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Anti-NMDAR encephalitis | Neurology Neuroimmunology & Neuroinflammation

Anti-NMDAR encephalitis | Neurology Neuroimmunology & Neuroinflammation | AntiNMDA | Scoop.it
From nn.neurology.org - January 3, 2020 11:40 PM
Abstract Objective To describe the detailed clinical characteristics, immunotherapy, and long-term outcomes of patients with anti-NMDA receptor (NMDAR) encephalitis in China. Methods A single-center, prospective study. Patients who met the diagnostic criteria were enrolled from 2011 to 2017 and followed up. The clinical features, treatment, and long-term outcomes were collected prospectively. Factors affecting the long-term prognosis were analyzed. Results The study included 220 patients. The most common clinical presentations were psychosis (82.7%) and seizures (80.9%). Of the patients, 19.5% had an underlying neoplasm; of which ovarian teratoma was 100% of tumors in females and only one male had lung cancer. Most patients (99.5%) received first-line therapy (glucocorticoids, IV immunoglobulin, or plasmapheresis alone or combined), and only 7.3% received second-line immunotherapy (rituximab, cyclophosphamide alone, or combined). Long-term immunotherapy (mycophenolate mofetil or azathioprine >1 year) was administered to 53.2% of patients. During the first 12 months, 207 (94.1%) patients experienced improvement, and 5 (2.3%) died, whereas 38 (17.3%) experienced relapses. At 12-month follow-up, 92.7% had favorable clinical outcomes (modified Rankin Scale score ≤2). Conclusions Patients in China present with psychosis and seizure frequently but have a low percentage of underlying neoplasms. Re-enforced first-line immunotherapy is effective in managing anti-NMDAR encephalitis in the acute phase. Although relapse is relatively common, with combined first-line and long-term immunotherapy, most patients reached favorable outcomes. Glossary AE=autoimmune encephalitis; AQP4=aquaporin-4; AZA=azathioprine; CTX=cyclophosphamide; HSV=herpes simplex virus; ICU=intensive care unit; IQR=interquartile range; IVIG=IV immunoglobulin; MMF=mycophenolate mofetil; MOG=myelin oligodendrocyte glycoprotein; mRS=modified Rankin Scale; MTX=methotrexate; NMDAR=NMDA receptor; PE=plasmapheresis; PUMCH=Peking Union Medical College Hospital; RTX=rituximab Anti-NMDA receptor (NMDAR) encephalitis is the most common type of autoimmune encephalitis (AE), which is associated with autoantibodies against neurosurface or synaptic antigens.1,–,3 Since its first report in 2007,1 with the proposed clinical approach,3 increasing numbers of anti-NMDAR encephalitis cases were identified. Differences in clinical characteristics and treatment strategies of anti-NMDAR encephalitis were reported among races and countries.4,–,10 Main barriers to AE management in China consist of the availability of referral centers, the timeliness of correct diagnosis, and financial concerns.11 In 2017, China proposed a domestic consensus on the management of AE, aiming to increase awareness of the disease and determine the optimal treatment for Chinese patients.12 However, limited data of clinical characteristics and long-term prognosis of Chinese anti-NMDAR patients are available owing to few reports with small sample size.9,11,13,14 Taking the advantage of Peking Union Medical College Hospital (PUMCH) as the national referral center for complicated disease, a prospective anti-NMDAR encephalitis disease cohort was established to describe the clinical characteristics, treatment regimen, and long-term outcomes of patients with anti-NMDAR encephalitis in China. Methods Study design and population In this study, patients with anti-NMDAR encephalitis were enrolled consecutively at PUMCH between May 2011 and December 2017. The inclusion criteria were as follows: (1) acute onset of 1 or more of the 8 major groups of manifestations: psychosis, memory deficit, speech disturbance, seizures, movement disorder, loss of consciousness, autonomic dysfunction, and central hypoventilation; (2) CSF tested positive for NMDAR antibodies (cell-based assay [EUROIMMUN, Lübeck, Germany]); and (3) reasonable exclusion of other disorders. To better understand the clinical characteristics, we also recorded the co-occurrence of fever, headache, arrhythmia, intensive care unit (ICU) admission, and other atypical symptoms. Because of limited resources of the hospital and financial concerns the patients, the absolute indications for ICU admission included severe anti-NMDAR encephalitis with ovarian teratoma requiring surgical operation, status epilepticus, mechanical ventilation requirement, and hemodynamic instability. Demographic data and ancillary tests results were recorded, including age at onset, sex, disease course, CSF tests results, MRI, and EEG results. All patients were screened at least once for systemic tumors at onset. Patients with tumors underwent tumor removal. Immunotherapy included first-line (corticosteroids, IV immunoglobulin [IVIG], or plasmapheresis [PE] alone or combined) and second-line (rituximab [RTX] and cyclophosphamide [CTX] alone or combined) immunotherapies.6,7 Long-term immunotherapy (mycophenolate mofetil [MMF] or azathioprine [AZA] >1 year) and other immunotherapy (intrathecal methotrexate [MTX]) were also administered.15,16 Patients were followed regularly in local hospitals or PUMCH neurology clinics. Treatment effects and long-term outcomes were assessed using the modified Rankin Scale (mRS). A poor response was defined as no improvement in the mRS score or as an mRS score ≥4 for 4 weeks; clinical improvement was defined as a decrease in the mRS score ≥1 point from that at the previous visit; relapse was defined as an exacerbation of previous symptoms or the occurrence of new symptoms after being stable for 2 months. Long-term favorable outcome was defined as an mRS score ≤2, and poor outcome was defined as an mRS score >2 at the end of follow-up. Statistical analysis Statistical analyses were performed using SPSS IBM 20.0. GraphPad Prism 6.0 was used to generate figures. Quantitative data with normal distributions are presented as mean ± SD, otherwise as medians with the interquartile range (IQR). The mRS scores before and after treatment were compared using the Wilcoxon test. Symptoms and demographic data were analyzed using the χ2 test or Fisher exact test for categorical variables and Mann-Whitney U test for continuous variables. Factors affecting outcome were assessed using binary logistic regression analysis. Kaplan-Meier curves with log-rank were used to analyze relapse frequency. p < 0.05 was considered significant. Standard protocol approvals, registrations, and patient consents This study was approved by the Ethics Committee of PUMCH (JS-891), and informed consent was obtained from each patient. All the data analyzed in the study were strictly anonymous. Data availability Anonymized data not published within this article will be made available by request from any qualified investigator. Results Clinical characteristics A total of 220 patients were enrolled, and all were tested for anti-NMDAR antibody with paired CSF and serum. All patients (100%) were positive for anti-NMDAR antibodies in CSF, and 157 (71.4%) were positive in serum. Review of the enrolled patients indicated that all patients met the diagnostic criteria proposed by Graus et al.3 The median age at onset was 21 (range 5–72) years, with 69 (31.4%) of the patients younger than 18 years. Overall, 143 (65.0%) patients were females, and 77 (35.0%) were males. Tumors were found in 43 (19.5%) patients: 42 females with ovarian teratomas and 1 male with lung cancer. All the female patients with ovarian teratomas underwent tumor removal, whereas the patient with lung cancer was treated with palliative therapy by an internist and later died of cancer. In addition, 8 patients were found to have prominent moles on the body surface, which were later resected. Pathologically, the moles were compound or intradermal nevi.17,18 The most common clinical manifestations of the anti-NMDAR encephalitis were psychosis (182, 82.7%) and seizures (178, 80.9%). Movement disorder presented more often in patients younger than 18 years than adult patients (38/69, 55.1% vs 56/151, 37.1%, p = 0.01). Table 1 describes the patients' clinical characteristics in detail. View inline View popup Table 1 Clinical characteristics of patients with anti-NMDA receptor encephalitis Figure 1 shows the distribution of female patients according to age and presence vs absence of tumor; the peak co-occurrence of ovarian teratoma was between 19 to 24 years. Figure 1 Distribution of female patients by age and presence or absence of ovarian teratoma Ancillary test results All patients underwent brain MRI at onset, and 79 (35.9%) had abnormal fluid-attenuated inversion recovery sequence signals, including 31 (14.1%) in the medial temporal lobe. Other involved areas included the frontal, parietal, and occipital cortices, diencephalon, cerebellum, and brainstem. Eleven (5.0%) patients had demyelinating lesions, of whom 4 were positive for aquaporin-4 (AQP4) antibody and 5 for myelin oligodendrocyte glycoprotein (MOG) antibody. Abnormal EEG findings were seen in 113 (51.4%) patients: 102 (46.4%) had slow activity and 14 (6.4%) epileptic discharges. However, as most patients received short-duration EEG instead of video EEG of 24 hours or longer, the percentage of delta-brush abnormality was unable to assess. Repeated lumbar punctures were performed for diagnosis and evaluation, and the CSF results at onset before immunotherapy were collected and analyzed. The analysis showed a median opening pressure of 170 (IQR 150–280) mmH2O. Of note, 81.3% of the patients had pleocytosis, the median white blood cell count was 14.0 (IQR 7.0–22.5) × 106/L, and 90.9% were of mononuclear cells (i.e., lymphocyte and monocytes). The protein level was elevated in 29.7% of the patients. Table 2 summarizes the main ancillary tests of the patients. View inline View popup Table 2 Summary of the main ancillary tests results Improvements in diagnosis accuracy and general hospitalization status Underrecognition and misdiagnosis were inevitable in the past, occurring at the initial visit to a local physician or admission to our hospital. In 2011, 4 patients were identified, taking a median duration of 9 (IQR 1–36) months before diagnosis was made. The misdiagnosis rate then was 75.0%, with most cases misdiagnosed as viral encephalitis. With increased awareness of AE, screening for anti-NMDAR antibodies at admission is now required for all cases with suspected encephalitis. By 2017, the misdiagnosis rate had decreased to 15.4%. Overall, 30 patients were misdiagnosed with viral encephalitis, 10 with schizophrenia, 2 with epilepsy, and 1 each with cerebral angiitis, cerebral vascular events, and tuberculosis. The percentages of correct diagnosis at the initial hospital visit over misdiagnosis by calendar year were shown in figure 2, indicating a growing number of referred patients and increased correct diagnosis identified over the years. Figure 2 Number of patients of correct diagnosis over misdiagnosis at the initial hospital visit by calendar year The median duration from onset to diagnosis was 2 (IQR 1–4) weeks. Immunotherapy was initiated the same day diagnosis was made and sometimes even before diagnosis at local hospitals as empirical treatment. The median length of hospitalization was 26 (IQR 14–42) days. However, severe patients who required intensive care stayed in the hospital for up to 117 days. Treatment outcomes Overall, 219 (99.5%) patients received first-line immunotherapy, in most cases a combined regimen of repeated steroids and IVIG. A total of 208 (94.5%) patients received steroids, of whom 103 (46.8%) received pulsed IV methylprednisolone. IVIG was administered to 199 (90.5%) patients, and 7 (3.2%) patients underwent PE. Second-line immunotherapy was administered to only a small proportion of the patients, usually because of the off-label use of RTX in AE, cost, IV and hospitalization requirements, and concerns about side effects. Twelve (5.5%) patients received RTX, and 4 (1.8%) received CTX. Long-term immunotherapy was administered mainly in patients who were enrolled later, as an add-on therapy for severe or refractory patients in the acute phase, or as maintenance therapy to prevent and manage relapses. In general, MMF was administered in 109 (49.5%) patients, 55 of whom at onset and 54 after relapse, and AZA was administered in 8 (3.6%) patients. In addition, intrathecal MTX was given to 8 (3.6%) severe patients. During the first 12 months, 207 (94.1%) patients experienced improvement, 8 (3.6%) were stable, and 5 (2.3%) patients died. All survival patients were followed for at least a year (range 12–72 months). At 12-month follow-up, 204 (92.7%) patients had attained satisfactory neurologic function (mRS score of 0, 1, and 2 in 144, 47, and 13 patients, respectively) compared with 23 (10.5%) patients with an mRS score ≤2 at onset, as shown in figure 3. The median mRS score at the last follow-up was 0 (IQR 0–1), which was significantly lower than the score of 4 (IQR 3–5) at onset (Z = −12.67, p < 0.0001). Figure 3 Distribution of mRS scores at onset and last follow-up mRS = modified Rankin Scale. Table 3 summarizes the comparisons between patients with favorable and poor clinical outcomes. Of interest, more patients with speech disturbance were identified in the favorable outcome group (p = 0.03). Further analysis indicated that patients with speech disturbance presented to the neurologist earlier than those without (20 days [IQR 12–34 days] vs 31 days [IQR 19–58 days], p = 0.008, Z = −2.665). However, age at onset, the rates of decreased consciousness level, central hypoventilation, ICU admission, mechanical ventilation, ovarian teratoma, and relapse were higher in the poor outcome subgroup, although none of these differences reached significance. View inline View popup Table 3 Comparisons of clinical data of patients with anti-NMDA receptor encephalitis Relapse During the first 12 months, 38 (17.3%) patients experienced a first relapse. Their median age was 21 (IQR 16–37) years, and the median duration from onset to the first relapse was 7 (IQR 5–10) months. Of the relapsed patients, 25 (65.8%) were female, and 5 had ovarian