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Jahansooz JR, Kameoka AM, Shibuya J, Abramowitz J. Recurrent anti-NMDA receptor encephalitis in first-trimester pregnancy with initially antibody-negative CSF. J Neuroimmunol 2025; 404:578602. [PMID: 40184911 DOI: 10.1016/j.jneuroim.2025.578602] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/31/2025] [Revised: 03/09/2025] [Accepted: 03/28/2025] [Indexed: 04/07/2025]
Abstract
Anti-N-methyl-d-aspartate receptor (anti-NMDAR) encephalitis is a paraneoplastic autoimmune encephalomyelitis that predominantly affects females in their reproductive years Dalmau et al., 2007 and Dalmau et al., 2019. It has been infrequently reported during pregnancy Dono et al., 2023 and Joubert et al., 2020. We describe a case of a 25-year-old G4P2 patient at 11 weeks gestation with a history of anti-NMDAR encephalitis who presented with intermittent confusion for two weeks. Initial antibody tests for anti-NMDAR encephalitis in the cerebrospinal fluid (CSF) were negative. Repeat serum labs drawn upon readmission to the emergency department (ED) 3 weeks later were positive, and results were confirmed with repeat CSF testing. Following treatment, the patient returned to baseline and delivered a developmentally healthy, full-term baby. Current gold-standard testing for anti-NMDAR encephalitis is through detection of NMDAR antibodies in the CSF Gresa-Arribas et al., 2014. However, CSF antibody testing early in the disease course may not be as sensitive as traditionally thought, and repeat testing is indicated if high suspicion continues.
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Affiliation(s)
- Julia R Jahansooz
- John A. Burns School of Medicine, University of Hawaii, Honolulu, HI, USA
| | - Alyssa M Kameoka
- John A. Burns School of Medicine, University of Hawaii, Honolulu, HI, USA
| | - Jineane Shibuya
- Department of Psychiatry, John A. Burns School of Medicine, University of Hawaii, Honolulu, HI, USA
| | - Janette Abramowitz
- Department of Psychiatry, John A. Burns School of Medicine, University of Hawaii, Honolulu, HI, USA.
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2
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Papi C, Milano C, Arlettaz L, Businaro P, Marmolejo L, Naranjo L, Planagumà J, Martinez-Hernandez E, Armangué T, Guasp M, Ruiz-García R, Aguilar E, Gastaldi M, Iorio R, Gaig C, Saiz A, Sabater L, Graus F, Dalmau JO, Spatola M. Assessing Commercial Tissue-Based Assays for Autoimmune Neurologic Disorders (II): Antibodies to Surface Antigens. NEUROLOGY(R) NEUROIMMUNOLOGY & NEUROINFLAMMATION 2025; 12:e200406. [PMID: 40393020 DOI: 10.1212/nxi.0000000000200406] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 01/31/2025] [Accepted: 03/19/2025] [Indexed: 05/22/2025]
Abstract
BACKGROUND AND OBJECTIVES Detecting neural surface antibodies (NSAbs) is essential for diagnosing autoimmune encephalitis. The recommended diagnostic strategy involves initial screening with tissue-based assays (TBAs), followed by confirmation with cell-based assays (CBAs). While specialized centers use in-house TBAs, many clinical laboratories depend on commercial TBAs, whose accuracy is yet to be fully assessed. METHODS We selected 92 CSF and 99 serum samples from patients with autoimmune encephalitis and NSAbs confirmed by in-house TBAs and CBAs (20 samples each for AMPAR, GABAAR, GABABR, IgLON5, LGI1, NMDAR, and CASPR2; 19 for mGluR5; 17 for DPPX; and 15 for mGluR1 antibodies), along with 50 CSF and 50 serum samples from negative controls. We assessed the performance of a commercial indirect immunofluorescence (IIF)-TBA (EUROIMMUN). Slides were evaluated as "positive" or "negative" by 2 experienced investigators and 2 less experienced raters. Discordant results were re-evaluated through interrater discussion and assessed using Cohen's kappa. RESULTS The experienced raters agreed on 94% (133/142) of CSF and 88% (131/149) of serum classifications (Cohen's kappa = 0.87 and 0.75, respectively, p < 0.001). Among CSF samples, 75% (106/142) were correctly identified while 19% (27/142) were misclassified (13 false positives, 14 false negatives). Among serum samples, 66% (98/149) were correctly identified while 22% (33/149) were misclassified (11 false positives, 22 false negatives). The poorest performance was seen in detecting NMDAR, GABAAR, and mGluR5 Abs, which were not identified in 5 of 10, 6 of 10, and 5 of 9 serum samples and in 4 of 10, 5 of 10, and 5 of 10 CSF samples, respectively. The overall sensitivity of the commercial IIF-TBA was 84% for CSF and 76% for serum while the specificity was 72% for CSF and 73% for serum. Less experienced raters correctly identified 69% (98/142) of CSF samples and 73% (109/149) of serum samples and misclassified 13% (18/142) of CSF samples and 11% (16/149) of serum samples, and 18% (26/142) of CSF samples and 16% (24/149) of serum samples remained discordant. DISCUSSION The diagnostic performance of EUROIMMUN IIF-TBA in detecting NSAbs in autoimmune encephalitis is suboptimal. NMDAR antibodies, among the most common NSAbs, can be missed in 50% of cases. This commercial TBA should not be used alone as a screening method nor as a confirmatory technique for NSAbs.
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Affiliation(s)
- Claudia Papi
- Neuroimmunology Program, Fundació de Recerca Clínic Barcelona-Institut d'Investigacions Biomèdiques August Pi i Sunyer (FRCB-IDIBAPS), University of Barcelona, Spain
- Caixa Research Institute (CRI), Barcelona, Spain
- Department of Neuroscience, Catholic University of the Sacred Heart, Rome, Italy
| | - Chiara Milano
- Neuroimmunology Program, Fundació de Recerca Clínic Barcelona-Institut d'Investigacions Biomèdiques August Pi i Sunyer (FRCB-IDIBAPS), University of Barcelona, Spain
- Caixa Research Institute (CRI), Barcelona, Spain
- Department of Clinical and Experimental Medicine, University of Pisa, Italy
| | - Lionel Arlettaz
- Service d'Immunologie et Allergologie, Institut Central des Hôpitaux, Hôpital du Valais, Sion, Switzerland
| | - Pietro Businaro
- Neuroimmunology Program, Fundació de Recerca Clínic Barcelona-Institut d'Investigacions Biomèdiques August Pi i Sunyer (FRCB-IDIBAPS), University of Barcelona, Spain
- Department of Brain and Behavioral Sciences, University of Pavia, Italy
- Neuroimmunology Research Section, IRCCS Mondino Foundation, Pavia, Italy
| | - Laura Marmolejo
- Neuroimmunology Program, Fundació de Recerca Clínic Barcelona-Institut d'Investigacions Biomèdiques August Pi i Sunyer (FRCB-IDIBAPS), University of Barcelona, Spain
- Caixa Research Institute (CRI), Barcelona, Spain
| | - Laura Naranjo
- Immunology Service, Biomedical Diagnostic Center, Hospital Clínic, Barcelona, Spain
| | - Jesús Planagumà
- Neuroimmunology Program, Fundació de Recerca Clínic Barcelona-Institut d'Investigacions Biomèdiques August Pi i Sunyer (FRCB-IDIBAPS), University of Barcelona, Spain
- Caixa Research Institute (CRI), Barcelona, Spain
| | - Eugenia Martinez-Hernandez
- Neuroimmunology Program, Fundació de Recerca Clínic Barcelona-Institut d'Investigacions Biomèdiques August Pi i Sunyer (FRCB-IDIBAPS), University of Barcelona, Spain
- Caixa Research Institute (CRI), Barcelona, Spain
| | - Thaís Armangué
- Neuroimmunology Program, Fundació de Recerca Clínic Barcelona-Institut d'Investigacions Biomèdiques August Pi i Sunyer (FRCB-IDIBAPS), University of Barcelona, Spain
- Caixa Research Institute (CRI), Barcelona, Spain
- Pediatric Neuroimmunology Unit, Neurology Department, Sant Joan de Déu Children's Hospital, ERN-RITA reference center, University of Barcelona, Spain
| | - Mar Guasp
- Neuroimmunology Program, Fundació de Recerca Clínic Barcelona-Institut d'Investigacions Biomèdiques August Pi i Sunyer (FRCB-IDIBAPS), University of Barcelona, Spain
- Caixa Research Institute (CRI), Barcelona, Spain
| | - Raquel Ruiz-García
- Immunology Service, Biomedical Diagnostic Center, Hospital Clínic, Barcelona, Spain
| | - Esther Aguilar
- Neuroimmunology Program, Fundació de Recerca Clínic Barcelona-Institut d'Investigacions Biomèdiques August Pi i Sunyer (FRCB-IDIBAPS), University of Barcelona, Spain
- Caixa Research Institute (CRI), Barcelona, Spain
| | - Matteo Gastaldi
- Neuroimmunology Research Section, IRCCS Mondino Foundation, Pavia, Italy
| | - Raffaele Iorio
- Department of Neuroscience, Catholic University of the Sacred Heart, Rome, Italy
| | - Carles Gaig
- Neuroimmunology Program, Fundació de Recerca Clínic Barcelona-Institut d'Investigacions Biomèdiques August Pi i Sunyer (FRCB-IDIBAPS), University of Barcelona, Spain
- Neurology Service, Hospital Clínic de Barcelona, Spain
| | - Albert Saiz
- Neuroimmunology Program, Fundació de Recerca Clínic Barcelona-Institut d'Investigacions Biomèdiques August Pi i Sunyer (FRCB-IDIBAPS), University of Barcelona, Spain
- Neurology Service, Hospital Clínic de Barcelona, Spain
| | - Lidia Sabater
- Neuroimmunology Program, Fundació de Recerca Clínic Barcelona-Institut d'Investigacions Biomèdiques August Pi i Sunyer (FRCB-IDIBAPS), University of Barcelona, Spain
- Caixa Research Institute (CRI), Barcelona, Spain
- Centro de Investigación Biomédica en Red, Enfermedades Raras (CIBERER), Spain; and
| | - Francesc Graus
- Neuroimmunology Program, Fundació de Recerca Clínic Barcelona-Institut d'Investigacions Biomèdiques August Pi i Sunyer (FRCB-IDIBAPS), University of Barcelona, Spain
| | - Josep O Dalmau
- Neuroimmunology Program, Fundació de Recerca Clínic Barcelona-Institut d'Investigacions Biomèdiques August Pi i Sunyer (FRCB-IDIBAPS), University of Barcelona, Spain
- Caixa Research Institute (CRI), Barcelona, Spain
- Neurology Service, Hospital Clínic de Barcelona, Spain
- Centro de Investigación Biomédica en Red, Enfermedades Raras (CIBERER), Spain; and
- Department of Neurology, University of Pennsylvania, PA
| | - Marianna Spatola
- Neuroimmunology Program, Fundació de Recerca Clínic Barcelona-Institut d'Investigacions Biomèdiques August Pi i Sunyer (FRCB-IDIBAPS), University of Barcelona, Spain
- Caixa Research Institute (CRI), Barcelona, Spain
- Service d'Immunologie et Allergologie, Institut Central des Hôpitaux, Hôpital du Valais, Sion, Switzerland
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Leypoldt F. Beyond the Lab Slip: Why Laboratory Expertise Matters in Neuronal Antibody Testing and Why Clinicians Should Care. NEUROLOGY(R) NEUROIMMUNOLOGY & NEUROINFLAMMATION 2025; 12:e200425. [PMID: 40393019 PMCID: PMC12094786 DOI: 10.1212/nxi.0000000000200425] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Download PDF] [Subscribe] [Scholar Register] [Received: 03/24/2025] [Accepted: 04/04/2025] [Indexed: 05/22/2025]
Affiliation(s)
- Frank Leypoldt
- Institute of Clinical Chemistry and Department of Neurology, University Hospital Schleswig-Holstein (UKSH) and Kiel University, Kiel, Germany
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Seery N, Wesselingh R, Beech P, McLaughlin L, Rushen T, Halliday AJ, Ter Horst L, Griffith SP, Forcadela M, Tan TH, Kazzi C, Nesbitt C, Broadley J, Buzzard K, Duncan A, D'Souza WJ, Tran Y, Van Der Walt A, Skinner G, Taylor BV, Swayne A, Brodtmann A, Gillis D, Butler EG, Kalincik T, Seneviratne UK, Macdonell RA, Blum S, Ramanathan S, Malpas CB, Reddel SW, Hardy TA, O'Brien TJ, Sanfilippo PG, Butzkueven H, Monif M, Australian Autoimmune Encephalitis Consortium. Rituximab Use for Relapse Prevention in Anti-NMDAR Antibody-Mediated Encephalitis: A Multicenter Cohort Study. NEUROLOGY(R) NEUROIMMUNOLOGY & NEUROINFLAMMATION 2025; 12:e200395. [PMID: 40446185 PMCID: PMC12153942 DOI: 10.1212/nxi.0000000000200395] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 10/08/2024] [Accepted: 02/25/2025] [Indexed: 06/18/2025]
Abstract
BACKGROUND AND OBJECTIVES Rituximab is an anti-CD20 monoclonal antibody used in patients with anti-NMDAR antibody (Ab)-mediated encephalitis as both an acute escalation therapy and a longer term relapse risk-reduction treatment. The potential long-term benefit of a single course administered during the acute disease phase on future relapse risk is uncertain. Moreover, the optimal dosing duration to reduce relapse risk is unknown. The aim of this study was to evaluate the effect of a single course of rituximab on relapse incidence. We also studied the duration of effect of a course of rituximab in adult patients with anti-NMDAR Ab-mediated encephalitis. METHODS We recruited 67 patients with anti-NMDAR Ab-mediated encephalitis from 10 Australian hospitals. Rituximab exposure was quantified as a time-varying covariate in Cox proportional hazard models. RESULTS A single course of rituximab was associated with longer time to first relapse (hazard ratio [HR] 0.11, 95% CI 0.02-0.70, p = 0.02). For patients in whom redosing is considered, rituximab was associated with longer time to first relapse at 6 months after the last infusion, after adjusting for concurrent immunotherapies and the presence of ovarian teratoma at disease onset (HR 0.05, 95% CI 0.00-0.48, p = 0.005). The treatment effect did not persist out to 12 months after a given course (HR 0.60, 95% CI 0.15-2.44, p = 0.47). DISCUSSION A single course of rituximab reduces the risk of relapse of anti-NMDAR antibody-mediated encephalitis. In select patients for whom redosing of rituximab is considered, administration at 6 months delays relapses. CLASSIFICATION OF EVIDENCE This study provides Class IV evidence that rituximab delays relapses in patients with anti-NMDAR antibody-mediated encephalitis.
