. NMDAR antibodies are common, and immunotherapy may be beneficial. 10.1002/mds.25626
    Relapse risk factors in anti-N-methyl-D-aspartate receptor encephalitis. Nosadini Margherita,Granata Tiziana,Matricardi Sara,Freri Elena,Ragona Francesca,Papetti Laura,Suppiej Agnese,Valeriani Massimiliano,Sartori Stefano, Developmental medicine and child neurology AIM:To identify factors that may predict and affect the risk of relapse in anti-N-methyl-D-aspartate receptor (NMDAR) encephalitis. METHOD:This was a retrospective study of an Italian cohort of patients with paediatric (≤18y) onset anti-NMDAR encephalitis. RESULTS:Of the 62 children included (39 females; median age at onset 9y 10mo, range 1y 2mo-18y; onset between 2005 and 2018), 21 per cent relapsed (median two total events per relapsing patient, range 2-4). Time to first relapse was median 31.5 months (range 7-89mo). Severity at first relapse was lower than onset (median modified Rankin Scale [mRS] 3, range 2-4, vs median mRS 5, range 3-5; admission to intensive care unit: 0/10 vs 3/10). At the survival analysis, the risk of relapsing was significantly lower in patients who received three or more different immune therapies at first disease event (hazard ratio 0.208, 95% confidence interval 0.046-0.941; p=0.042). Neurological outcome at follow-up did not differ significantly between patients with relapsing and monophasic disease (mRS 0-1 in 39/49 vs 12/13; p=0.431), although follow-up duration was significantly longer in relapsing (median 84mo, range 14-137mo) than in monophasic patients (median 32mo, range 4-108mo; p=0.002). INTERPRETATION:Relapses may occur in about one-fifth of children with anti-NMDAR encephalitis, are generally milder than at onset, and may span over a long period, although they do not seem to be associated with severity in the acute phase or with outcome at follow-up. Aggressive immune therapy at onset may reduce risk of relapse. WHAT THIS PAPER ADDS:Relapses of anti-N-methyl-D-aspartate receptor encephalitis may span over a long period. Relapses were not associated with severity in the acute phase or outcome at follow-up. Aggressive immune therapy at onset appears to decrease risk of relapse. 10.1111/dmcn.14267
    Persistent MOG-IgG positivity is a predictor of recurrence in MOG-IgG-associated optic neuritis, encephalitis and myelitis. Oliveira Luana Michelli,Apóstolos-Pereira Samira Luisa,Pitombeira Milena Sales,Bruel Torretta Pedro Henrique,Callegaro Dagoberto,Sato Douglas Kazutoshi Multiple sclerosis (Houndmills, Basingstoke, England) BACKGROUND:MOG-IgG-associated optic neuritis, encephalitis and myelitis (MONEM) is a recently recognized group of inflammatory central nervous system (CNS) disorders distinct from multiple sclerosis and neuromyelitis optica spectrum disorders. Limited data are available regarding the predictors of relapse in this condition. OBJECTIVE:We aimed to evaluate the longitudinal serostatus of patients with MOG-IgG and to correlate serostatus with long-term clinical outcomes. METHODS:Of 574 consecutive patients who presented with demyelinating inflammatory CNS disorders, we included 31 patients who were MOG-IgG-positive. Patients with MOG-IgG were followed up from 2011 to 2017 at the School of Medicine, University of São Paulo, Brazil. RESULTS:Relapsing disease occurred in 23 out of 31 patients (74%), while 8 (26%) exhibited a monophasic course. All monophasic patients, as well as the majority of relapsing patients, became seronegative during clinical remission. Patients exhibiting disease activity in the last 2 years were more likely to remain positive, with higher medium titres than those found in patients in clinical remission. CONCLUSION:MOG-IgG patients usually present with a relapsing course, and the risk of relapse was associated with longitudinally persistent MOG-IgG seropositivity. In contrast, patients who experienced a single attack became spontaneously seronegative for MOG-IgG during long-term follow-up. 10.1177/1352458518811597