teratomas at disease onset. Thorough clinical and laboratory examinations were conducted to rule out other etiologies and to validate the diagnosis. Two patients were treated at local hospitals before antibodies were tested, whereas 10/36 (27.8%) patients showed elevated antibody titer at relapse during serial serum antibody monitoring. Of the 17 patients who underwent lumbar puncture, CSF antibodies were detected in 15 (88.2%) patients. MRI was abnormal in 8 (21.1%) patients, and an ovarian teratoma was detected in only 1 (2.6%) patient at relapse. A delay in treatment was associated with relapse (p < 0.01). However, neither tumor status (p = 0.58) nor treatment regimen (p = 0.34) was statistically associated with relapse frequency (figure e-1, links.lww.com/NXI/A157). All relapsed patients underwent reinitiation of the first-line immunotherapy, and 18 patients were also given long-term MMF. Subsequently, 12 (31.6%) patients experienced further relapses (range 2–4 episodes). There was no significant difference in the occurrence of subsequent relapse between MMF-treated patients and other patients (4/18, 22.2% vs 8/20, 40.0%, p = 0.31). Subsequent relapses were similar to, or worse than, the initial episodes in only 3 (7.9%) patients. The initial hospitalization duration was 25 (IQR 14–43) days, and the subsequent hospitalizations were all shorter than 14 days. Between 2011 and 2017, 80 (36.4%) patients experienced relapse, and 21 (26.3%) experienced multiple relapses (range 2–4 episodes). Most patients had a first relapse during the first 24 months (64/80, 80.0%). However, relapses up to 6 years after onset were also reported in our cohort. Discussion To our knowledge, this is the largest Chinese anti-NMDAR encephalitis cohort to date. In our study, anti-NMDAR encephalitis is predominantly found in females (65.0%) with the median age at onset of 21 years. Most patients presented with psychiatric symptoms and seizures, and younger patients presented more often with movement disorders, which are consistent with previous studies.6,7 However, our study reported a low ICU admission rate. The large cohort study of Titulaer et al.7 reported that 75% (435/563) of patients with mRS score ≥4 were admitted to the ICU. In our study, because of limited availability of medical recourses and concern of expenses, only 68/133 (51.1%) of the severe patients (mRS score ≥4) were admitted to the ICU. The prevalence of an underlying neoplasm varied among studies. Titulaer et al.7 reported that 38% of the patients had a tumor, and Asian patients were more likely (45%) to have a teratoma. However, only 19.5% of the patients in our cohort had a tumor, with 29.4% of the females had an ovarian teratoma. Other studies of Chinese or Asian patients have also reported low prevalence of tumors (Lim et al., 22.7%; Wang et al., 8%; Liu et al., 6.7%; and Zhang et al., 8.1%).8,11,13,14 The heterogeneity among reports may be due to sample sizes and selection bias or other factors including genetic backgrounds and epidemiologic reasons, and future studies are required. In tumor-negative patients, herpes simplex virus (HSV) infection has been reported to be the possible trigger. However, as the gold standard for the infection is PCR testing, which is expensive and time consuming, most patients received empirical treatment before or even without a definite diagnosis of HSV encephalitis. Thus post-HSV anti-NMDAR encephalitis was unable to assess in our current study. Brain MRI findings provide further evidence that anti-NMDAR encephalitis is a “diffuse encephalopathy.”6 Abnormal signals were reported in 35.9% of the patients, predominantly in the medial temporal lobe. Signals in other areas of the cortex, diencephalon, brainstem, and cerebellum were also reported. Notably, “overlapping syndrome” was identified in 11 (5.0%) patients with both MRI demyelinating lesions and anti-AQP4 or anti-MOG antibodies.19 Studies have suggested more intense immunotherapy requirements and more residual deficits in these patients.19,20 In our series, all these patients received long-term immunotherapy with MMF, and 10 (90.9%) had favorable clinical outcomes. In the management of anti-NMDAR encephalitis, repeated first-line immunotherapy was frequently used in our cohort, whereas second-line immunotherapy was administered in a small portion of patients owing to the off-label use of RTX for AE in China, cost, hospitalization requirements, and concerns about side effect.9,11,14,15 However, long-term immunotherapy was administered to 117 (53.2%) patients, including MMF to 109 (49.5%). With combined therapy of re-enforced first-line therapy and long-term immunotherapy, 204 (92.7%) patients reached favorable clinical outcomes, and the median mRS score decreased significantly from 4 to 0 at a follow-up of 12 months. Compared with other reports (Dalmau et al., 77%; Tituaer et al., 79%; Wang et al., 80.4%; Liu et al., 64%; and Zhang et al., 89.2%),6,7,11,13,14 we observed more satisfactory clinical outcomes. Speech disturbance was found to be more frequent in the group with favorable outcome. Further analysis indicated that patients with speech distance were diagnosed earlier. Thus, this could be a confounder reflecting better recognition and therefore quicker treatment. Relapses were relatively common in our cohort. The definition of relapse in our study, along with other proposed definitions,7,21,22 is based more on observations and descriptions of clinical symptoms. Nevertheless, thorough examinations are needed to rule out other disorders and validate the diagnosis. When monitoring and evaluating the relapses, MRI was frequently unremarkable. The serum antibody titer did not correlate with the clinical severity perfectly, and some relapsed antibodies were detected only in the CSF, as previously reported.6,22 However, serial CSF monitoring may be impractical during follow-up, and better indicators should be identified in future studies. Neither tumor status nor treatment regimen was associated with relapse frequency statistically, possibly due to the low prevalence of tumor and variety in the treatment regimens used in our cohort. Long-term MMF did not prevent further relapses, possibly because of the relatively small sample size, and the role of long-term immunotherapy warrants further investigation. Although most patients experienced a first relapse within 24 months, relapse 6 years after onset was also reported. Other reports also suggested that AE relapse could occur years after the initial episode.21,23,24 Therefore, extended follow-up is essential. Our study has several limitations. As the national referral center for complicated disease, our cohort may be biased by more refractory cases. The analysis for each individual treatment, particularly for long-term immunotherapy, and the assessment of relapses warrants further study. Parameters other than the mRS score are required to describe fully the outcomes of anti-NMDAR encephalitis, especially in evaluating the cognitive or behavioral function, which usually remains last in these patients. Despite these limitations, our study adds to the present knowledge of anti-NMDAR encephalitis, and acts as a precursor for future multicenter studies with more comprehensive evaluations, and studies to further evaluate the efficacy of each individual treatment. We describe the clinical characteristics, immunotherapy regimens, and long-term outcomes of patients with anti-NMDAR encephalitis in China. Repeated first-line therapy is effective in managing acute phase encephalitis, and the efficacy of long-term immunotherapy warrants further study. Although relapses are relatively common, most patients reached favorable outcomes. Further multicenter studies with more advanced study design, more detailed evaluation, and extended follow-up are required. Study funding The study was supported by (1) National Key Research and Development Program of China (Grant no. 2016YFC0901500); (2) Center for Rare Diseases Research, Chinese Academy of Medical Sciences, Beijing, China (Grant no. 2016ZX310174-4); and (3) Beijing Municipal Science and Technology Foundation (Grant no. Z161100000516094). Disclosure The authors report no disclosures. Go to Neurology.org/NN for full disclosures. Acknowledgment The authors thank Prof. Jianming Wang of Peking Union Medical College Hospital and Prof. Jiawei Wang of Beijing Tongren Hospital Affiliated to Capital Medical University for providing advice for the article. They also thank Dr. Yan Zhang of Xuanwu Hospital Affiliated to Capital Medical University, Dr. Yongqiang Hu of Beijing Fengtai Youanmen Hospital, and Beijing Encephalitis Group for contributing participants. Appendix Authors Footnotes Go to Neurology.org/NN for full disclosures. Funding information is provided at the end of the article. ↵* These authors contributed equally to the manuscript. The Article Processing Charge was funded by National Key Research and Development Program of China (Grant no. 2016YFC0901500); Center for Rare Diseases Research, Chinese Academy of Medical Sciences, Beijing, China (Grant no. 2016ZX310174-4); and Beijing Municipal Science and Technology Foundation (Grant no. Z161100000516094). Received April 21, 2019. Accepted in final form September 12, 2019. Copyright © 2019 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American Academy of Neurology. This is an open access article distributed under the terms of the Creative Commons Attribution-NonCommercial-NoDerivatives License 4.0 (CC BY-NC-ND), which permits downloading and sharing the work provided it is properly cited. The work cannot be changed in any way or used commercially without permission from the journal. References 1.↵Dalmau J, Tuzun E, Wu HY, et al. Paraneoplastic anti-N-methyl-D-aspartate receptor encephalitis associated with ovarian teratoma. Ann Neurol 2007;61:25–36.OpenUrlCrossRefPubMed 2.↵Dalmau J, Gleichman AJ, Hughes EG, et al. Anti-NMDA-receptor encephalitis: case series and analysis of the effects of antibodies. Lancet Neurol 2008;7:1091–1098.OpenUrlCrossRefPubMed 3.↵Graus F, Titulaer MJ, Balu R, et al. A clinical approach to diagnosis of autoimmune encephalitis. Lancet Neurol 2016;15:391–404.OpenUrlCrossRefPubMed 4.↵Iizuka T, Sakai F, Ide T, et al. Anti-NMDA receptor encephalitis in Japan: long-term outcome without tumor removal. Neurology 2008;70:504–511.OpenUrlCrossRefPubMed 5.↵Irani SR, Bera K, Waters P, et al. N-methyl-D-aspartate antibody encephalitis: temporal progression of clinical and paraclinical observations in a predominantly non-paraneoplastic disorder of both sexes. Brain 2010;133:1655–1667.OpenUrlCrossRefPubMed 6.↵Dalmau J, Lancaster E, Martinez-Hernandez E, Rosenfeld MR, Balice-Gordon R. Clinical experience and laboratory investigations in patients with anti-NMDAR encephalitis. Lancet Neurol 2011;10:63–74.OpenUrlCrossRefPubMed 7.↵Titulaer MJ, McCracken L, Gabilondo I, et al. Treatment and prognostic factors for long-term outcome in patients with anti-NMDA receptor encephalitis: an observational cohort study. Lancet Neurol 2013;12:157–165.OpenUrlCrossRefPubMed 8.↵Lim JA, Lee ST, Jung KH, et al. Anti-N-methyl-d-aspartate receptor encephalitis in Korea: clinical features, treatment, and outcome. J Clin Neurol 2014;10:157–161.OpenUrlPubMed 9.↵Yuan J, Peng B, Guan H, et al. Immunotherapy strategy for 35 cases of severe anti-N-methyl-D-aspartate receptor encephalitis. Natl Med J China 2016;96:1035–1039.OpenUrl 10.↵Bartolini L, Muscal E. Differences in treatment of anti-NMDA receptor encephalitis: results of a worldwide survey. J Neurol 2017;264:647–653.OpenUrl 11.↵Wang W, Li JM, Hu FY, et al. Anti-NMDA receptor encephalitis: clinical characteristics, predictors of outcome and the knowledge gap in southwest China. Eur J Neurol 2016;23:621–629.OpenUrl 12.↵Association NBoCM. Chinese expert consensus on the diagnosis and management of autoimmune encephalitis. Chin J Neurol 2017;50:91–98.OpenUrl 13.↵Liu L, Song ZH, Guo J, et al. Clinical analysis of 45 Chinese patients with anti-N-methyl-D-aspartate receptor encephalitis. Chin J Neurol 2014;47:474–481.OpenUrl 14.↵Zhang Y, Liu G, Jiang M, Chen W, He Y, Su Y. Clinical characteristics and prognosis of severe anti-N-methyl-D-aspartate receptor encephalitis patients. Neurocrit Care 2018;29:264–272.OpenUrl 15.↵Guan HZ, Xu XL, Zhu YC, et al. Clinical and immunological analysis of mycophenolate mofetil treatment in anti-leucine-rich glioma-inactivated 1 encephalitis. Chin J Neurol 2018;51:281–287.OpenUrl 16.↵Yang XZ, Cui LY, Ren HT, Qu T, Guan HZ. Anti-NMDAR encephalitis after resection of melanocytic nevi: report of two cases. BMC Neurol 2015;15:165.OpenUrl 17.↵Yang XZ, Zhu HD, Ren HT, et al. Utility and safety of intrathecal methotrexate treatment in severe anti-N-methyl-D-aspartate receptor encephalitis: a pilot study. Chin Med J (Engl) 2018;131:156–160.OpenUrl 18.↵Yin H, Zhu C, Ren H, et al. Resection of melanocytic nevi as a potential treatment of anti-NMDAR encephalitis patients without tumor: report of three cases. Neurol Sci 2018;39:165–167.OpenUrl 19.↵Titulaer MJ, Hoftberger R, Iizuka T, et al. Overlapping demyelinating syndromes and anti-N-methyl-D-aspartate receptor encephalitis. Ann Neurol 2014;75:411–428.OpenUrlCrossRefPubMed 20.↵Fan S, Xu Y, Ren H, et al. Comparison of myelin oligodendrocyte glycoprotein (MOG)-antibody disease and AQP4-IgG-positive neuromyelitis optica spectrum disorder (NMOSD) when they co-exist with anti-NMDA (N-methyl-D-aspartate) receptor encephalitis. Mult Scler Relat Disord 2018;20:144–152.OpenUrl 21.↵Gabilondo I, Saiz A, Galan L, et al. Analysis of relapses in anti-NMDAR encephalitis. Neurology 2011;77:996–999.OpenUrlCrossRefPubMed 22.↵Gresa-Arribas N, Titulaer MJ, Torrents A, et al. Antibody titres at diagnosis and during follow-up of anti-NMDA receptor encephalitis: a retrospective study. Lancet Neurol 2014;13:167–177.OpenUrlCrossRefPubMed 23.↵Arino H, Armangue T, Petit-Pedrol M, et al. Anti-LGI1-associated cognitive impairment: presentation and long-term outcome. Neurology 2016;87:759–765.OpenUrl 24.↵van Sonderen A, Thijs RD, Coenders EC, et al. Anti-LGI1 encephalitis: clinical syndrome and long-term follow-up. Neurology 2016;87:1449–1456.OpenUrl
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Josep Dalmau receives the “Scientific Breakthrough 2023” Award from the American Brain Foundation