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Affiliation(s)
- Nabil Seery
- Department of Neuroscience, Monash University, Melbourne, Australia
- Department of Neurology, Alfred Health, Melbourne, Australia
| | - Robb Wesselingh
- Department of Neuroscience, Monash University, Melbourne, Australia
- Department of Neurology, Alfred Health, Melbourne, Australia
| | - Paul Beech
- Department of Radiology, Alfred Health, Melbourne, Australia
- Department of Radiology, Monash Health, Melbourne, Australia
| | - Laurie McLaughlin
- Department of Neurology, Princess Alexandra Hospital, Australia
- School of Medicine, The University of Queensland, Australia
| | - Tiffany Rushen
- Department of Neuroscience, Monash University, Melbourne, Australia
- Department of Neurology, Alfred Health, Melbourne, Australia
| | - Amy J Halliday
- Department of Medicine, St Vincent's Hospital, University of Melbourne, Australia
| | - Liora Ter Horst
- Department of Neurology, Princess Alexandra Hospital, Australia
- School of Medicine, The University of Queensland, Australia
| | - Sarah P Griffith
- Department of Neuroscience, Monash University, Melbourne, Australia
- Department of Neurology, Alfred Health, Melbourne, Australia
| | | | - Tracie H Tan
- Department of Neuroscience, Monash University, Melbourne, Australia
- Department of Neurology, Alfred Health, Melbourne, Australia
| | - Christina Kazzi
- Department of Neuroscience, Monash University, Melbourne, Australia
- Department of Neurology, Alfred Health, Melbourne, Australia
| | - Cassie Nesbitt
- Department of Neurology, Alfred Health, Melbourne, Australia
- Department of Neuroscience, University Hospital Geelong, Geelong, Australia
| | - James Broadley
- Department of Neuroscience, Monash University, Melbourne, Australia
- Department of Neurology, Alfred Health, Melbourne, Australia
| | | | - Andrew Duncan
- Department of Medicine, St Vincent's Hospital, University of Melbourne, Australia
| | - Wendyl J D'Souza
- Department of Medicine, St Vincent's Hospital, University of Melbourne, Australia
| | - Yang Tran
- Department of Medicine, St Vincent's Hospital, University of Melbourne, Australia
- Department of Pathology, St Vincent's Hospital, Melbourne, Australia
| | - Anneke Van Der Walt
- Department of Neuroscience, Monash University, Melbourne, Australia
- Department of Neurology, Alfred Health, Melbourne, Australia
| | - Genevieve Skinner
- Department of Neurology, Princess Alexandra Hospital, Australia
- School of Medicine, The University of Queensland, Australia
| | - Bruce V Taylor
- Department of Neurology, Royal Hobart Hospital, Australia
| | - Andrew Swayne
- Department of Neurology, Princess Alexandra Hospital, Australia
- School of Medicine, The University of Queensland, Australia
| | - Amy Brodtmann
- Department of Neuroscience, Monash University, Melbourne, Australia
- Department of Neurosciences, Eastern Health, Melbourne, Australia
- Department of Neurology, Royal Melbourne Hospital, Australia
| | - David Gillis
- Division of Immunology, Pathology Queensland Central Laboratory, Herston, Australia
| | | | - Tomas Kalincik
- CORe, Department of Medicine, The University of Melbourne, Australia
- Neuroimmunology Centre, Department of Neurology, Royal Melbourne Hospital, Australia
| | - Udaya K Seneviratne
- Department of Neuroscience, Monash University, Melbourne, Australia
- Department of Medicine, St Vincent's Hospital, University of Melbourne, Australia
- Department of Neuroscience, Monash Health, Melbourne, Australia
| | | | - Stefan Blum
- Department of Neurology, Princess Alexandra Hospital, Australia
- School of Medicine, The University of Queensland, Australia
| | - Sudarshini Ramanathan
- Department of Neurology and Concord Clinical School, Concord Hospital, Australia
- Translational Neuroimmunology Group, Kids Neuroscience Centre and Brain and Mind Centre, Faculty of Medicine and Health, University of Sydney, Australia
| | - Charles B Malpas
- Department of Neuroscience, Monash University, Melbourne, Australia
- Department of Medicine (Royal Melbourne Hospital), University of Melbourne, Australia
- Melbourne School of Psychological Sciences, University of Melbourne, Australia; and
| | - Stephen W Reddel
- Department of Neurology and Concord Clinical School, Concord Hospital, Australia
- Brain and Mind Centre, University of Sydney, Australia
| | - Todd A Hardy
- Department of Neurology and Concord Clinical School, Concord Hospital, Australia
- Brain and Mind Centre, University of Sydney, Australia
| | - Terence J O'Brien
- Department of Neuroscience, Monash University, Melbourne, Australia
- Department of Neurology, Alfred Health, Melbourne, Australia
| | | | - Helmut Butzkueven
- Department of Neuroscience, Monash University, Melbourne, Australia
- Department of Neurology, Alfred Health, Melbourne, Australia
| | - Mastura Monif
- Department of Neuroscience, Monash University, Melbourne, Australia
- Department of Neurology, Alfred Health, Melbourne, Australia
- Department of Neurology, Royal Melbourne Hospital, Australia
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Liu J, Li M, Liu J, Zheng D, Zhou Y, Li Y, Chen X, Lin Y, Yang L, Xu X, Jiang Y, Peng F. Multicenter experience with Efgartigimod in the treatment of anti-NMDAR encephalitis compared with IVIG and SPA-IA during acute attacks. Life Sci 2025; 371:123597. [PMID: 40180242 DOI: 10.1016/j.lfs.2025.123597] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/05/2025] [Revised: 03/20/2025] [Accepted: 03/27/2025] [Indexed: 04/05/2025]
Abstract
OBJECTIVES The purpose of this study was to evaluate the efficacy of Efgartigimod (EFG) in anti-N-methyl-d-aspartate receptor (anti-NMDAR) encephalitis patients during acute attacks. METHODS A case-control study was designed to compare 26 anti-NMDAR encephalitis patients who were treated with EFG, and 15 patients with intravenous immunoglobulin (IVIG), and 23 patients with immunoadsorption with staphylococcal protein A column (SPA-IA) treatment. RESULTS At baseline, no significant differences in mRS scores were observed among the EFG, IVIG, and SPA-IA groups of anti-NMDAR encephalitis patients. When compared with the IVIG group, patients treated with EFG had significantly decreased serum IgG levels. Compared with the SPA-IA group, EFG-treated patients had lower CSF anti-NMDAR antibody titers at admission (p = 0.039) and higher post-treatment IgG levels (p = 0.002). When compared with the IVIG group, SPA-IA patients had higher CASE scores (p = 0.022) and baseline IgG levels (p = 0.023). All groups improved the symptoms of anti-NMDAR encephalitis patients after treatment during acute attacks, with significant decreases in mRS and CASE scores from admission to discharge (p < 0.01). In the EFG and SPA-IA groups, there was a significant reduction in anti-NMDAR antibody titers in both CSF and serum (p < 0.01), while no remarkable decrease was found in the IVIG group. Additionally, serum IgG levels significantly decreased in both the EFG and SPA-IA groups post treatment and during the 1-month follow-up. By the 3-month of follow-up, IgG levels in the blood of both groups remained below the baseline levels. CONCLUSION EFG could be an elegant alternative to both IVIG and SPA-IA therapies for anti-NMDAR encephalitis during acute attacks. It has a better effect on reducing antibody titers than IVIG and is comparable to SPA-IA therapy, and no serious adverse events were observed during infusion.
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Affiliation(s)
- Jia Liu
- Department of Neurology, The Third Affiliated Hospital of Sun Yat-sen University, 600# Tianhe Road, Guangzhou 510630, China
| | - Min Li
- Department of Neurology, The Third Affiliated Hospital of Sun Yat-sen University, 600# Tianhe Road, Guangzhou 510630, China
| | - Junyu Liu
- Department of Neurology, The Third Affiliated Hospital of Sun Yat-sen University, 600# Tianhe Road, Guangzhou 510630, China
| | - Dong Zheng
- Department of Neurology, The Affiliated Brain Hospital, Guangzhou Medical University, China
| | - Yanxia Zhou
- Department of Neurology, Shenzhen Second People's Hospital, China
| | - Yi Li
- Department of Neurology, Sun Yat-Sen Memorial Hospital of Sun Yat-Sen University, China
| | - Xialing Chen
- Department of Neurology, Dong Guan Kang Hua Hospital, China
| | - Yanni Lin
- Department of Neurology, Yulin Frist People's Hospital, China
| | - Lu Yang
- Department of Neurology, The Third Affiliated Hospital of Sun Yat-sen University, 600# Tianhe Road, Guangzhou 510630, China
| | - Xiaofeng Xu
- Department of Neurology, The Third Affiliated Hospital of Sun Yat-sen University, 600# Tianhe Road, Guangzhou 510630, China.
| | - Ying Jiang
- Department of Neurology, The Third Affiliated Hospital of Sun Yat-sen University, 600# Tianhe Road, Guangzhou 510630, China.
| | - Fuhua Peng
- Department of Neurology, The Third Affiliated Hospital of Sun Yat-sen University, 600# Tianhe Road, Guangzhou 510630, China.
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Steriade C, Bauer J, Bien CG. Autoimmune encephalitis-associated epilepsy. Nat Rev Neurol 2025; 21:312-326. [PMID: 40316743 DOI: 10.1038/s41582-025-01089-4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 04/14/2025] [Indexed: 05/04/2025]
Abstract
Autoimmune encephalitis (AE), defined by clinical criteria and its frequent association with neural autoantibodies, often manifests with seizures, which usually stop with immunotherapy. However, a subset of encephalitic conditions present with recurrent seizures that are resistant to immunotherapy. Three primary neurological constellations that fall within this subset are discussed in this Perspective: temporal lobe epilepsy with antibodies against glutamic acid decarboxylase, epilepsy in the context of high-risk paraneoplastic antibodies, and epilepsy following adequately treated surface antibody-mediated AE. These entities all share a common mechanism of structural injury and potentially epileptogenic focal neural loss, often induced by cytotoxic T cells. Recently, we have proposed conceptualizing these conditions under the term autoimmune encephalitis-associated epilepsy (AEAE). Here, we discuss the new concept of AEAE as an emerging field of study. We consider the clinical characteristics of patients who should be investigated for AEAE and highlight the need for judicious use of traditional epilepsy therapeutics alongside immunotherapeutic considerations that are of uncertain and incomplete efficacy for this group of disorders. Last, we discuss future efforts needed to diagnose individuals before structural epileptogenesis has superseded inflammation and to develop improved therapeutics that target the specific immunological or functional disturbances in this entity.
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Affiliation(s)
- Claude Steriade
- New York University Comprehensive Epilepsy Center, New York, NY, USA.
- NYU Neuroscience Institute, NYU Langone Medical Center, New York, NY, USA.
| | - Jan Bauer
- Medical University of Vienna, Vienna, Austria
| | - Christian G Bien
- Dept. of Epileptology, Krankenhaus Mara, Bethel Epilepsy Center, Medical School OWL, Bielefeld University, Bielefeld, Germany
- Laboratory Krone, Bad Salzuflen, Germany
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7
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Joseph K, van der Hock S, Seth I, Hapangama N, Gibson L, Cuomo R, Rozen WM, Dhupar N. Association of ovarian teratoma with anti-N-methyl-D-aspartate receptor encephalitis: a case report and narrative review. Arch Gynecol Obstet 2025; 311:1535-1541. [PMID: 39496807 PMCID: PMC12055894 DOI: 10.1007/s00404-024-07779-6] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/23/2024] [Accepted: 10/08/2024] [Indexed: 11/06/2024]
Abstract
BACKGROUND Anti-N-methyl-D-aspartate receptor (NMDAR) encephalitis is a potentially life-threatening autoimmune disorder which is strongly associated with ovarian teratomas in young female patients. The primary aim is to highlight the importance of considering NMDAR encephalitis in the differential diagnosis of young female patients presenting with acute or subacute neuropsychiatric symptoms, especially when accompanied by ovarian teratomas. CASE DESCRIPTION This case report and literature review detail the presentation, diagnosis, and treatment of a 35-year-old G4P3 Indigenous woman who initially presented with neuropsychiatric symptoms and fever, having a history of extensive drug and alcohol use. Misdiagnosed initially, the patient's lack of response to standard treatments led to further investigations, revealing paraneoplastic anti-NMDAR encephalitis secondary to a left ovarian teratoma. The report examines the treatment regimen followed, including prednisolone, intravenous immunoglobulin, rituximab injections, and laparoscopic bilateral salpingo-oophorectomy. CONCLUSIONS This case underscores the critical need for increased clinical vigilance for anti-NMDAR encephalitis in patients, particularly young females, presenting with neuropsychiatric symptoms and potential ovarian teratomas. The literature review accompanying the case report provides valuable insights into the presentation, diagnosis, and management of this complex condition. Lastly, this study emphasised the diagnostic challenges inherent in paraneoplastic neuropsychiatric syndromes, advocating for a multidisciplinary approach in similar clinical scenarios.
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Affiliation(s)
- Konrad Joseph
- Department of Surgery, Port Macquarie Hospital, Port Macquarie, NSW, Australia
| | - Sarah van der Hock
- Faculty of Science, Medicine, and Health, The University of Melbourne, Melbourne, VIC, Australia.
| | - Ishith Seth
- Faculty of Science, Medicine, and Health, The University of Melbourne, Melbourne, VIC, Australia
- Faculty of Science, Medicine, and Health, Monash University, Melbourne, VIC, Australia
| | - Nipuni Hapangama
- Department of Obstetrics and Gynaecology, Murrumbidgee Health, Wagga Wagga, NSW, Australia
| | - Lara Gibson
- Department of Obstetrics and Gynaecology, Joan Kirner Women's and Children's Hospital, Western Health, St Albans, Australia
| | - Roberto Cuomo
- Department of Medicine, Surgery and Neuroscience, University of Siena, Siena, Italy
| | - Warren M Rozen
- Faculty of Science, Medicine, and Health, The University of Melbourne, Melbourne, VIC, Australia
- Faculty of Science, Medicine, and Health, Monash University, Melbourne, VIC, Australia
| | - Nita Dhupar
- Department of Obstetrics and Gynaecology, Murrumbidgee Health, Wagga Wagga, NSW, Australia
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8
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Pădureanu V, Dop D, Pădureanu R, Pîrșcoveanu DFV, Olaru G, Streata I, Bugă AM. Anti-NMDA Receptor Encephalitis: A Narrative Review. Brain Sci 2025; 15:518. [PMID: 40426689 PMCID: PMC12110449 DOI: 10.3390/brainsci15050518] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/08/2025] [Revised: 05/14/2025] [Accepted: 05/18/2025] [Indexed: 05/29/2025] Open
Abstract
Antibodies against the NR1 or NR2 subunits of the NMDA receptor are linked to anti-N-methyl-D-aspartate (NMDA) receptor encephalitis, a type of encephalitis that mainly affects women. Clinicians who treat patients of all ages should be aware of this type of encephalitis since it may be a treatable differential for symptoms and indicators observed in neurology and psychiatric clinics. Auditory and visual hallucinations, delusions, altered behavior (often accompanied by agitation), reduced consciousness, motor disruption (from dyskinesia to catatonia), seizures, and autonomic dysfunction are typical clinical characteristics. In recent years, the incidence of autoimmune encephalitis diagnoses has markedly risen among adults, children, and adolescents. This fact is unequivocally connected to the dynamic evolution of novel diagnostic techniques and the advancement of medical knowledge. A specific variant of this illness is anti-NMDA receptor encephalitis. Psychiatrists frequently serve as the initial specialists to treat patients with this diagnosis, owing to the manifestation of psychiatric symptoms associated with the condition. The differential diagnosis is quite challenging and predominantly relies on the patient's history and the manifestation of characteristic clinical signs. Given its high prevalence, anti-NMDA receptor encephalitis should be included in the differential diagnosis in routine psychiatric treatment. We provide an overview of the research on the condition, covering its prognosis, management, epidemiology, differential diagnosis, and clinical presentation.
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Affiliation(s)
- Vlad Pădureanu
- Department of Internal Medicine, University of Medicine and Pharmacy Craiova, 200349 Craiova, Romania;
| | - Dalia Dop
- Department of Pediatrics, University of Medicine and Pharmacy Craiova, 200349 Craiova, Romania
| | - Rodica Pădureanu
- Department of Internal Medicine, University of Medicine and Pharmacy Craiova, 200349 Craiova, Romania;
| | | | - Gabriela Olaru
- Doctoral School, University of Medicine and Pharmacy Craiova, 200349 Craiova, Romania;
| | - Ioana Streata
- Department of Molecular Biology, University of Medicine and Pharmacy Craiova, 200349 Craiova, Romania
| | - Ana Maria Bugă
- Department of Biochemistry, University of Medicine and Pharmacy Craiova, 200349 Craiova, Romania
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Kapoor M, Khoo A, Lunn MPT, Reddel S, Carr AS. Immunoglobulin use in neurology: a practical approach. Pract Neurol 2025; 25:228-240. [PMID: 39097408 DOI: 10.1136/pn-2022-003655] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 07/03/2024] [Indexed: 08/05/2024]
Abstract
Human immunoglobulin, delivered either intravenously (IVIg) or subcutaneously, is used to treat a range of immune-mediated neurological disorders. It has a role in acute or subacute inflammatory disease control and as a maintenance therapy in chronic disease management. This review considers mechanisms of IVIg action and the evidence for IVIg in neurological conditions. We use Guillain-Barré syndrome and chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) as frameworks to demonstrate an approach to IVIg use in acute and chronic dysimmune neurological conditions across two different healthcare systems: the UK and Australia. We highlight the benefits and limitations of IVIg and focus on practical considerations such as informed consent, managing risks and adverse effects, optimal dosing and monitoring response. We use these basic clinical practice principles to discuss the judicious use of an expensive and scarce blood product with international relevance.
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Affiliation(s)
- Mahima Kapoor
- Neuroscience / FMNHS / School of Translational Medicine, Monash University, Melbourne, Victoria, Australia
| | - Anthony Khoo
- Flinders University College of Medicine and Public Health, Adelaide, South Australia, Australia
- Department of Neurology, Flinders Medical Centre, Bedford Park, South Australia, Australia
| | - Michael P T Lunn
- Centre for Neuromuscular Diseases, National Hospital for Neurology and Neurosurgery, London, UK
- UCL Queen Square Institute of Neurology, Faculty of Brain Sciences, University College London, London, UK
| | - Stephen Reddel
- ANZAC Research Institute, Central Clinical School, University of Sydney, Sydney, New South Wales, Australia
| | - Aisling S Carr
- UCL Queen Square Institute of Neurology, Faculty of Brain Sciences, University College London, London, UK
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10
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Li F, He Y, Chen X, Yang A, Zhang J, Zang W. Clinical spectrum and long-term outcomes of antibody-negative severe autoimmune encephalitis: a retrospective study. Front Immunol 2025; 16:1591771. [PMID: 40443652 PMCID: PMC12119582 DOI: 10.3389/fimmu.2025.1591771] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/11/2025] [Accepted: 04/28/2025] [Indexed: 06/02/2025] Open
Abstract
Objective The aims of the study were to characterize the clinical manifestations and outcomes of patients with antibody-negative severe autoimmune encephalitis (AE). Methods This retrospective, monocentric study recruited patients from the Neurology Department of Henan Provincial People's Hospital between April 2017 and December 2023. All patients underwent neural antibody testing in both blood and cerebrospinal fluid (CSF) and met the diagnostic criteria for autoantibody-negative but probable severe AE, with available 1-year follow-up data. Results In total, 124 patients with autoantibody-negative severe AE were analyzed. Among them, 27.4% achieved good functional outcomes at discharge. Older age (OR 1.034, 95% confidence interval [CI] 1.010-1.058, p = 0.004) and the presence of dyskinesia/dystonia (OR 8.463, 95% CI 3.282-21.820, p < 0.001) were predictive of poor short-term outcomes. At the 1-year follow-up, 54.8% experienced favorable long-term outcomes. Independent predictors of unfavorable long-term outcomes included older age (OR 1.076, 95% CI 1.018-1.136, p = 0.009), longer hospital stays (OR 1.264, 95% CI 1.105-1.446, p = 0.001), the presence of refractory status epilepticus (OR 14.765, 95% CI 1.759-123.935, p = 0.013) and higher CASE scores at discharge (OR 2.079, 95% CI 1.450-2.980, p < 0.001). Additionally, 30.6% of patients had relapsed, with refractory status epilepticus being an independent risk factor for relapse. Conclusion Although patients with antibody-negative severe AE experience significant disability in the early stages of their disease, the majority eventually regain independent functioning. Older age at disease onset, longer hospital stays, the presence of refractory status epilepticus and higher CASE scores at discharge may predict a poor long-term prognosis.