From www.clinicbarcelona.org - May 23, 2023 2:38 PM
The accolade recognises the commitment of this Clínic Barcelona-IDIBAPS researcher to deepening our understanding of autoimmune neurological diseases such...
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IDIBAPS creates three multidisciplinary research programs to encourage collaboration among its groups

From www.clinicbarcelona.org - September 5, 2023 11:21 AM
They are the Translational cancer research program, the Synaptic autoimmunity in neurology, psychiatry and cognitive neuroscience program and the Lymphoid...
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ExTINGUISH: A Beacon of Hope for NMDAR Encephalitis

From youtu.be - August 6, 2023 7:10 PM
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MR Imaging Findings in a Large Population of Autoimmune Encephalitis | American Journal of Neuroradiology

MR Imaging Findings in a Large Population of Autoimmune Encephalitis | American Journal of Neuroradiology | AntiNMDA | Scoop.it
From www.ajnr.org - July 27, 2023 11:18 AM
Research ArticleAdult Brain MR Imaging Findings in a Large Population of Autoimmune Encephalitis S. Gillon, M. Chan, J. Chen, E.L. Guterman, X. Wu, C.M. Glastonbury and Y. Li American Journal of Neuroradiology July 2023, 44 (7) 799-806; DOI: https://doi.org/10.3174/ajnr.A7907 ArticleFigures & DataInfo & MetricsReferences PDF This article requires a subscription to view the full text. If you have a subscription you may use the login form below to view the article. Access to this article can also be purchased. AbstractBACKGROUND AND PURPOSE: Autoimmune encephalitis is a rare condition in which autoantibodies attack neuronal tissue, causing neuropsychiatric disturbances. This study sought to evaluate MR imaging findings associated with subtypes and categories of autoimmune encephalitis.MATERIALS AND METHODS: Cases of autoimmune encephalitis with specific autoantibodies were identified from the medical record (2009–2019). Cases were excluded if no MR imaging of the brain was available, antibodies were associated with demyelinating disease, or >1 concurrent antibody was present. Demographics, CSF profile, antibody subtype and group (group 1 intracellular antigen or group 2 extracellular antigen), and MR imaging features at symptom onset were reviewed. Imaging and clinical features were compared across antibody groups using χ2 and Wilcoxon rank-sum tests.RESULTS: Eighty-five cases of autoimmune encephalitis constituting 16 distinct antibodies were reviewed. The most common antibodies were anti-N-methyl-D-aspartate (n = 41), anti-glutamic acid decarboxylase (n = 7), and anti-voltage-gated potassium channel (n = 6). Eighteen of 85 (21%) were group 1; and 67/85 (79%) were group 2. The median time between MR imaging and antibody diagnosis was 14 days (interquartile range, 4–26 days). MR imaging had normal findings in 33/85 (39%), and 20/33 (61%) patients with normal MRIs had anti-N-methyl-D-aspartate receptor antibodies. Signal abnormality was most common in the limbic system (28/85, 33%); 1/68 (1.5%) had susceptibility artifacts. Brainstem and cerebellar involvement were more common in group 1, while leptomeningeal enhancement was more common in group 2.CONCLUSIONS: Sixty-one percent of patients with autoimmune encephalitis had abnormal brain MR imaging findings at symptom onset, most commonly involving the limbic system. Susceptibility artifact is rare and makes autoimmune encephalitis less likely as a diagnosis. Brainstem and cerebellar involvement were more common in group 1, while leptomeningeal enhancement was more common in group 2.ABBREVIATIONS:AIEautoimmune encephalitisanti-Gq1banti-ganglioside Q1banti-LGI1anti-leucine-rich glioma inactivated 1CASPR2contactin-associated protein-like 2GABAgamma-aminobutyric acidGADglutamic acid decarboxylaseGFAPglial fibrillary acidic proteinNMDAN-methyl-D-aspartatePD-1programmed cell death protein 1VGCCvoltage gated calcium channelVGKCvoltage-gated potassium channel© 2023 by American Journal of NeuroradiologyView Full Text Log in using your username and password Username * Password * Forgot your user name or password? PreviousNext Back to top In this issue American Journal of Neuroradiology Vol. 44, Issue 7 1 Jul 2023 Table of ContentsIndex by authorComplete Issue (PDF) Print Download PDF Email Article Citation Tools Share Tweet WidgetFacebook LikeGoogle Plus One Purchase Related ArticlesNo related articles found.PubMedGoogle Scholar Cited By...No citing articles found.CrossrefGoogle Scholar More in this TOC Section Cost-Effectiveness Analysis of 68Ga-DOTATATE PET/MRI in Radiotherapy Planning in Patients with Intermediate-Risk Meningioma Choroid Plexus Calcification Correlates with Cortical Microglial Activation in Humans: A Multimodal PET, CT, MRI Study Show more ADULT BRAIN Similar Articles
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Elevated blood and cerebrospinal fluid biomarkers of microglial activation and blood‒brain barrier disruption in anti-NMDA receptor encephalitis | Journal of Neuroinflammation | Full Text

Elevated blood and cerebrospinal fluid biomarkers of microglial activation and blood‒brain barrier disruption in anti-NMDA receptor encephalitis | Journal of Neuroinflammation | Full Text | AntiNMDA | Scoop.it
From jneuroinflammation.biomedcentral.com - July 27, 2023 11:01 AM
Background Anti-NMDA receptor (NMDAR) encephalitis is an autoimmune disease characterized by complex neuropsychiatric syndrome and cerebrospinal fluid (CSF) NMDAR antibodies. Triggering receptor expressed on myeloid cells 2 (TREM2) has been reported to be associated with inflammation of the...
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Anti-N-methyl-d-aspartate receptor encephalitis and positive human herpesvirus-7 deoxyribonucleic acid in cerebrospinal fluid: a case report | Journal of Medical Case Reports | Full Text

Anti-N-methyl-d-aspartate receptor encephalitis and positive human herpesvirus-7 deoxyribonucleic acid in cerebrospinal fluid: a case report | Journal of Medical Case Reports | Full Text | AntiNMDA | Scoop.it
From jmedicalcasereports.biomedcentral.com - July 14, 2023 2:17 PM
Background Anti-N-methyl-d-aspartate receptor encephalitis is a neuroautoimmune syndrome typically presenting with seizures, psychiatric symptoms, and autonomic dysfunction. Human herpesvirus-7 is often found with human herpesvirus-6 and infects leukocytes such as T-cells, monocytes–macrophages,...
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We have a winner! - The Anti-NMDA Receptor Encephalitis Foundation Prize, 2023

We have a winner! - The Anti-NMDA Receptor Encephalitis Foundation Prize, 2023 | AntiNMDA | Scoop.it
From www.antinmdafoundation.org - June 25, 2023 2:58 PM
It’s that time of year again, when the Foundation is delighted to offer its annual Anti-NMDA Receptor Encephalitis Foundation Prize to a promising neurology trainee ...Read More...
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Antibodies Associated With Autoimmune Encephalitis in Patients With Presumed Neurodegenerative Dementia | Neurology Neuroimmunology & Neuroinflammation