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Affiliation(s)
- Fangfang Li
- Department of Neurology, Henan Provincial People’s Hospital, Zhengzhou University People’s Hospital, Zhengzhou, Henan, China
| | - Yu He
- Department of Neurology, Henan Provincial People’s Hospital, Zhengzhou University People’s Hospital, Zhengzhou, Henan, China
- Department of Neurology, Henan University People’s Hospital, Zhengzhou, China
| | - Xiaoqian Chen
- The Second Affiliated Hospital of Luohe Medical College, Luohe, Henan, China
| | - Ali Yang
- Department of Neurology, Henan Provincial People’s Hospital, Zhengzhou University People’s Hospital, Zhengzhou, Henan, China
| | - Jiewen Zhang
- Department of Neurology, Henan Provincial People’s Hospital, Zhengzhou University People’s Hospital, Zhengzhou, Henan, China
| | - Weizhou Zang
- Department of Neurology, Henan Provincial People’s Hospital, Zhengzhou University People’s Hospital, Zhengzhou, Henan, China
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Wu S, Huang HW, Panchal A, Chowdhury EA, Shah DK. Quantitation of regional distribution of antibodies in rat brain following systemic and intra-CNS administration. J Cereb Blood Flow Metab 2025:271678X251333536. [PMID: 40357752 PMCID: PMC12075156 DOI: 10.1177/0271678x251333536] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/19/2024] [Revised: 03/20/2025] [Accepted: 03/24/2025] [Indexed: 05/15/2025]
Abstract
Antibody therapy has demonstrated great potential for treating central nervous system (CNS) disorders. Since therapeutic efficacy relies on sufficient exposure in specific brain regions, quantitative understanding of antibody distribution within the brain is crucial. Additionally, insights into antibody brain distribution help elucidate how pathological antibodies accumulate during encephalitis. Accordingly, this study investigated the regional distribution of a non-target-binding antibody (trastuzumab) and a brain-target-binding antibody (anti-NMDAR1) following systemic and intra-CNS administration in rats. After systemic administration, both antibodies showed similar distribution across brain regions, with the olfactory bulb exhibiting significantly higher concentrations. Other regions had comparable exposure, with the striatum or hippocampus showing the lowest exposure. Intra-CSF administration resulted in similar distribution patterns but achieved significantly higher concentrations than systemic administration. In contrast, intra-striatal administration led to diverse distribution, with the highest concentrations near the injection site. Calculations based on striatum and interstitial fluid (ISF) concentrations indicated antibody accumulation in the perivascular space after intra-CNS administration. Target binding influenced distribution primarily after intra-CSF administration, where anti-NMDAR1 showed lower ISF concentrations early and reduced CSF concentrations later. These findings provide valuable quantitative insights for optimizing brain-targeted antibody therapies and understanding pathological antibody distribution in CNS disorders.
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Affiliation(s)
- Shengjia Wu
- Department of Pharmaceutical Sciences, School of Pharmacy and Pharmaceutical Sciences, The State University of New York at Buffalo, Buffalo, NY, USA
| | - Hsien Wei Huang
- Department of Pharmaceutical Sciences, School of Pharmacy and Pharmaceutical Sciences, The State University of New York at Buffalo, Buffalo, NY, USA
| | - Aditi Panchal
- Department of Pharmaceutical Sciences, School of Pharmacy and Pharmaceutical Sciences, The State University of New York at Buffalo, Buffalo, NY, USA
| | - Ekram Ahmed Chowdhury
- Department of Pharmaceutical Sciences, School of Pharmacy and Pharmaceutical Sciences, The State University of New York at Buffalo, Buffalo, NY, USA
| | - Dhaval K Shah
- Department of Pharmaceutical Sciences, School of Pharmacy and Pharmaceutical Sciences, The State University of New York at Buffalo, Buffalo, NY, USA
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Shen L, Liu H, Liu X, Zhang L, Wang J, Yang N, Yan N. An adolescent patient with anti-N-methyl-D-aspartate receptor encephalitis with motor aphasia as the first symptom and complicated by peripheral nerve damage: A case report and literature review. Medicine (Baltimore) 2025; 104:e42436. [PMID: 40355209 PMCID: PMC12074118 DOI: 10.1097/md.0000000000042436] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/18/2024] [Accepted: 12/05/2024] [Indexed: 05/14/2025] Open
Abstract
RATIONALE Anti-N-methyl-D-aspartate receptor (anti-NMDAR) encephalitis is a type of autoimmune encephalitis, and the common first symptoms are mental disorders, seizures, and rarely aphasia in patients. Meanwhile, movement disorders associated with anti-NMDAR encephalitis are usually chorea and dystonia, with peripheral nerve damage being rare. PATIENT CONCERNS We present a case of anti-NMDAR encephalitis with motor aphasia as the first symptom. The patient, a 16-year-old female, was admitted to the hospital with further progression of the disease, complicated by grand mal seizures with peripheral nerve damage. DIAGNOSES Anti-NMDAR encephalitis. INTERVENTIONS The patient accepted first-line therapy, including methylprednisolone and intravenous immunoglobulin shock therapy, rituximab second-line treatment (rituximab), and third-line therapies (mycophenolate mofetil), as well as efgartigimod as an additional therapy. OUTCOMES After 6 weeks of comprehensive treatment, the patient's muscle strength in both lower limbs recovered, and the psychiatric symptoms and seizures improved. LESSONS This case broadens the range of clinical symptoms of anti-NMDAR encephalitis, and we should recognize that motor aphasia may also be one of the first symptoms in adolescent patients with anti-NMDAR encephalitis. What's more, efgartigimod may be a promising treatment for patients with anti-NMDAR encephalitis.
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Affiliation(s)
- Lei Shen
- Department of Neurosurgery, Zhongnan Hospital of Wuhan University, Wuhan, China
| | - Hanxing Liu
- Department of Neurology, Zhongnan Hospital of Wuhan University, Wuhan, China
| | - Xi Liu
- Department of Neurology, Zhongnan Hospital of Wuhan University, Wuhan, China
| | - Lei Zhang
- Department of Neurology, Zhongnan Hospital of Wuhan University, Wuhan, China
| | - Jin Wang
- Department of Neurology, Zhongnan Hospital of Wuhan University, Wuhan, China
| | - Niao Yang
- Department of Cardiology, Wuhan University of Science & Technology, Hanyang Hospital, Wuhan, China
| | - Nao Yan
- Department of Neurology, Zhongnan Hospital of Wuhan University, Wuhan, China
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13
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Polunosika E, Pastare D, Karelis G, Vasylovska V. Development of anti-NMDA receptor encephalitis in a patient with multiple sclerosis. BMJ Case Rep 2025; 18:e263945. [PMID: 40345675 PMCID: PMC12067385 DOI: 10.1136/bcr-2024-263945] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/29/2024] [Accepted: 04/21/2025] [Indexed: 05/11/2025] Open
Abstract
Anti-N-methyl-D-aspartate (anti-NMDA) receptor encephalitis is a rare subtype of autoimmune encephalitis, often presenting with early-onset, disease-specific neuropsychiatric symptoms. This case report describes a female patient with relapsing-remitting multiple sclerosis (RRMS) who developed anti-NMDA receptor encephalitis while receiving disease-modifying treatment. She exhibited neurocognitive symptoms and atypical magnetic resonance findings. Clinical and laboratory findings, including lumbar puncture, confirmed the presence of IgG antibodies against the GluN1 subunit of the NMDA receptor, establishing the diagnosis. First-line therapy with methylprednisolone and plasma exchange proved refractory, and immunoglobulin therapy yielded only a suboptimal response. Rituximab achieved the optimal therapeutic effect; however, therapy was followed by recurrent COVID-19 infection in this previously unvaccinated patient. This report highlights the complexities of diagnosis, differential considerations, therapeutic strategies and the detrimental impact of anti-NMDA receptor encephalitis and RRMS on the patient's quality of life.
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Affiliation(s)
- Elīna Polunosika
- Neurology and Neurosurgery, Riga East University Hospital, Riga, Latvia
| | - Daina Pastare
- Neurology and Neurosurgery, Riga East University Hospital, Riga, Latvia
| | - Guntis Karelis
- Neurology and Neurosurgery, Riga East University Hospital, Riga, Latvia
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David Cancino CA, Trenado C, Kaplan PW, Gómez Ávila FA, Fernández González-Aragón MDC, Moreno Avellán ÁJ, Soto Rincón CA, Quiñones Pesqueira GA, San-Juan D. Quantitative Electroencephalography Biomarkers in Patients With Anti-N-methyl-D-aspartate Receptor Encephalitis: A Case-Control Study. J Clin Neurophysiol 2025; 42:314-322. [PMID: 39724935 DOI: 10.1097/wnp.0000000000001124] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/28/2024] Open
Abstract
PURPOSE Anti-N-methyl-D-aspartate receptor (NMDAR) encephalitis is an autoimmune reaction involving Immunoglobulin G antibodies against GluN1 subunit of NMDAR. Absence of biomarkers for early diagnosis and prognosis poses a challenge. Several small case-control studies have emphasized the prospect of quantitative EEG measurements. This study aimed to analyze and identify novel scalp quantitative EEG biomarkers and their implications on outcome of NMDRA encephalitis compared with a control group. METHODS Retrospective (2012-2021) case-control study of patients with NMDRA encephalitis and with acute/subacute encephalitis from other causes. Clinical variables and outcomes were assessed with modified Rankin Scale at admission, discharge, and follow-up. All patients underwent extensive diagnostic workup, including scalp EEG within 72 hours of admission. Quantitative EEG was calculated for Renyi, Tsalis entropy, Hjorth complexity, mean energy, and spectral power of the following frequency bands and ratios: delta (0.5-4 Hz), theta (5-8 Hz), alpha (9-14 Hz), beta (15-30 Hz), gamma (31-45 Hz), gamma-beta, beta/alpha, beta/theta, and beta/delta. Descriptive statistics, power frequency bands, complexity measures, and Wilcoxon rank sum test were used. RESULTS Patients with anti-NMDAR encephalitis had significantly higher delta frequency peak power, higher beta/alpha and gamma/beta frequency ratios, lower alpha and beta peak power, and lower beta/delta frequency ratio than the control group. In patients with anti-NMDAR encephalitis, higher delta and alpha peak power had the worst clinical outcome, at discharge and follow-up, and patients with higher gamma peak power had better outcomes. CONCLUSIONS Quantitative EEG is a valuable tool to differentiate anti-NMDAR encephalitis from other inflammatory encephalitis and predict outcomes in patients with anti-NMDAR encephalitis.
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Affiliation(s)
| | - Carlos Trenado
- Institute of Clinical Neuroscience and Medical Psychology, University Hospital Düsseldorf, Düsseldorf, Germany
| | - Peter W Kaplan
- Department of Neurology, Johns Hopkins Bayview Medical Center, Baltimore, Maryland, U.S.A. ; and
| | - Felipe Alberto Gómez Ávila
- Clinical Neurophysiology Department, National Institute of Neurology and Neurosurgery, Mexico City, Mexico
| | | | - Álvaro José Moreno Avellán
- Clinical Neurophysiology Department, National Institute of Neurology and Neurosurgery, Mexico City, Mexico
| | - Carlos Alberto Soto Rincón
- Clinical Neurophysiology Department, National Institute of Neurology and Neurosurgery, Mexico City, Mexico
| | | | - Daniel San-Juan
- Clinical Neurophysiology Department, National Institute of Neurology and Neurosurgery, Mexico City, Mexico
- Epilepsy Clinic, National Institute of Neurology and Neurosurgery, Mexico City, Mexico
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15
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Bose G, Thebault SDX, Fadda G, Brooks JA, Freedman MS. Role of soluble biomarkers in treating multiple sclerosis and neuroinflammatory conditions. Neurotherapeutics 2025:e00588. [PMID: 40254498 DOI: 10.1016/j.neurot.2025.e00588] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/15/2024] [Revised: 03/23/2025] [Accepted: 04/01/2025] [Indexed: 04/22/2025] Open
Abstract
Multiple sclerosis (MS) is a complex, chronic immune-mediated disease characterized by acute and progressive inflammatory damage of the central nervous system. MS manifests clinically with unpredictable neurological symptoms from focal inflammatory attacks as well as gradual neurodegeneration which contribute significantly to long-term disability progression. As treatment options advance, developing more personalized strategies capture heterogeneous mechanisms of injury which may be targeted or predict outcomes has been a focus of ongoing investigation. The role of soluble biomarkers has emerged as a pivotal tool to assist in these goals. Early promising candidates include neurofilament light chain (NfL) and glial fibrillary acidic protein (GFAP); these intermediate filaments that are expressed in neurons and astrocytes, respectively, are reliably measurable from blood samples and can reveal clinical and subclinical changes, as well as predict progression. Changes in these biomarkers can indicate a response to therapy, thus potentially be used as endpoints in clinical trials. Furthermore, recent research has identified a potential role of these and other soluble biomarkers in other neuroimmunological conditions including neuromyelitis spectrum disorder (NMOSD) and myelin oligodendrocyte glycoprotein associated disease (MOGAD), autoimmune encephalitis, neurosarcoidosis, neuropsychiatric involvement in connective tissue disorders and vasculitides, and a host of neurodegenerative conditions. By integrating biomarker analysis into routine clinical assessments, healthcare providers may move toward a more nuanced and individualized care model, better equipped to meet the challenges posed by these multifaceted diseases. Understanding the dynamics of these biomarkers has many applications that can improve personalized medicine in MS.
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Affiliation(s)
- Gauruv Bose
- Department of Medicine, The University of Ottawa and Ottawa Hospital Research Institute, Canada.
| | - Simon D X Thebault
- Department of Medicine, The University of Ottawa and Ottawa Hospital Research Institute, Canada; Department of Neurology and Neurosurgery, Montreal Neurological Institute and McGill University Health Centre, Canada
| | - Giulia Fadda
- Department of Medicine, The University of Ottawa and Ottawa Hospital Research Institute, Canada
| | - John A Brooks
- Department of Medicine, The University of Ottawa and Ottawa Hospital Research Institute, Canada
| | - Mark S Freedman
- Department of Medicine, The University of Ottawa and Ottawa Hospital Research Institute, Canada
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16
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Vaughn M, Powell S, Risbrough V, Zhou X. A novel simple immunoassay for quantification of blood anti-NMDAR1 autoantibodies. PeerJ 2025; 13:e19212. [PMID: 40183041 PMCID: PMC11967420 DOI: 10.7717/peerj.19212] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/10/2024] [Accepted: 03/05/2025] [Indexed: 04/05/2025] Open
Abstract
Low titers of blood circulating anti-NMDAR1 autoantibodies have been reported in a significant subset of the general human population. Currently, immunohistochemical staining and cell-based assays are the standard methods for their detection and semi-quantification. However, detection and quantification of these low titers of blood circulating anti-NMDAR1 autoantibodies are problematic because of high non-specific background. Development of a new method to more accurately quantify these low titers of blood anti-NMDAR1 autoantibodies will facilitate studies on their potential impacts on psychiatric symptoms and cognition. We previously reported a robust production of anti-NMDAR1 autoantibodies against the ligand binding domain of NMDAR1. As a proof of principle, we report the development of a novel simple immunoassay for quantification of cross-species blood anti-NMDAR1 autoantibodies and its validation with immunohistochemistry and cell-based assays in both humans and mice. Specificity of our quantification was also investigated.
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Affiliation(s)
- Melonie Vaughn
- Department of Psychiatry, University of California, San Diego, La Jolla, CA, United States of America
| | - Susan Powell
- Department of Psychiatry, University of California, San Diego, La Jolla, CA, United States of America
- VA Mental Illness Research and Clinical Core, San Diego, CA, United States of America
- VA Research Service, San Diego, CA, United States of America
| | - Victoria Risbrough
- Department of Psychiatry, University of California, San Diego, La Jolla, CA, United States of America
- VA Research Service, San Diego, CA, United States of America
- VA Center of Excellence for Stress and Mental Health, San Diego, CA, United States of America
| | - Xianjin Zhou
- Department of Psychiatry, University of California, San Diego, La Jolla, CA, United States of America
- VA Mental Illness Research and Clinical Core, San Diego, CA, United States of America
- VA Research Service, San Diego, CA, United States of America
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17
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Xie Z, Zhang J, Liu L, Hu E, Wang J. Prediction model for severe autoimmune encephalitis: a tool for risk assessment and individualized treatment guidance. Front Neurol 2025; 16:1575835. [PMID: 40170898 PMCID: PMC11958171 DOI: 10.3389/fneur.2025.1575835] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/13/2025] [Accepted: 03/05/2025] [Indexed: 04/03/2025] Open
Abstract
Background Severe autoimmune encephalitis (AE) can cause significant neurological deficits, status epilepticus, status dystonicus, and even death, which can be life-threatening to patients. Accurate risk stratification for severe AE progression is critical for optimizing therapeutic strategies. The comprehensive prediction models for severe AE based on routine clinical data and laboratory indicators remain lacking. Objective To develop and validate a prediction model for severe AE to optimize individualized treatment. Methods We collected clinical data and laboratory examination results from 207 patients with confirmed AE. The study population was divided into development and validation cohort. A prediction model for severe AE was constructed using a nomogram and was rigorously validated both internally and externally. Severe AE was defined as modified Rankin Scale (mRS) > 2 and Clinical Assessment Scale for Encephalitis (CASE) > 4. Results The variables ultimately included in the nomogram for the severe AE predictive model were age, psychiatric and/or behavioral abnormalities, seizures, decreased level of consciousness, cognitive impairment, involuntary movements, autonomic dysfunction, and increased intrathecal IgG synthesis rate. It demonstrated excellent discriminative capacity and calibration through internal-external validation. Conclusion The prediction model has highly feasibility in clinical practice, and holds promise as an important tool for risk assessment and guiding individualized treatment in patients with AE.
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Affiliation(s)
| | | | | | | | - Jiawei Wang
- Department of Neurology, Beijing Tongren Hospital, Capital Medical University, Beijing, China
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18
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Zhang S, Li H, Lin P, Liu D, Wang Z, Yang J, Ruan S, Zhao Y, Lan Z, Yang X, Wang Y, You Y, Wu X, Wang H, Liu H, Yang H, Feng H, Zhang L, Zhou H, Xu Q, Ou T, Lu Y, Gao C, Qiu W, Hao J, Long Y. A Comparative Study of 141 Glial Fibrillary Acidic Protein Immunoglobulin G Positive Cases. Eur J Neurol 2025; 32:e70102. [PMID: 40052359 PMCID: PMC11886414 DOI: 10.1111/ene.70102] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/23/2024] [Revised: 02/06/2025] [Accepted: 02/15/2025] [Indexed: 03/09/2025]
Abstract
BACKGROUND Glial fibrillary acidic protein-immunoglobulin G (GFAP-IgG) positivity is associated with autoimmune GFAP astrocytopathy (GFAP-A), but also with other autoimmune encephalitides and viral infections. We attempted to elucidate the characteristics of GFAP-A in relation to other GFAP-IgG-positive encephalitides and constructed a differential diagnosis model. METHODS 141 GFAP-IgG-positive cases were identified, including 52 astrocytopathy (GFAP-A group), 48 autoimmune encephalitis (AE-G), and 41 viral encephalitis (VE-G). Multivariate logistic regression was employed to create a diagnostic model, with validation using an external cohort. RESULT Compared to the AE-G group, the GFAP-A patients showed more onset age ≥ 50 years, headache, fever, consciousness disturbance, MRI radial vascular enhancement, cerebrospinal fluid (CSF) antibody titer grade ≥ 4, and CSF proteins ≥ 700 mg/L, but less female sex, limb numbness, visual disturbances, and CSF chloride ≤ 120 mmol/L. Among these, CSF antibody titer grade ≥ 4, CSF protein ≥ 700 mg/L, and absence of visual disturbances were independent risk factors for GFAP-A diagnosis. Compared to the VE-G group, the GFAP-A patients showed more course ≥ 14 days, onset age ≥ 50 years, limb weakness, serum potassium ≤ 3.9 mmol/L, CSF antibody titer grade ≥ 4, CSF leukocytes ≤ 46*10, MRI radial vascular enhancement, MRI involvement of brainstem, and MRI involvement of spinal cord, but less headache, fever, nausea, and vomiting. Among these, serum potassium ≤ 3.9 mmol/L, MRI spinal cord involvement, and absence of nausea and vomiting were independent risk factors for GFAP-A diagnosis. CONCLUSIONS Based on critical clinical indicators identified, we constructed a differential diagnosis model for GFAP-A.
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Affiliation(s)
- Shifeng Zhang
- Department of Neurology, Institute of Neuroscience, Key Laboratory of Neurogenetics and Channelopathies of Guangdong Province and the Ministry of Education of ChinaThe Second Affiliated Hospital, Guangzhou Medical UniversityGuangzhouChina
| | - Huilu Li
- Department of Neurology, Institute of Neuroscience, Key Laboratory of Neurogenetics and Channelopathies of Guangdong Province and the Ministry of Education of ChinaThe Second Affiliated Hospital, Guangzhou Medical UniversityGuangzhouChina
- Department of NeurologyThe Third Affiliated Hospital of sun Yat‐Sen UniversityGuangzhouGuangdongChina
| | - Peihao Lin
- Department of Neurology, Institute of Neuroscience, Key Laboratory of Neurogenetics and Channelopathies of Guangdong Province and the Ministry of Education of ChinaThe Second Affiliated Hospital, Guangzhou Medical UniversityGuangzhouChina
| | - Ding Liu
- Department of NeurologyThe Third Xiangya Hospital, Central South UniversityChangshaHunanChina
| | - Zhanhang Wang
- Department of NeurologyGuangdong 999 Brain HospitalGuangZhouGuangdongChina
| | - Jie Yang
- Department of Neurology, Institute of Neuroscience, Key Laboratory of Neurogenetics and Channelopathies of Guangdong Province and the Ministry of Education of ChinaThe Second Affiliated Hospital, Guangzhou Medical UniversityGuangzhouChina
| | - Shishuang Ruan
- Department of NeurologyXuanwu Hospital of Capital Medical UniversityBeijingChina
| | - Yinan Zhao
- Department of NeurologyXuanwu Hospital of Capital Medical UniversityBeijingChina
| | - Zhike Lan
- Department of NeurologyGuangdong 999 Brain HospitalGuangZhouGuangdongChina
| | - Xiao Yang
- Department of NeurologyGeneral Hospital of Ningxia Medical UniversityYinchuanNingxiaChina
| | - Yue Wang
- Department of NeurologyThe Second Affiliated Hospital of Army Medical UniversityChongqingChina
| | - Yong You
- Department of NeurologyThe Second Affiliated Hospital of Hainan Medical UniversityHaikouHainanChina
| | - Xiuling Wu
- Department of NeurologyTangshan Gongren HospitalTangshanHebeiChina
| | - Haiyang Wang
- Department of NeurologyJining no. 1 People's HospitalJiningShandongChina
| | - Hongli Liu
- Department of NeurologyFirst Hospital of QinhuangdaoQinhuangdaoHebeiChina
| | - Huan Yang
- Department of NeurologyXiangya Hospital of Central South UniversityChangshaHunanChina
| | - Huiyu Feng
- Department of NeurologyThe First Affiliated Hospital of sun Yat‐Sen UniversityGuangzhouGuangdongChina
| | - Lu Zhang
- Department of NeurologyThe First Affiliated Hospital of Zhengzhou UniversityZhengzhouHenanChina
| | - Houshi Zhou
- Department of NeurologyShantou Central HospitalShantouGuangdongChina
| | - Qianhui Xu
- Department of Neurology, Shenzhen People's Hospital, The Second Clinical Medical College of Jinan UniversityThe First Affiliated Hospital of Southern University of Science and TechnologyShenzhenGuangdongChina
| | - Tengfei Ou
- Department of NeurologyThe Second People's Hospital of FoshanFoshanGuangdongChina
| | - Yuhua Lu
- Department of NeurologyPeople's Hospital of Chongqing Banan DistrictChongqingChina
| | - Cong Gao
- Department of Neurology, Institute of Neuroscience, Key Laboratory of Neurogenetics and Channelopathies of Guangdong Province and the Ministry of Education of ChinaThe Second Affiliated Hospital, Guangzhou Medical UniversityGuangzhouChina
| | - Wei Qiu
- Department of NeurologyThe Third Affiliated Hospital of sun Yat‐Sen UniversityGuangzhouGuangdongChina
| | - Junwei Hao
- Department of NeurologyXuanwu Hospital of Capital Medical UniversityBeijingChina
| | - Youming Long
- Department of Neurology, Institute of Neuroscience, Key Laboratory of Neurogenetics and Channelopathies of Guangdong Province and the Ministry of Education of ChinaThe Second Affiliated Hospital, Guangzhou Medical UniversityGuangzhouChina
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19
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Mazowiecki M, Flet-Berliac L, Roux J, Lépine A, Chretien P, Hacein-Bey-Abina S, Giorgi L, Villega F, Cheuret E, Benaiteau M, Rogemond V, Picard G, Baer S, Cleuziou P, Lametery E, Desguerre I, Aubart M, Chevignard M, Le Grand R, Horellou P, Leroy C, Joubert B, Honnorat J, Deiva K. Long-Term Clinical and Biological Prognostic Factors of Anti-NMDA Receptor Encephalitis in Children. NEUROLOGY(R) NEUROIMMUNOLOGY & NEUROINFLAMMATION 2025; 12:e200346. [PMID: 39715492 DOI: 10.1212/nxi.0000000000200346] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 06/28/2024] [Accepted: 11/22/2024] [Indexed: 12/25/2024]
Abstract
BACKGROUND AND OBJECTIVES Anti-NMDAR encephalitis (NMDARE) is a severe neurologic condition, and recently, the NMDAR Encephalitis One-Year Functional Status (NEOS) score has emerged as a 1-year prognostic tool. This study aimed to evaluate NEOS score and biomarker (neurofilament light chains [NfL], total-Tau protein, glial fibrillary acidic protein, and serum cytokines) correlation with modified Rankin Scale (mRS), cognitive impairment, and clinical recovery in pediatric NMDARE over 2 years. METHODS In this French multicenter observational study, 104 pediatric patients with NMDARE were followed for a minimum of 2 years. Clinical data and serum/plasma samples were collected. Biomarker levels, measured using electroluminescence mesoscale discovery (MSD) S-PLEX, were compared between patients and controls and assessed for correlations with disease activity, mRS, cognitive/language impairment, and recovery status at 2 years. RESULTS At a median follow-up of 39.5 months, 68 percent of patients had unfavorable recovery and 54% had significant cognitive impairment. Both outcomes were strongly associated with younger age at diagnosis (OR 6.10 [1.91-27.3] p < 0.01 and 5.69 [1.46-27.7] p = 0.02, respectively). A higher NEOS score was significantly correlated with increased cognitive impairment (OR 2.53 [1.52-4.21], p < 0.001), higher mRS scores (OR 2.12 [1.34-3.57], p < 0.01), and unfavorable recovery at 2 years (OR 2.00 [1.30-3.06], p = 0.015). Elevated NfL levels were significantly associated with unfavorable recovery (OR 3.62 [1.29-10.9] p = 0.012) and severe cognitive impairment (OR 3.77 [1.38-10.9] p = 0.012) at 2 years. The combined area under the curve (AUC) for NfL and NEOS was significantly higher than the AUCs of NEOS and NfL alone (p = 0.01). DISCUSSION The NEOS score strongly predicts long-term outcomes in NMDARE, with its predictive value extending beyond the first-year mR prediction. NfL levels at disease onset seem to improve accuracy in predicting poor outcomes, providing valuable information for treatment decisions and future clinical trials.