Antibodies Associated With Autoimmune Encephalitis in Patients With Presumed Neurodegenerative Dementia | Neurology Neuroimmunology & Neuroinflammation | AntiNMDA | Scoop.it
From nn.neurology.org - June 19, 2023 9:45 PM
AbstractBackground & Objectives Autoimmune encephalitis (AIE) may present with prominent cognitive disturbances without overt inflammatory changes in MRI and CSF. Identification of these neurodegenerative dementia diagnosis mimics is important because patients generally respond to immunotherapy. The objective of this study was to determine the frequency of neuronal antibodies in patients with presumed neurodegenerative dementia and describe the clinical characteristics of the patients with neuronal antibodies.Methods In this retrospective cohort study, 920 patients were included with neurodegenerative dementia diagnosis from established cohorts at 2 large Dutch academic memory clinics. In total, 1,398 samples were tested (both CSF and serum in 478 patients) using immunohistochemistry (IHC), cell-based assays (CBA), and live hippocampal cell cultures (LN). To ascertain specificity and prevent false positive results, samples had to test positive by at least 2 different research techniques. Clinical data were retrieved from patient files.Results Neuronal antibodies were detected in 7 patients (0.8%), including anti-IgLON5 (n = 3), anti-LGI1 (n = 2), anti-DPPX, and anti-NMDAR. Clinical symptoms atypical for neurodegenerative diseases were identified in all 7 and included subacute deterioration (n = 3), myoclonus (n = 2), a history of autoimmune disease (n = 2), a fluctuating disease course (n = 1), and epileptic seizures (n = 1). In this cohort, no patients with antibodies fulfilled the criteria for rapidly progressive dementia (RPD), yet a subacute deterioration was reported in 3 patients later in the disease course. Brain MRI of none of the patients demonstrated abnormalities suggestive for AIE. CSF pleocytosis was found in 1 patient, considered as an atypical sign for neurodegenerative diseases. Compared with patients without neuronal antibodies (4 per antibody-positive patient), atypical clinical signs for neurodegenerative diseases were seen more frequently among the patients with antibodies (100% vs 21%, p = 0.0003), especially a subacute deterioration or fluctuating course (57% vs 7%, p = 0.009).Discussion A small, but clinically relevant proportion of patients suspected to have neurodegenerative dementias have neuronal antibodies indicative of AIE and might benefit from immunotherapy. In patients with atypical signs for neurodegenerative diseases, clinicians should consider neuronal antibody testing. Physicians should keep in mind the clinical phenotype and confirmation of positive test results to avoid false positive results and administration of potential harmful therapy for the wrong indication.GlossaryAD=Alzheimer dementia; AIE=autoimmune encephalitis; CBA=cell-based assays; DLB=dementia with Lewy bodies; IHC=immunohistochemistry; LN=live hippocampal cell cultures; PPA=primary progressive aphasia; PSP=progressive supranuclear palsy; RPD=rapidly progressive dementia; VGCC=voltage-gated calcium channelCognitive dysfunction can be the presenting and most prominent symptom in patients with autoimmune encephalitis (AIE).1,2 In contrast to neurodegenerative diseases, patients with antibody-mediated encephalitis might benefit from immunotherapy and improve considerably.3,4 The presence of neuronal antibodies has been reported predominantly in rapidly progressive dementia (RPD).5,6 However, AIE can present less fulminantly and is therefore potentially missed, resulting in diagnosis and treatment delay or even misdiagnosis.7,8 We hypothesized that a small—but not insignificant—part of dementia syndromes is indeed caused by antibody-mediated encephalitis and underdiagnosed, withholding these patients' available treatments. The wish to diagnose every single patient with autoimmune encephalitis is in opposition with the risk for false positive tests.9 Therefore, we strictly adhere to confirmation of positive test results with 2 different test techniques. In this study, we describe the frequency of neuronal antibodies in a cohort of patients diagnosed with various dementia syndromes in a memory clinic. In addition, we present clues to improve clinical recognition of AIE in dementia syndromes.MethodsPatients and Laboratory StudiesIn this retrospective multicenter study, we tested for the presence of neuronal antibodies in serum and CSF samples from patients diagnosed with neurodegenerative dementia diagnosis, included earlier prospectively in established cohorts at 2 large Dutch academic memory clinics (Erasmus University Medical Center, Amsterdam University Medical Centers, location VUmc)10 between 1998 and 2016 (84% last 10 years). All patients fulfilled the core clinical criteria for dementia, as defined by the National Institutes of Aging-Alzheimer Association workgroups.11 Patients were classified into 4 subgroups (based on diagnostic criteria): Alzheimer dementia (AD), frontotemporal dementia (FTD; both behavioral variant and primary progressive aphasia [PPA]), dementia with Lewy bodies (DLB), and other dementia syndromes.11,-,14 Rapidly progressive dementia was defined as dementia within 12 months or death within 2 years after the appearance of the first cognitive symptoms.15 Patients with vascular dementia were not included. Clinic information was retrieved from the prospectively collected data. A subacute deterioration was defined as a marked progression of symptoms in 3 months and a fluctuating course as a disease course fluctuating over a longer period (e.g., weeks to months; different from the fluctuations within a day as seen in some patients with DLB). Dementia markers were scored according to the reference values (per year and per center; included in Table 1).View inline View popup Table 1 Patient Characteristics of Auto-antibody Positive PatientsAll samples, stored in both cohorts' biobanks, were screened for immunoreactivity with immunohistochemistry (IHC), as previously described.16 Preferably, paired serum and CSF were tested for optimal sensitivity and specificity. Samples that were showing a positive or questionable staining pattern were tested more extensively using validated commercial cell-based assays (CBA) and in-house CBA (eTable 1, links.lww.com/NXI/A869). In addition, these samples were tested with live hippocampal cell cultures (LN).16,17 To ascertain specificity, only samples that could be confirmed by CBA or LN were scored as positive because there is a higher risk for false-positive test results in this population with a low a priori chance to have encephalitis.9,18 If IHC was suggestive for antibodies against intracellular (paraneoplastic) targets, this was explored by a different IHC technique.19 Anti-thyroid peroxidase (TPO), voltage-gated calcium channel (VGCC), or low titer glutamic acid decarboxylase antibodies were not tested for because these are generally nonspecific at these ages and are not associated with dementia syndromes.Antibody-positive patients were described exploratory and compared with a randomly selected antibody-negative group (ratio 1:4) matched for memory clinic, dementia subtype, sex, and age (±5 years). For these comparisons, medical records were additionally assessed for both the antibody-positive and antibody-negative patients. All antibody-positive patients were reviewed by a panel consisting of neurologists specialized in neurodegenerative (F.J., H.S., J.S.) or autoimmune diseases (J.V., P.S.S., M.T.), and a consensus classification of AIE vs AIE with a neurodegenerative dementia comorbidity was reached.Statistical AnalysisWe used IBM SPSS 25.0 (SPSS Inc) and Prism 8.4.3 (GraphPad) for statistical analysis. Baseline characteristics were analyzed using the Fisher exact test, the Fisher-Freeman-Halton test, or the Kruskal-Wallis test, when appropriate. For group comparisons, encompassing categorical data, we used the Pearson χ2 test or the Fisher-Freeman-Halton test, when appropriate. Continuous data were analyzed using the Mann-Whitney U test. All p-values were two-sided and considered statistically significant when below 0.05. We applied no correction for multiple testing, and therefore, p values between 0.05 and 0.005 should be interpreted carefully.Standard Protocol Approvals, Registrations, and Patient ConsentsThe study was approved by The Institutional Review Boards of Erasmus University Medical Center Rotterdam and Amsterdam University Medical Center, location VUmc. Written informed consent was obtained from all patients.Data AvailabilityAny data not published within this article are available at the Erasmus MC University Medical Center. Patient-related data will be shared on reasonable request from any qualified investigator, maintaining anonymization of the individual patients.ResultsIn total, 1,398 samples from 920 patients were tested (Figure; in 478, both CSF and serum [52%]). Three-hundred fifty-eight patients were classified as AD (39%), 283 FTD (31%), and 161 DLB (17%). The fourth subgroup with other dementia syndromes consisted of 118 patients (13%), including progressive supranuclear palsy (n = 48, 5%) and corticobasal syndrome (n = 29, 3%). The median age at disease onset was 62 years (range 16–90 years). Male patients were overrepresented (n = 542, 59%), and 60 patients (7%) fulfilled the criteria for rapidly progressive dementia (RPD; eTable 2, links.lww.com/NXI/A869).