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Affiliation(s)
- Maxime Mazowiecki
- Pediatric Neurology Departement, Assistance Publique-Hôpitaux de Paris, Paris-Saclay University Hospitals, Bicêtre Hospital, and Paris-Saclay University, Le Kremlin-Bicêtre
| | - Lorraine Flet-Berliac
- Pediatric Neurology Departement, Assistance Publique-Hôpitaux de Paris, Paris-Saclay University Hospitals, Bicêtre Hospital, and Paris-Saclay University, Le Kremlin-Bicêtre
| | - Julia Roux
- Pediatric Neurology Departement, Assistance Publique-Hôpitaux de Paris, Paris-Saclay University Hospitals, Bicêtre Hospital, and Paris-Saclay University, Le Kremlin-Bicêtre
| | - Anne Lépine
- Pediatric Neurology Department, Assistance Publique des Hôpitaux de Marseille, Hôpital Universitaire, Marseille
| | - Pascale Chretien
- Clinical Immunology Laboratory, Assistance Publique des Hôpitaux de Paris, Hôpitaux Universitaires Paris-Saclay, Bicêtre Hospital, and Paris-Saclay University, Le Kremlin-Bicêtre
- UTCBS, UMR8258 CNRS-U1267 INSERM, Faculté de Pharmacie de Paris, Université de Paris
| | - Salima Hacein-Bey-Abina
- Clinical Immunology Laboratory, Assistance Publique des Hôpitaux de Paris, Hôpitaux Universitaires Paris-Saclay, Bicêtre Hospital, and Paris-Saclay University, Le Kremlin-Bicêtre
- UTCBS, UMR8258 CNRS-U1267 INSERM, Faculté de Pharmacie de Paris, Université de Paris
| | - Laetitia Giorgi
- Pediatric Neurology Departement, Assistance Publique-Hôpitaux de Paris, Paris-Saclay University Hospitals, Bicêtre Hospital, and Paris-Saclay University, Le Kremlin-Bicêtre
- National Referral Center for Rare Inflammatory Brain and Spinal Diseases, Le Kremlin-Bicêtre; and
| | - Frederic Villega
- Pediatric Neurology Department, CICp-1401, University Children Hospital, Bordeaux
- Interdisciplinary Institute for Neurosciences, CNRS UMR 5297
| | - Emmanuel Cheuret
- Pediatric Neurology Department, Purpan University Hospital, Toulouse
| | - Marie Benaiteau
- Reference Center on autoimmune encephalitis, Hospices Civils de Lyon, Institut MELIS, Inserm U1314/CNRS UMR 5284, Université Claude Bernard Lyon 1
| | - Veronique Rogemond
- Reference Center on autoimmune encephalitis, Hospices Civils de Lyon, Institut MELIS, Inserm U1314/CNRS UMR 5284, Université Claude Bernard Lyon 1
| | - Geraldine Picard
- Reference Center on autoimmune encephalitis, Hospices Civils de Lyon, Institut MELIS, Inserm U1314/CNRS UMR 5284, Université Claude Bernard Lyon 1
| | - Sarah Baer
- Department of Neuropediatrics, ERN EpiCare, Hôpitaux Universitaires de Strasbourg
- Institute for Genetics and Molecular and Cellular Biology (IGBMC), University of Strasbourg, CNRS UMR7104, INSERM U1258, Illkirch, France
| | - Pierre Cleuziou
- Department of Pediatric Neurology, Lille University Hospital
| | - Elodie Lametery
- Pediatric Department, Grenoble Alpes University Hospital, Hôpital Albert Michallon
| | - Isabelle Desguerre
- Pediatric Neurology Department Necker-Enfants Malades Hospital, University of Paris, AP-HP
| | - Mélodie Aubart
- Pediatric Neurology Department Necker-Enfants Malades Hospital, University of Paris, AP-HP
| | - Mathilde Chevignard
- Rehabilitation Department for Children with Acquired Neurological Injury, Saint-Maurice Hospitals (M.C.); Saint Maurice Hospitals
- Sorbonne Université, CNRS, INSERM, Laboratoire d'Imagerie Biomédicale (LIB)
- Sorbonne Université, GRC 24 Handicap Moteur Cognitif et Réadaptation (HaMCRe), Paris
| | - Roger Le Grand
- Université Paris-Saclay, CEA, INSERM Center for Immunology of Viral, Auto-Immune, Hematological and Bacterial diseases (IMVA-HB/IDMIT)
| | - Philippe Horellou
- Université Paris-Saclay, CEA, INSERM Center for Immunology of Viral, Auto-Immune, Hematological and Bacterial diseases (IMVA-HB/IDMIT)
- National Referral Center for Rare Inflammatory Brain and Spinal Diseases, Le Kremlin-Bicêtre; and
| | - Carole Leroy
- Université Paris-Saclay, CEA, INSERM Center for Immunology of Viral, Auto-Immune, Hematological and Bacterial diseases (IMVA-HB/IDMIT)
- National Referral Center for Rare Inflammatory Brain and Spinal Diseases, Le Kremlin-Bicêtre; and
| | - Bastien Joubert
- Reference Center on autoimmune encephalitis, Hospices Civils de Lyon, Institut MELIS, Inserm U1314/CNRS UMR 5284, Université Claude Bernard Lyon 1
| | - Jerome Honnorat
- Reference Center on autoimmune encephalitis, Hospices Civils de Lyon, Institut MELIS, Inserm U1314/CNRS UMR 5284, Université Claude Bernard Lyon 1
| | - Kumaran Deiva
- Pediatric Neurology Departement, Assistance Publique-Hôpitaux de Paris, Paris-Saclay University Hospitals, Bicêtre Hospital, and Paris-Saclay University, Le Kremlin-Bicêtre
- Université Paris-Saclay, CEA, INSERM Center for Immunology of Viral, Auto-Immune, Hematological and Bacterial diseases (IMVA-HB/IDMIT)
- National Referral Center for Rare Inflammatory Brain and Spinal Diseases, Le Kremlin-Bicêtre; and
- Institut Universitaire de France, France
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20
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Zhao X, Wu F, Zhao S, Chen W, Si W, Li Y, Zhang D, Wang J, Wang N, Sun L, Sun Z, Chang H, Du G. The clinical value of the neutrophil-to-lymphocyte ratio, systemic immune-inflammation index, monocyte-to-lymphocyte ratio and platelet-to-lymphocyte ratio for predicting the severity of patients with autoimmune encephalitis. Front Neurol 2025; 16:1498007. [PMID: 40093740 PMCID: PMC11906310 DOI: 10.3389/fneur.2025.1498007] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/18/2024] [Accepted: 02/17/2025] [Indexed: 03/19/2025] Open
Abstract
Background The systemic inflammation index (SII), neutrophil-to-lymphocyte ratio (NLR), monocyte-to-lymphocyte ratio (MLR) and platelet-to-lymphocyte ratio (PLR) are inflammatory markers in peripheral blood, which have been proven to be associated with some central nervous system diseases. We aimed to evaluate the association of SII, NLR MLR and PLR with the severity of autoimmune encephalitis (AE) and to compare the predictive value of those biomarkers in the early identification of ICU admission. Methods This retrospective study was conducted in three medical centers in China. We included 176 patients diagnosed with AE and 200 age and gender-matched healthy controls and correlated their demographic and clinical data. The SII, NLR, MLR and PLR levels were calculated from the blood routine tests. The severity of the patients was evaluated by the Clinical Assessment Scale for Autoimmune Encephalitis (CASE) and the modified Rankin Scale (mRS) at admission, and the patients were divided into two groups according to the ICU admission. Results The SII, NLR, MLR and PLR were significantly higher in AE patients than that in HCs (<0.001 for all). The SII and NLR were positively correlated with the CASE score (r = 0.243, p = 0.001; r = 0.237, p = 0.002) and the mRS score (r = 0.185, p = 0.014; r = 0.185, p = 0.014) in AE patients. The MLR and PLR were only positively correlated with the CASE score (r = 0.242, p = 0.001; r = 0.158, p = 0.036). The SII and NLR of the ICU group were significantly higher than that of the non-ICU group. The result of receiver operating characteristic (ROC) analysis showed that NLR was the best predictor of ICU admission for AE patients (AUC = 0.701). NLR and MLR had similar predictive ability (AUC = 0.654; AUC = 0.608) and were superior to PLR. The optimal NLR cut-off value for the incidence of ICU was 3.906. Conclusion Increased SII, NLR, MLR and PLR at admission are positively correlated with the CASE score of AE patients. Among the four indexes, the NLR is the best predictor of ICU admission, which may be helpful for clinicians to monitor disease progression and identify potentially severe patients of AE.