<img class="highwire-fragment fragment-image" alt="Figure" width="440" height="305" src="https://nn.neurology.org/content/nnn/10/5/e200137/F1.medium.gif">Download figure Open in new tab Download powerpoint Figure Flowchart of Patient Inclusion With Antibody ResultsIn total, 920 patients (1,398 samples) with a presumed neurodegenerative dementia syndrome were tested for the presence of neuronal antibodies in serum and CSF. Neuronal antibodies were detected in 7 patients (0.8%, 95% CI 0.2–1.3); five among the 358 Alzheimer disease patients. Subclassification of the ‘other’ group is provided in supplementary table eTable 2 (links.lww.com/NXI/A869). AD = Alzheimer disease; DLB = diffuse Lewy body dementia; DPPX = dipeptidyl aminopeptidase-like protein 6; FTD = frontotemporal dementia; IgLON5 = Ig-like domain-containing protein family member 5; LGI1 = leucin-rich glioma inactivated protein 1; NMDAR = N-methyl-d-aspartate receptor; S = serum.Neuronal antibodies were detected in 7 patients (0.8%; 5 in the AD group: 1.4%; Figure), including anti-IgLON5 (n = 3), anti-LGI1 (n = 2), anti-DPPX (n = 1), and anti-NMDAR antibodies (n = 1; Table 1). Among these 7, 4 patients were diagnosed retrospectively with an exclusive diagnosis of AIE, while 3 patients were classified to have AIE (anti-IgLON5 [n = 2] and anti-NMDAR antibodies [n = 1]) with a neurodegenerative dementia comorbidity. No patients with antibodies fulfilled the criteria for RPD, yet a subacute deterioration later in the disease was reported in 3 patients. Atypical clinical signs for neurodegenerative diseases were present in 7 of 7 antibody-positive patients (100% vs 21% in antibody-negative patients, p = 0.0003; Table 2). These included a subacute deterioration (n = 3), myoclonus (n = 2), a fluctuating disease course over months (n = 1), a history of autoimmune disease (n = 2), and epileptic seizures (n = 1; Table 1). Brain MRI of none of the patients demonstrated abnormalities suggestive for active AIE, in particular no hippocampal swelling nor increased T2-signal intensity. CSF pleocytosis was found in 1 patient. CSF biomarkers (t-tau, p-tau, and Aβ42) were tested in 5 of 7 patients, and t-tau and p-tau were increased in 4, while a low Aβ42 was seen in 2. Of note, only 1 patient had the combination of reduced Aβ42 and increased p-tau/t-tau, and was diagnosed with a comorbid AD. No patient received immunotherapy. Two patients still alive (1 anti-LG1, 1 anti-DPPX positive) were contacted but refused to visit our clinic to try very delayed immunotherapy trials. It is of interest that the patient with anti-DPPX antibodies showed spontaneous improvement of cognitive disturbances, atypical for a pure neurodegenerative disease.View inline View popup Table 2 Comparisons Between Patients With Neuronal Auto-antibodies and Antibody-Negative PatientsCompared with the patients without neuronal antibodies, subacute cognitive deterioration or fluctuating course was present more frequently (4/7 [57%] vs 2/28 [7%], p = 0.009). Although movement disorders (myoclonus) and autoimmune disorders were present in 2 of 7 patients each, this did not reach significance (Table 2).DiscussionIn this large, multicenter, cohort study consisting of patients with a presumed neurodegenerative dementia diagnosis, we show that a small, but clinically relevant proportion (0.8%) have neuronal antibodies. In this particular group, 4 of 7 antibody-positive patients presented with an atypical clinical course (subacute deterioration or fluctuating disease course), which is considered as a clinical clue (‘red flag’) for an antibody-mediated etiology of dementia.4 It is important that a fluctuating disease course was observed over a longer period (e.g., weeks or months) in AIE and should not be confused with shorter fluctuations of cognition or alertness (over the day) in DLB. Other known red flags, which we observed in these 7 patients, were myoclonus, epilepsy, pleocytosis, or a history of autoimmune disorders, as described earlier.1,4,-,6 Compared with antibody-negative patients, no significant difference was found related to these symptoms alone, probably due to the low number of positive patients and related low power. However, atypical clinical signs for neurodegenerative diseases together were seen significantly more frequently in the antibody-positive group. Within this cohort mostly devoid of patients with RPD, none of the antibody-positive patients fulfilled the criteria for RPD, nor ancillary testing showed specific signs for AIE in most patients. This implicates that AIE can resemble more protracted, progressive neurodegenerative dementia syndromes, as we reported earlier.1Three antibody-positive patients had IgLON5 antibodies, which is a very rare and known to have heterogeneous (chronic) clinical manifestations, including pronounced sleep problems, cognitive dysfunction, and movement disorders.20,21 Misdiagnosis with progressive supranuclear palsy (PSP) is reported, mainly associated with the preceding movement disorders. In addition, half of the patients have cognitive impairment of whom 20% fulfilled clinical criteria for dementia.21 It is of interest that IgLON5 disease shares features with neurodegeneration because autopsy studies showed tau deposits.22 However, there is a strong HLA association,20 and studies show that antibodies directly bind to surface IgLON5 on neurons and directly alter neuronal function and structure,23 suggesting a primary inflammatory disease.In previous research, a notably higher frequency (14%) of neuronal antibodies in patients with dementia was reported by Giannocaro et al.24 The discrepancy with our test results is probably explained by differences in patient selection and antibody testing methodology. First, 30% of the patients in the cohort described by Giannocaro et al. demonstrated CSF inflammatory abnormalities, indicating a relatively high pretest probability of antibody-positivity compared with our study.24 A lack of CSF pleocytosis probably better represents the population of memory clinics. Second, the previous study exclusively tested serum by cell-based assay without confirmatory tests nor testing antibodies in CSF.24 We only considered antibody test results positive when confirmed by additional techniques to avoid suboptimal specificity and false-positive test results.9Previous studies, including our own, suggested RPD as a relevant red flag for AIE,1,4,9,25 but we cannot determine this from our study based on the design of our study. We included patients at tertiary memory clinics without overt signs or symptoms suggestive for encephalitis. Therefore, the amount of patients with RPD included was very limited (7%), comparable with other large dementia cohort studies, as was the amount of patients with abnormal ancillary testing suggestive for AIE because this would have prompted a different approach than referral to a tertiary memory clinic. These patients with RPD and ancillary testing suggestive of AIE were not included in our study. Inclusion of those patients would have likely increased our rate of positivity.The strength of our study is the large number of paired samples (serum and CSF combined) from a cohort with various presumed neurodegenerative diseases without AIE suspicion, representative for academic memory clinics. A limitation is the lack of neuropathologic data to support our findings and make diagnoses of neurodegeneration or inflammation definite. To confirm if the symptoms are related to the presence of antibodies, we tried to overcome this concern in different ways. First, the presence of antibodies in serum and CSF was confirmed by different techniques (cell-based assay, tissue immunohistochemistry, and cultured live neurons), indicating optimal test specificity. Second, afterward patients were thoroughly reviewed by a panel of neurologists specialized in neurodegenerative or autoimmune disease to detect atypical signs and symptoms related to AIE. This is a very large cohort of patients with dementia examined for the presence of neuronal antibodies. Nevertheless, an important limitation of this study is the small number of antibody-positive patients, underpowering the probability to identify significant differences between antibody-positive and antibody-negative patients. The low number of patients with RPD has probably added to this small number, and a prospective study including patients with RPD is recommended. Nevertheless, several probable red flags could be identified. Diagnosing AIE in patients with dementia is highly relevant because these patients might respond to immunotherapy. Therefore, clinicians should test for neuronal antibody in patients demonstrating red flags suggestive for an autoimmune etiology, if possible early in disease course. When profound temporal lobe atrophy already has developed, little effect is to be expected. Red flags identified in this study are subacute deterioration or fluctuating course. Other red flags described previously, we also see reflected in our study, are autoimmune disorders, myoclonus, seizures, and pleocytosis,1,4,-,6 Preferably, both serum and CSF should be tested and confirmed by additional techniques. Always consider the possibility of a false positive test result, especially when only using a single technique (like the commercial cell-based assay). If the clinical phenotype is atypical, confirmation in a research laboratory should be mandatory. The use of antibody panels is discouraged, especially including the paraneoplastic blots, because these are associated with higher risks of lack of clinical relevance.26 This caution is even more warranted for tests not associated with neurodegenerative syndromes, but with a history of nonspecificity, including VGKC (in the absence of LGI1 or CASPR2), VGCC, anti-TPO, and low-titer anti-GAD65.27,-,30 Further research should focus on improving clinical recognition of AIE in patients with dementia determining the effect of immunotherapy in this specific patient category and assessing the frequency of AIE in RPD.In conclusion, we have shown that a clinically relevant, albeit small proportion of patients with a suspected neurodegenerative disease and nonrapidly progressive course have neuronal antibodies indicative of AIE.Study FundingM.J. Titulaer was supported by an Erasmus MC fellowship and has received funding from the Netherlands Organization for Scientific Research (NWO, Veni incentive), ZonMw (Memorabel program), the Dutch Epilepsy Foundation (NEF 14-19 & 19-08), Dioraphte (2001 0403), and E-RARE JTC 2018 (UltraAIE, 90030376505). F. Leypoldt has received funding from the German Ministry of Education and Research (01GM1908A) and the Era-Net funding program (LE3064/2-1).DisclosureA.E.M. Bastiaansen reports no disclosures. R.W. van Steenhoven reports no disclosures. Research programs of Wiesje van der Flier have been funded by ZonMW, now, EUFP7, EU-JPND, Alzheimer Nederland, Hersenstichting CardioVascular Onderzoek Nederland, Health∼Holland, Topsector Life Sciences & Health, stichting Dioraphte, Gieskes-Strijbis fonds, stichting Equilibrio, Edwin Bouw fonds, Pasman stichting, stichting Alzheimer & Neuropsychiatrie Foundation, Philips, Biogen MA Inc, Novartis-NL, Life-MI, AVID, Roche BV, Fujifilm, and Combinostics. W.M. van der Flier holds the Pasman chair. W.M. van der Flier is recipient of ABOARD, which is a public-private partnership receiving funding from ZonMW (#73305095007) and Health Holland, Topsector Life Sciences & Health (PPP-allowance; #LSHM20106). All funding is paid to her institution. WF has performed contract research for Biogen MA Inc and Boehringer Ingelheim. All funding is paid to her institution. W.M. van der Flier has been an invited speaker at Boehringer Ingelheim, Biogen MA Inc, Danone, Eisai, WebMD Neurology (Medscape), and Springer Healthcare. All funding is paid to her institution. W.M. van der Flier is consultant to Oxford Health Policy Forum CIC, Roche, and Biogen MA Inc. All funding is paid to her institution. W.M. van der Flier participated in advisory boards of Biogen MA Inc and Roche. All funding is paid to her institution. W.M. van der Flier is a member of the steering committee of PAVE and Think Brain Health. W.M. van der Flier was an associate editor of Alzheimer, Research & Therapy in 2020/2021. W.M. van der Flier is an associate editor at Brain. Research of C. Teunissen was supported by the European Commission (Marie Curie International Training Network, Grant Agreement No. 860197 (MIRIADE)), Innovative Medicines Initiatives 3TR (Horizon 2020, Grant No. 831434), EPND (IMI 2 Joint Undertaking (JU) under Grant Agreement No. 101034344) and JPND (bPRIDE), National MS Society (Progressive MS alliance) and Health Holland, the Dutch Research Council (ZonMW), Alzheimer Drug Discovery Foundation, The Selfridges Group Foundation, Alzheimer Netherlands, and Alzheimer Association. C. Teunissen is recipient of ABOARD, which is a public-private partnership receiving funding from ZonMW (#73305095007) and Health∼Holland, Topsector Life Sciences & Health (PPP-allowance, #LSHM20106). ABOARD also receives funding from Edwin Bouw Fonds and Gieskes-Strijbisfonds. C. Teunissen has a collaboration contract with ADx Neurosciences, Quanterix, and Eli Lilly, performed contract research or received grants from AC-Immune, Axon Neurosciences, Bioconnect, Bioorchestra, Brainstorm Therapeutics, Celgene, EIP Pharma, Eisai, Grifols, Novo Nordisk, PeopleBio, Roche, Toyama, and Vivoryon. She serves on editorial boards of Medidact Neurologie/Springer, Alzheimer Research and Therapy, and Neurology: Neuroimmunology & Neuroinflammation and is an editor of a Neuromethods book Springer. She had speaker contracts for Roche, Grifols, and Novo Nordisk. E. de Graaff holds a patent for the detection of anti-DNER antibodies. M.M.P. Nagtzaam reports no disclosures. M. Paunovic reports no disclosures. S. Franken reports no disclosures. M.W.J. Schreurs reports no disclosures. F. Leypoldt has received speakers honoraria from Grifols, Roche, Novartis, Alexion, and Biogen and serves on an advisory board for Roche and Biogen. He works for an academic institution (University Hospital Schleswig-Holstein) which offers commercial autoantibody testing. P.A.E. Sillevis Smitt holds a patent for the detection of anti-DNER and received research support from Euroimmun. J.M. de Vries reports no disclosures. H. Seelaar reports no disclosures. J.C. van Swieten reports no disclosures. F.J. de Jong reports no disclosures. Y.A.L. Pijnenburg Research of Alzheimer center Amsterdam is part of the neurodegeneration research program of Amsterdam Neuroscience. Alzheimer Center Amsterdam is supported by Stichting Alzheimer Nederland and Stichting VUmc fonds. The chair of Wiesje van der Flier is supported by the Pasman stichting. M.J. Titulaer has filed a patent, on behalf of the Erasmus MC, for methods for typing neurologic disorders and cancer, and devices for use therein, and has received research funds for serving on a scientific advisory board of Horizon Therapeutics, for consultation at Guidepoint Global LLC, for consultation at UCB, for teaching colleagues by Novartis. MT has received an unrestricted research grant from Euroimmun AG and from CSL Behring. Go to Neurology.org/NN for full disclosure.AcknowledgmentThe authors thank all patients for their participation. The authors also thank Esther Hulsenboom and Ashraf Jozefzoon-Aghai for their technical assistance. M.W.J. Schreurs, F. Leypoldt, P.A.E. Sillevis Smitt, J.M. de Vries, and M.J. Titulaer of this publication are members of the European Reference Network for Rare Immunodeficiency, Autoinflammatory, and Autoimmune Diseases—Project ID No. 739543 (ERN-RITA; HCP Erasmus MC and University Hospital Schleswig-Holstein). H. Seelaar, J.C. van Swieten, and F.J. de Jong of this publication are members of the European Reference Network for Rare Neurological Diseases—Project ID 73910. Research of the VUmc Alzheimer center is part of the neurodegeneration research program of Amsterdam Neuroscience. The Alzheimer Center VUmc is supported by Alzheimer Nederland and Stichting VUmc Fonds. The clinical database structure was developed with funding from Stichting Dioraphte.Appendix Authors<img class="highwire-fragment fragment-image" alt="Table" src="https://nn.neurology.org/content/nnn/10/5/e200137/T3.medium.gif"; width="599" height="2531">FootnotesGo to Neurology.org/NN for full disclosures. Funding information is provided at the end of the article.The Article Processing Charge was funded the authors.Submitted and externally peer reviewed. The handling editor was Editor Josep O. Dalmau, MD, PhD, FAAN.Received December 8, 2022.Accepted in final form May 8, 2023.Copyright © 2023 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American Academy of Neurology.This is an open access article distributed under the terms of the Creative Commons Attribution-NonCommercial-NoDerivatives License 4.0 (CC BY-NC-ND), which permits downloading and sharing the work provided it is properly cited. The work cannot be changed in any way or used commercially without permission from the journal.References1.↵Bastiaansen AEM, van Steenhoven RW, de Bruijn M, et al. Autoimmune encephalitis resembling dementia syndromes. Neurol Neuroimmunol Neuroinflamm. 2021;8(5):e1039.OpenUrlAbstract/FREE Full Text2.↵Lancaster E, Lai M, Peng X, et al. Antibodies to the GABA(B) receptor in limbic encephalitis with seizures: case series and characterisation of the antigen. Lancet Neurol. 2010;9(1):67-76.OpenUrlCrossRefPubMed3.↵Titulaer MJ, McCracken L, Gabilondo I, et al. 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Lancet Psychiatry. 2020;7(2):122-123.OpenUrl19.↵van Coevorden-Hameete MH, Titulaer MJ, Schreurs MW, et al. Detection and characterization of autoantibodies to neuronal cell-surface antigens in the central nervous system. Front Mol Neurosci. 2016;9:37.OpenUrl20.↵Sabater L, Gaig C, Gelpi E, et al. A novel non-rapid-eye movement and rapid-eye-movement parasomnia with sleep breathing disorder associated with antibodies to IgLON5: a case series, characterisation of the antigen, and post-mortem study. Lancet Neurol. 2014;13(6):575-586.OpenUrlCrossRefPubMed21.↵Gaig C, Compta Y, Heidbreder A, et al. Frequency and characterization of movement disorders in anti-IgLON5 disease. Neurology. 2021;97(14):e1367–e1381.OpenUrlAbstract/FREE Full Text22.↵Gelpi E, Hoftberger R, Graus F, et al. Neuropathological criteria of anti-IgLON5-related tauopathy. Acta Neuropathol. 2016;132(4):531-543.OpenUrlCrossRefPubMed23.↵Landa J, Gaig C, Plaguma J, et al. Effects of IgLON5 antibodies on neuronal cytoskeleton: a link between autoimmunity and neurodegeneration. Ann Neurol. 2020;88(5):1023-1027.OpenUrlCrossRefPubMed24.↵Giannoccaro MP, Gastaldi M, Rizzo G, et al. Antibodies to neuronal surface antigens in patients with a clinical diagnosis of neurodegenerative disorder. Brain Behav Immun. 2021;96:106-112.OpenUrl25.↵Hermann P, Zerr I. Rapidly progressive dementias - aetiologies, diagnosis and management. Nat Rev Neurol. 2022;18(6):363-376.OpenUrl26.↵Dechelotte B, Muniz-Castrillo S, Joubert B, et al. Diagnostic yield of commercial immunodots to diagnose paraneoplastic neurologic syndromes. Neurol Neuroimmunol Neuroinflamm. 2020;7(3):e701.OpenUrlAbstract/FREE Full Text27.↵van Sonderen A, Schreurs MW, de Bruijn MA, et al. The relevance of VGKC positivity in the absence of LGI1 and Caspr2 antibodies. Neurology. 2016;86(18):1692-1699.OpenUrlCrossRefPubMed28.↵Muñoz Lopetegi A, Boukhrissi S, Bastiaansen A, et al. Neurological syndromes related to anti-GAD65: clinical and serological response to treatment. Neurol Neuroimmunol Neuroinflamm. 2020;7(3):e696.OpenUrlAbstract/FREE Full Text29.↵Mattozzi S, Sabater L, Escudero D, et al. Hashimoto encephalopathy in the 21st century. Neurology. 2020;94(2):e217-e224.OpenUrlAbstract/FREE Full Text30.↵Flanagan EP, Geschwind MD, Lopez-Chiriboga AS, et al. Autoimmune encephalitis misdiagnosis in adults. JAMA Neurol. 2023;80(1):30-39.OpenUrl
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Research study - can you help?