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Affiliation(s)
- Xin Zhao
- Department of Neurology, The First Affiliated Hospital, College of Clinical Medicine of Henan University of Science and Technology, Luoyang, China
| | - Fen Wu
- Department of Clinical Laboratory, Liaocheng Third People’s Hospital, Liaocheng, China
| | - Shunfeng Zhao
- Department of Clinical Laboratory, Liaocheng Third People’s Hospital, Liaocheng, China
| | - Wenna Chen
- Department of Neurology, The First Affiliated Hospital, College of Clinical Medicine of Henan University of Science and Technology, Luoyang, China
| | - Wei Si
- Department of Neurology, The First Affiliated Hospital, College of Clinical Medicine of Henan University of Science and Technology, Luoyang, China
| | - Yuanrui Li
- Department of Neurology, The First Affiliated Hospital, College of Clinical Medicine of Henan University of Science and Technology, Luoyang, China
| | - Dengke Zhang
- Department of Neurology, The First Affiliated Hospital, College of Clinical Medicine of Henan University of Science and Technology, Luoyang, China
| | - Jing Wang
- China National Clinical Research Center for Neurological Diseases, Beijing Tiantan Hospital, Capital Medical University, Beijing, China
| | - Ningning Wang
- Department of Neurology, Tianjin Medical University General Hospital, Tianjin, China
| | - Lina Sun
- China National Clinical Research Center for Neurological Diseases, Beijing Tiantan Hospital, Capital Medical University, Beijing, China
| | - Zhiyu Sun
- Department of Neurobiology, School of Basic Medical Sciences, Capital Medical University, Beijing, China
| | - Haoxiao Chang
- China National Clinical Research Center for Neurological Diseases, Beijing Tiantan Hospital, Capital Medical University, Beijing, China
| | - Ganqin Du
- Department of Neurology, The First Affiliated Hospital, College of Clinical Medicine of Henan University of Science and Technology, Luoyang, China
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21
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Gong X, Liu Y, Ma Y, Yan B, An D, Guo Y, Liu X, Li X, Cai L, Deng X, Zhou D, Li JM, Hong Z. Long-term maintenance of mycophenolate mofetil in anti-NMDA receptor encephalitis (LEARN): a multicentre, open-label, blinded-endpoint, randomised controlled trial. J Neurol Neurosurg Psychiatry 2025:jnnp-2024-335400. [PMID: 40015729 DOI: 10.1136/jnnp-2024-335400] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/10/2024] [Accepted: 02/05/2025] [Indexed: 03/01/2025]
Abstract
BACKGROUND Anti-N-methyl-D-aspartate receptor encephalitis (NMDARE) is a severe autoimmune disorder with high morbidity and mortality. Current treatments have limitations including relapse, highlighting the need for effective maintenance therapy. This study evaluates the efficacy and safety of mycophenolate mofetil (MMF) as long-term adjunctive therapy to first-line treatment in newly diagnosed patients with NMDARE. METHODS We conducted a prospective, randomised, open-label trial in four academic centres in China. Patients aged 14 and older with acute NMDARE, who received first-line treatments within 2 weeks of presentation to the hospital and had a modified Rankin scale (mRS) score of 2 or more, were recruited. Participants were randomly assigned to receive first-line treatment with or without MMF (0.5 g two times per day for 24 months). Primary outcomes included relapse rates and time to relapse, with secondary outcomes including cognitive deficits, treatment response (the proportion of patients with≥1 point improvement in mRS within 4 weeks) and adverse events (AEs). RESULTS Of 100 patients (52% female; median age 27), those in the MMF group had fewer relapses (5.9% vs 26.5%; p=0.006) and better treatment response (84.3% vs 65.3%; p=0.03). No significant difference was found in long-term functional prognosis at 12 and 24 months. However, MMF patients had less fatigue, cognitive impairment, depression and seizures. AEs were mild-to-moderate, with no deaths or anaphylactic reactions. CONCLUSIONS This study provides Class II evidence that long-term adjunctive treatment of MMF to first-line treatment of NMDARE resulted in a lower risk of relapse and was well tolerated beyond the 24 months of treatment. TRIAL REGISTRATION NUMBER ChiCTR2100044362.
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Affiliation(s)
- Xue Gong
- Department of Neurology, West China Hospital of Sichuan University, Chengdu, Sichuan, China
| | - Yue Liu
- Department of Neurology, West China Hospital of Sichuan University, Chengdu, Sichuan, China
| | - Yaru Ma
- Department of Neurology, West China Hospital of Sichuan University, Chengdu, Sichuan, China
| | - Bo Yan
- Department of Neurology, Chengdu Shangjin Nanfu Hospital, Chengdu, Sichuan, People's Republic of China, Chengdu, Sichuan, China
| | - Dongmei An
- Department of Neurology, West China Hospital of Sichuan University, Chengdu, Sichuan, China
- Department of Neurology, West China Tianfu Hospital, Chengdu, Sichuan, People's Republic of China
| | - Yonghua Guo
- Department of Neurology, People's Hospital of Leshan, Leshan, Sichuan, People's Republic of China, Leshan, Sichuan, China
| | - Xu Liu
- Department of Neurology, West China Hospital of Sichuan University, Chengdu, Sichuan, China
| | - Xingjie Li
- Department of Neurology, West China Hospital of Sichuan University, Chengdu, Sichuan, China
| | - Linjun Cai
- Department of Neurology, West China Hospital of Sichuan University, Chengdu, Sichuan, China
- West China Hospital of Medicine, Chengdu, Sichuan, China
| | - Xiaolin Deng
- Department of Neurology, West China Hospital of Sichuan University, Chengdu, Sichuan, China
| | - Dong Zhou
- Department of Neurology, West China Hospital of Sichuan University, Chengdu, Sichuan, China
| | - Jin-Mei Li
- Department of Neurology, West China Hospital of Sichuan University, Chengdu, Sichuan, China
| | - Zhen Hong
- Department of Neurology, West China Hospital of Sichuan University, Chengdu, Sichuan, China
- Institute of Brain science and Brain-inspired technology, West China Hospital, Sichuan University, Chengdu, Sichuan, People's Republic of China
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22
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Maguire PA. Diagnostic testing in psychiatry: insights and examples from a Bayesian perspective. Australas Psychiatry 2025; 33:162-167. [PMID: 39571141 PMCID: PMC11804144 DOI: 10.1177/10398562241300887] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/07/2025]
Abstract
OBJECTIVE To demonstrate the application of Bayes' theorem to diagnostic testing in clinical settings, especially with respect to rare diseases, enhancing an understanding of pre-test probability and its implications. CONCLUSION Bayes' theorem enables the revision of the conditional probabilities of an event occurring when new information is acquired. It demonstrates that when the prevalence of a disease is very low, there are a high number of false positives, thereby reducing the clinical utility and cost benefit profile of the diagnostic test, even in the presence of relatively high sensitivities and specificities of the chosen test.
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Affiliation(s)
- Paul A Maguire
- Paul A Maguire, Academic Unit of Psychiatry and Addiction Medicine, School of Medicine and Psychology, The Australian National University, Building 4, Level 2, Canberra Hospital, PO Box 11, Woden, Canberra, ACT 2605, Australia. Emails: ;
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23
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Qiu Z, Xu F, Zhang M, Yang X, Han Y, Li D, Liu L, Chen J, Gao L, Xue Q, Hou Y, Sun Y, Di L, Fan C, Liang J, Han Y, Dong H, Hao J, Liu Z. Clinical Features of Glutamic Acid Decarboxylase-65 Neurological Autoimmunity: A Case Series From China. CNS Neurosci Ther 2025; 31:e70237. [PMID: 39976255 PMCID: PMC11840705 DOI: 10.1111/cns.70237] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/01/2024] [Revised: 12/21/2024] [Accepted: 01/15/2025] [Indexed: 02/21/2025] Open
Abstract
OBJECTIVE To explore the clinical phenotypes, characteristics, immunotherapy response, and outcomes of glutamic acid decarboxylase-65 (GAD65) neurological autoimmunity. METHODS We performed a retrospective review of patients diagnosed with GAD65 neurological autoimmunity in the Department of Neurology at Xuanwu Hospital over the past 6 years (2017-2023). The clinical and laboratory data, imaging, therapeutic response, and long-term prognosis of those patients were collected and analyzed. RESULTS Among the 37 patients displaying significant neurological impairment, there were 14 males (37.8%) and 23 females (62.2%), with a median age of onset of 41.5 (25-59) years and a median interval of 9 (1.5-36) months from onset to a definitive diagnosis. Clinical phenotypes included epilepsy (15, 40.5%), limbic encephalitis (7, 18.9%), brainstem dysfunction (2, 5.4%), parkinsonism (2, 5.4%), peripheral neuropathy (3, 8.1%), cerebellar ataxia (1, 2.7%), and overlap syndromes (7, 18.9%). Out of 36 patients who received immunotherapy, the median time from onset to initiation of immunotherapy was 8.5 (1.5-37.5) months. Four cases were lost to follow-up, leaving a median follow-up period of 20.5 (16-37.25) months among the remaining 32 patients. Most patients (26, 81.3%) responded positively to immunotherapy, with some showing mild improvement or no response. Some patients showed inadequate responses to treatments such as mycophenolate mofetil (MMF), but significant improvement is observed after switching to rituximab (RTX). The relationship between the timing of initiating immunotherapy and prognosis by Spearman's rank correlation only showed weak correlation. CONCLUSION The clinical spectrum of GAD65 neurological autoimmunity appeared highly diverse. Immunotherapy can benefit the majority of patients, and early treatment appeared to be associated with good prognosis. RTX may be more effective than MMF; however, this requires more rigorous prospective studies to explore.
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Affiliation(s)
- Zhandong Qiu
- Department of NeurologyXuanwu Hospital Capital Medical University, National Center for Neurological DisordersBeijingChina
| | - Fang Xu
- Department of NeurologyXuanwu Hospital Capital Medical University, National Center for Neurological DisordersBeijingChina
| | - Mengyao Zhang
- Department of NeurologyXuanwu Hospital Capital Medical University, National Center for Neurological DisordersBeijingChina
| | - Xixi Yang
- Department of NeurologyXuanwu Hospital Capital Medical University, National Center for Neurological DisordersBeijingChina
| | - Yan Han
- Department of NeurologyXuanwu Hospital Capital Medical University, National Center for Neurological DisordersBeijingChina
| | - Dawei Li
- Department of NeurologyXuanwu Hospital Capital Medical University, National Center for Neurological DisordersBeijingChina
| | - Liang Liu
- Department of NeurologyXuanwu Hospital Capital Medical University, National Center for Neurological DisordersBeijingChina
| | - Jia Chen
- Department of NeurologyXuanwu Hospital Capital Medical University, National Center for Neurological DisordersBeijingChina
| | - Lehong Gao
- Department of NeurologyXuanwu Hospital Capital Medical University, National Center for Neurological DisordersBeijingChina
| | - Qing Xue
- Department of NeurologyXuanwu Hospital Capital Medical University, National Center for Neurological DisordersBeijingChina
| | - Yue Hou
- Department of NeurologyXuanwu Hospital Capital Medical University, National Center for Neurological DisordersBeijingChina
| | - Ying Sun
- Department of NeurologyXuanwu Hospital Capital Medical University, National Center for Neurological DisordersBeijingChina
| | - Li Di
- Department of NeurologyXuanwu Hospital Capital Medical University, National Center for Neurological DisordersBeijingChina
| | - Chunqiu Fan
- Department of NeurologyXuanwu Hospital Capital Medical University, National Center for Neurological DisordersBeijingChina
| | - Junhua Liang
- Department of NeurologyXuanwu Hospital Capital Medical University, National Center for Neurological DisordersBeijingChina
| | - Yue Han
- Department of NeurologyXuanwu Hospital Capital Medical University, National Center for Neurological DisordersBeijingChina
| | - Huiqing Dong
- Department of NeurologyXuanwu Hospital Capital Medical University, National Center for Neurological DisordersBeijingChina
| | - Junwei Hao
- Department of NeurologyXuanwu Hospital Capital Medical University, National Center for Neurological DisordersBeijingChina
| | - Zheng Liu
- Department of NeurologyXuanwu Hospital Capital Medical University, National Center for Neurological DisordersBeijingChina
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24
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Ishikawa R, Sugimoto T, Ohno N, Iizuka T, Nomura E. A Case of Anti-N-Methyl-D-Aspartate Receptor (NMDAR) Encephalitis With Video-Documented Psychogenic Nonepileptic Seizures (PNES)-Mimicking Episodes Initially Considered as Somatic Symptom Disorder. Cureus 2025; 17:e79384. [PMID: 40130117 PMCID: PMC11931596 DOI: 10.7759/cureus.79384] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 02/20/2025] [Indexed: 03/26/2025] Open
Abstract
Anti-N-methyl-D-aspartate receptor (NMDAR) encephalitis is an autoimmune disorder characterized by psychiatric symptoms, seizures, and dyskinesias. This case report describes a 30-year-old woman who was initially suspected of having a somatic symptom disorder because of the development of seizures mimicking psychogenic non-epileptic seizures (PNES). At presentation, she was able to engage in conversation and follow instructions, but exhibited slight fever, sensory abnormalities, and non-stereotypical seizures. Over the course of two weeks, she fell into a catatonic stupor. Cerebrospinal fluid (CSF) analysis revealed only mild pleocytosis with CSF-restricted oligoclonal bands. Electroencephalogram, which was unremarkable at presentation, subsequently showed an extreme delta brush pattern. NMDAR antibodies were detected in CSF with two independent assays, confirming the diagnosis of anti-NMDAR encephalitis. First-line immunotherapy with steroids, plasma exchange, and immunoglobulins was ineffective, but second-line immunotherapy with cyclophosphamide led to improvement. This case underscores the importance of considering anti-NMDAR encephalitis in patients with PNES-mimicking episodes, which can be misleading and delay appropriate diagnosis and treatment.