Research study - can you help? | AntiNMDA | Scoop.it
From www.encephalitis.info - June 19, 2023 9:38 PM
Researchers at Kings College London are looking for young people to travel to London and help with an encephalitis study...
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Sociocultural Influences in Autoimmune Encephalitis Without Neurologic Symptoms

Sociocultural Influences in Autoimmune Encephalitis Without Neurologic Symptoms | AntiNMDA | Scoop.it
From www.psychiatrist.com - June 19, 2023 9:33 PM
This complex case highlights barriers to identifying autoimmune encephalitis when no neurologic symptoms are present, which are normally central to disease detection.
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Anti N-Methyl-D-Aspartate receptor antibody associated Acute Demyelinating Encephalomyelitis in a patient with COVID-19: a case report | Journal of Medical Case Reports | Full Text

Anti N-Methyl-D-Aspartate receptor antibody associated Acute Demyelinating Encephalomyelitis in a patient with COVID-19: a case report | Journal of Medical Case Reports | Full Text | AntiNMDA | Scoop.it
From jmedicalcasereports.biomedcentral.com - June 19, 2023 9:27 PM
Background Anti N-Methyl-D-Aspartate (NMDA) receptor antibody associated ADEM is a diagnosis that was first described relatively recently in 2007 by Dalmau et al. The recent COVID-19 pandemic has resulted in multiple neurological complications being reported.
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Autoimmune Encephalitis Consensus Criteria | Neurology Clinical Practice

Autoimmune Encephalitis Consensus Criteria | Neurology Clinical Practice | AntiNMDA | Scoop.it
From cp.neurology.org - June 14, 2023 7:42 PM
June 2023; 13 (3) Editorial Autoimmune Encephalitis Consensus CriteriaLessons Learned From Real-World Practice View ORCID ProfileJeffrey M. Gelfand, Chu-Yueh Guo First published April 25, 2023, DOI: https://doi.org/10.1212/CPJ.0000000000200155 Full PDF Citation Permissions Make Comment See Comments Downloads133 Share Article Info & Disclosures This article requires a subscription to view the full text. If you have a subscription you may use the login form below to view the article. Access to this article can also be purchased. Autoimmune encephalitis (AE) encompasses a spectrum of neurologic disorders caused by brain inflammation, a subset of which is associated with autoantibodies to neuronal cell-surface antigens such as anti-N-methyl-d-aspartate (NMDA) receptor AE or anti-leucine-rich glioma-inactivated 1 (LGI1) AE.1 Up to half of patients with AE, however, do not have abnormal neuronal or glial autoantibodies identified and are classified as having “seronegative” AE.2 Clinical antibody testing can take several days to result, a time in which clinicians caring for patients with suspected AE may wish to initiate empiric immunosuppressive therapy. Antibody testing is also not readily accessible in some health care settings and, even when technically available, may require time-consuming advocacy with local clinical laboratories to justify relatively costly send-out testing. To add further complexity, some patients with immunoreactive (e.g., laboratory true-positive) antibodies do not have clinical AE, and over-reliance and misapplication of antibody testing were identified as important contributors to AE misdiagnosis in a 2023 multicenter analysis.3FootnotesFunding information and disclosures are provided at the end of the article. Full disclosure form information provided by the authors is available with the full text of this article at Neurology.org/cp.See page e200151© 2023 American Academy of NeurologyView Full Text AAN Members We have changed the login procedure to improve access between AAN.com and the Neurology journals. If you are experiencing issues, please log out of AAN.com and clear history and cookies. (For instructions by browser, please click the instruction pages below). After clearing, choose preferred Journal and select login for AAN Members. You will be redirected to a login page where you can log in with your AAN ID number and password. When you are returned to the Journal, your name should appear at the top right of the page. Google Safari Microsoft Edge Firefox Click here to login AAN Non-Member Subscribers Click here to login Purchase access For assistance, please contact: AAN Members (800) 879-1960 or (612) 928-6000 (International) Non-AAN Member subscribers (800) 638-3030 or (301) 223-2300 option 3, select 1 (international) Sign Up Information on how to subscribe to Neurology and Neurology: Clinical Practice can be found here Purchase Individual access to articles is available through the Add to Cart option on the article page. Access for 1 day (from the computer you are currently using) is US$ 39.00. Pay-per-view content is for the use of the payee only, and content may not be further distributed by print or electronic means. The payee may view, download, and/or print the article for his/her personal, scholarly, research, and educational use. Distributing copies (electronic or otherwise) of the article is not allowed. You May Also be Interested in Back to top Safety and Efficacy of Tenecteplase and Alteplase in Patients With Tandem Lesion Stroke: A Post Hoc Analysis of the EXTEND-IA TNK Trials Dr. Nicole Sur and Dr. Mausaminben Hathidara ► Watch Related Articles Autoimmune Encephalitis Criteria in Clinical Practice Topics Discussed All Clinical Neurology Autoimmune diseases Encephalitis Alert Me Alert me when eletters are published
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Predictive Value of Serum Neurofilament Light Chain Levels in Anti-NMDA Receptor Encephalitis

Predictive Value of Serum Neurofilament Light Chain Levels in Anti-NMDA Receptor Encephalitis | AntiNMDA | Scoop.it
From pubmed.ncbi.nlm.nih.gov - June 14, 2023 7:41 PM
Increased serum NfL levels reflect neuroaxonal damage in anti-NMDAR encephalitis. No relationship was identified with disease severity, whereas the association with outcome was confounded by age.The implied role of sampling timing on NfL levels also limits the applicability of NfL as a prognostic...
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Frontiers | The MOG antibody associated encephalitis preceded by COVID-19 infection; a case study and systematic review of the literature

Frontiers | The MOG antibody associated encephalitis preceded by COVID-19 infection; a case study and systematic review of the literature | AntiNMDA | Scoop.it
From www.frontiersin.org - September 5, 2023 11:22 AM
BackgroundNew neurological complications of COVID-19 infection have been reported in recent research. Among them, the spectrum of anti-MOG positive diseases, defined as anti-MOG antibody associated disease (MOGAD), is distinguished, which can manifest as optic neuritis, myelitis, or various forms...
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Enceph-IG Study - Institute of Infection, Veterinary and Ecological Sciences - University of Liverpool

Enceph-IG Study - Institute of Infection, Veterinary and Ecological Sciences - University of Liverpool | AntiNMDA | Scoop.it
From www.liverpool.ac.uk - August 6, 2023 7:27 PM
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A Rare Presentation of Steroid-responsive Encephalopathy Associated with Autoimmune Thyroiditis with Neuropsychiatric Symptoms: A Case Report

A Rare Presentation of Steroid-responsive Encephalopathy Associated with Autoimmune Thyroiditis with Neuropsychiatric Symptoms: A Case Report | AntiNMDA | Scoop.it
From touchneurology.com - July 27, 2023 11:22 AM
A 42-year-old woman presented in the emergency department with acute onset whole-body myoclonic jerks for 1 day.On enquiry, the patient’s parents advised...
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Pioneering Research in Autoimmune Neurology: Vanda Lennon, M.D., Ph.D.

Pioneering Research in Autoimmune Neurology: Vanda Lennon, M.D., Ph.D. | AntiNMDA | Scoop.it
From news.mayocliniclabs.com - July 27, 2023 11:05 AM
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New center to spotlight neurological autoimmune disorders

New center to spotlight neurological autoimmune disorders | AntiNMDA | Scoop.it
From bioengineer.org - July 14, 2023 2:19 PM
How do neurological disorders arise that are caused, triggered, or influenced by antibodies? What better possibilities are there for diagnosis – and above all for treatment? These are the questions addressed by the new Clinical Research Unit “BecauseY” headed by Charité – Universitätsmedizin Berlin.
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Progressive alliance advances science through patient-powered research

Progressive alliance advances science through patient-powered research | AntiNMDA | Scoop.it
From news.mayocliniclabs.com - July 14, 2023 2:16 PM
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ENCEPH-IG Trial: The Challenges Of Running A Rare Disease Trial - Centre for Trials Research

ENCEPH-IG Trial: The Challenges Of Running A Rare Disease Trial - Centre for Trials Research | AntiNMDA | Scoop.it
From blogs.cardiff.ac.uk - June 19, 2023 9:46 PM
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30 neurological disorders every doctor should know about –

30 neurological disorders every doctor should know about – | AntiNMDA | Scoop.it
From theneurologylounge.com - June 19, 2023 9:42 PM
Neurology is a jungle of disorders and syndromes. This creates a challenge for doctors and medical students... What to prioritise for learning and practice? *** To solve this conundrum... We combed the extensive database of Neurochecklists...
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A score that predicts 1-year functional status in patients with anti-NMDA receptor encephalitis

A score that predicts 1-year functional status in patients with anti-NMDA receptor encephalitis | AntiNMDA | Scoop.it
From pubmed.ncbi.nlm.nih.gov - June 19, 2023 9:34 PM
The NEOS score accurately predicts 1-year functional status in patients with anti-NMDAR encephalitis. This score could help estimate the clinical course following diagnosis and may aid in identifying patients who could benefit from novel therapies.
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Canadian Blood Services needs thousands more donors to roll up their sleeves | CBC News

Canadian Blood Services needs thousands more donors to roll up their sleeves | CBC News | AntiNMDA | Scoop.it
From www.cbc.ca - June 19, 2023 9:28 PM
Canadian Blood Services is looking to fill 150,000 appointments for people willing to donate their blood or plasma to tackle a shortage.
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A catatonic woman awakened after 20 years. Her story may change psychiatry – My Health CRM

A catatonic woman awakened after 20 years. Her story may change psychiatry – My Health CRM | AntiNMDA | Scoop.it
From myhealthcrm.com - June 14, 2023 7:43 PM
New research suggests that a subset of patients with psychiatric conditions such as schizophrenia may actually have autoimmune disease that attacks the brain...
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Case Report: Paroxysmal weakness of unilateral limb as an initial symptom in anti-LGI1 encephalitis: a report of five cases

Case Report: Paroxysmal weakness of unilateral limb as an initial symptom in anti-LGI1 encephalitis: a report of five cases | AntiNMDA | Scoop.it
From pubmed.ncbi.nlm.nih.gov - June 14, 2023 7:41 PM
Anti-leucine-rich glioma-inactivated 1 (LGI1) encephalitis is the second most common kind of autoimmune encephalitis following anti-N-methyl-d-aspartate receptor (NMDAR) encephalitis.Anti-LGI1 encephalitis is characterized by cognitive impairment or rapid progressive dementia, psychiatric disorders...
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Medical Moment: The signs of ‘brain-on-fire’ disease

Medical Moment: The signs of ‘brain-on-fire’ disease | AntiNMDA | Scoop.it
From www.wndu.com - June 14, 2023 7:40 PM
(WNDU) - Imagine being totally fine one day, then the next, you’re having hallucinations, seizures, memory loss, and even trouble talking.It’s called “brain-on-fire” disease or anti-NMDA receptor encephalitis. It’s a rare neurological disorder that can cause inflammation in the brain.It occurs when the body’s immune system mistakenly attacks the NMDA receptors in the brain, which are responsible for regulating communication between nerve cells. Brain-on-fire disease is often misdiagnosed as other neurological disorders or psychiatric illnesses because its symptoms are similar to those of many other conditions.However, a blood or cerebrospinal fluid test can help diagnose the disease by detecting the presence of antibodies that attack the NMDA receptors in the brain. The disease is rare as it affects one in 1.5 million people a year.Katie Miller would be one of those people.Hunting, mountain biking, horseback riding - you name it, Katie Miler would do it... until she couldn’t.“I just didn’t feel like myself, like normal,” Katie recalled.“Katie said, ‘Mom, I feel like my brain snapped,’” said Colleen Miller, Katie’s mother.Local doctors admitted Katie into a psychiatric ward, but what was happening to Katie wasn’t mental; it was physical.“What happens is you’re perfectly normal one day, and suddenly overnight, this person can become paranoid, can start having visual hallucinations, auditory hallucinations,” explained Stacy Clardy, MD, PhD, an autoimmune neurologist at the University of Utah.Anti-NMDA receptor encephalitis is misdiagnosed as a psychiatric disorder in up to 40% of patients.“So, for many of the females, especially after puberty, they can develop what’s called an ovarian dermoid cyst or an ovarian teratoma,” Dr. Clardy said.These cysts often have hair and teeth in them. The immune system sees it as foreign and attacks it, but...“In these cysts, there is a component of tissue that really is brain tissue,” Dr. Clardy continued.Within four days, Katie was catatonic and needed a ventilator to breathe. There is no single approved treatment. That’s why a five-year, nationwide clinical trial is testing whether a drug called Inebilizumab will stop the assault on the brain. It has the potential to improve outcomes for patients who are not responding to other treatments and may also lead to fewer long-term neurological effects.Katie had her cyst removed; she can’t remember three months of her life. But now, with various medications, Katie is on her way to recovery.Up to 50% of patients can suffer long-term consequences, especially cognitive and mood symptoms.Copyright 2023 WNDU. All rights reserved.
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