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Affiliation(s)
- Ruoyi Ishikawa
- Department of Clinical Neuroscience and Therapeutics, Hiroshima University, Hiroshima, JPN
- Department of Neurology, Hiroshima City Hiroshima Citizens Hospital, Hiroshima, JPN
| | - Takamichi Sugimoto
- Department of Clinical Neuroscience and Therapeutics, Hiroshima University Graduate School of Biomedical and Health Sciences, Hiroshima, JPN
- Department of Neurology, Hiroshima City Hiroshima Citizens Hospital, Hiroshima, JPN
| | - Narumi Ohno
- Department of Clinical Neuroscience and Therapeutics, Hiroshima University Graduate School of Biomedical and Health Sciences, Hiroshima, JPN
- Department of Neurology, Hiroshima City Hiroshima Citizens Hospital, Hiroshima, JPN
| | - Takahiro Iizuka
- Department of Neurology, Kitasato University, School of Medicine, Kanagawa, JPN
| | - Eiichi Nomura
- Department of Neurology, Hiroshima City Hiroshima Citizens Hospital, Hiroshima, JPN
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25
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Kataoka H, Nanaura H, Sugie K. Prognostic factors of subacute comprehensive encephalitis: a retrospective study. ENCEPHALITIS 2025; 5:6-14. [PMID: 39788114 PMCID: PMC11732267 DOI: 10.47936/encephalitis.2024.00136] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/23/2024] [Revised: 11/24/2024] [Accepted: 11/25/2024] [Indexed: 01/12/2025] Open
Abstract
Purpose The etiology of encephalitis is unknown in 40%-50% of cases, so a comprehensive examination of encephalitis would be significant and meaningful. The short-term outcomes in appropriately managed patients are also unknown. Short-term clinical outcomes following onset can provide clinicians with clues regarding the clinical course in the immediate future. We investigated cases of encephalitis, including viral and autoimmune encephalitis, to determine the predictable risk factors that can be assessed to determine a short-term prognosis. Methods We studied 90 patients with encephalitis. Poor and good outcomes were defined as scores of ≥3 and ≤2 on the modified Rankin scale, respectively. Multivariate logistic regression analysis using 19 independent variables was performed. Results Multivariate logistic regression analysis identified cranial magnetic resonance imaging (MRI) lesions (odds ratio [OR], 3.119; 95% confidence interval [CI], 1.166-8.344; p = 0.023) and the need for mechanical ventilation (OR, 4.461; 95% CI, 1.685-11.813; p = 0.003)) as being significantly associated with poor outcomes. In 57 patients with subacute encephalitis presenting with cranial MRI lesions, bilateral lesions on cranial MRI (OR, 5.078; 95% CI, 1.516-17.007; p = 0.008) and the need for mechanical ventilation (OR, 4.461; 95% CI, 1.135-13.584; p = 0.031) were significantly associated with poor outcomes. Conclusion The location of brain lesions, lateral or bilateral, on the initial MRI during the acute phase of encephalitis may be a useful predictor of the outcome during the first 2 months after encephalitis onset, even in cases of encephalitis of unknown etiology.
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Affiliation(s)
- Hiroshi Kataoka
- Department of Neurology, Nara Medical University, Nara, Japan
| | - Hitoki Nanaura
- Department of Neurology, Nara Medical University, Nara, Japan
| | - Kazuma Sugie
- Department of Neurology, Nara Medical University, Nara, Japan
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26
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Thomas T, Lim M. Augmented (diagnostic) Reality: A clinical prediction rule for the early recognition and diagnosis of paediatric NMDA-receptor antibody encephalitis. Eur J Paediatr Neurol 2025; 54:A2. [PMID: 40050192 DOI: 10.1016/j.ejpn.2025.03.003] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 03/28/2025]
Affiliation(s)
- Terrence Thomas
- Neurology Service, Department of Paediatrics, KK Women's and Children's Hospital, Singapore.
| | - Ming Lim
- Children's Neurosciences, Evelina London Children's Hospital at Guy's and St Thomas' NHS Foundation Trust, London, UK; Faculty of Life Sciences and Medicine, King's College London, UK
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27
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Zhou J, Greenfield AL, Loudermilk RP, Bartley CM, Chen C, Chen X, Leroux MA, Lu Y, Necula D, Ngo TT, Tran BT, Honma PS, Lauderdale K, Zhao C, Zhou X, Wang H, Nicoll RA, Wang C, Paz JT, Palop JJ, Wilson MR, Pleasure SJ. Disrupted callosal connectivity underlies long-lasting sensory-motor deficits in an NMDA receptor antibody encephalitis mouse model. J Clin Invest 2024; 135:e173493. [PMID: 39739422 PMCID: PMC11870732 DOI: 10.1172/jci173493] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/25/2023] [Accepted: 12/20/2024] [Indexed: 01/02/2025] Open
Abstract
N-methyl-d-aspartate (NMDA) receptor-mediated autoimmune encephalitis (NMDAR-AE) frequently results in persistent sensory-motor deficits, especially in children, yet the underlying mechanisms remain unclear. This study investigated the long-term effects of exposure to a patient-derived GluN1-specific mAb during a critical developmental period (from postnatal day 3 to day 12) in mice. We observed long-lasting sensory-motor deficits characteristic of NMDAR-AE, along with permanent changes in callosal axons within the primary somatosensory cortex (S1) in adulthood, including increased terminal branch complexity. This complexity was associated with paroxysmal recruitment of neurons in S1 in response to callosal stimulation. Particularly during complex motor tasks, mAb3-treated mice exhibited significantly reduced interhemispheric functional connectivity between S1 regions, consistent with pronounced sensory-motor behavioral deficits. These findings suggest that transient exposure to anti-GluN1 mAb during a critical developmental window may lead to irreversible morphological and functional changes in callosal axons, which could significantly impair sensory-motor integration and contribute to long-lasting sensory-motor deficits. Our study establishes a new model of NMDAR-AE and identifies novel cellular and network-level mechanisms underlying persistent sensory-motor deficits in this context. These insights lay the foundation for future research into molecular mechanisms and the development of targeted therapeutic interventions.
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Affiliation(s)
- Jing Zhou
- Department of Neurology
- Weill Institute for Neurosciences
- Center for Encephalitis and Meningitis, and
| | | | | | - Christopher M. Bartley
- Weill Institute for Neurosciences
- Center for Encephalitis and Meningitis, and
- Department of Psychiatry and Behavioral Sciences, UCSF, San Francisco, California, USA
| | - Chun Chen
- Gladstone Institute of Neurological Disease, San Francisco, California, USA
| | - Xiumin Chen
- Department of Neurology and Institute of Neuroscience of Soochow University, Second Affiliated Hospital of Soochow University, Suzhou, China
- Department of Cellular and Molecular Pharmacology, University of California, San Francisco, California, USA
| | | | - Yujun Lu
- Engineering Research Center of Traditional Chinese Medicine Intelligent Rehabilitation, Ministry of Education, Pudong New Area, Shanghai, China
| | - Deanna Necula
- Gladstone Institute of Neurological Disease, San Francisco, California, USA
- Neuroscience Graduate Program, UCSF, San Francisco, California, USA
| | - Thomas T. Ngo
- Department of Neurology
- Weill Institute for Neurosciences
- Center for Encephalitis and Meningitis, and
| | - Baouyen T. Tran
- Department of Neurology
- Weill Institute for Neurosciences
- Center for Encephalitis and Meningitis, and
| | - Patrick S. Honma
- Gladstone Institute of Neurological Disease, San Francisco, California, USA
- Neuroscience Graduate Program, UCSF, San Francisco, California, USA
| | - Kelli Lauderdale
- Gladstone Institute of Neurological Disease, San Francisco, California, USA
| | - Chao Zhao
- Center for Data Driven Discovery in Biomedicine, Children’s Hospital of Philadelphia, Philadelphia, Pennsylvania, USA
| | | | - Hong Wang
- Department of Neurology
- Weill Institute for Neurosciences
| | - Roger A. Nicoll
- Department of Cellular and Molecular Pharmacology, University of California, San Francisco, California, USA
- Division of Membrane Physiology, Department of Molecular and Cellular Physiology. Department of Physiology, UCSF, San Francisco, California, USA
| | - Cong Wang
- Institute of Rehabilitation, Shanghai Jiao Tong University School of Medicine, Shanghai, China
- Queensland Brain Institute, The University of Queensland, St. Lucia, Brisbane, Australia
| | - Jeanne T. Paz
- Department of Neurology
- Weill Institute for Neurosciences
- Gladstone Institute of Neurological Disease, San Francisco, California, USA
- Neuroscience Graduate Program, UCSF, San Francisco, California, USA
| | - Jorge J. Palop
- Department of Neurology
- Weill Institute for Neurosciences
- Gladstone Institute of Neurological Disease, San Francisco, California, USA
- Neuroscience Graduate Program, UCSF, San Francisco, California, USA
| | - Michael R. Wilson
- Department of Neurology
- Weill Institute for Neurosciences
- Center for Encephalitis and Meningitis, and
| | - Samuel J. Pleasure
- Department of Neurology
- Weill Institute for Neurosciences
- Center for Encephalitis and Meningitis, and
- Programs in Neuroscience and Developmental Stem Cell Biology, Eli and Edythe Broad Center of Regeneration Medicine and Stem Cell Research, Kavli Institute for Fundamental Neuroscience, San Francisco, California, USA
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28
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Miller JS, Rose M, Roell J, Ubhe S, Liu T, Segal BM, Bell EH. A mini review of leveraging biobanking in the identification of novel biomarkers in neurological disorders: insights from a rapid single-cell sequencing pipeline. Front Neurosci 2024; 18:1473917. [PMID: 39777270 PMCID: PMC11703919 DOI: 10.3389/fnins.2024.1473917] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/31/2024] [Accepted: 12/10/2024] [Indexed: 01/11/2025] Open
Abstract
Recent successes in the identification of biomarkers and therapeutic targets for diagnosing and managing neurological diseases underscore the critical need for cutting-edge biobanks in the conduct of high-caliber translational neuroscience research. Biobanks dedicated to neurological disorders are particularly timely, given the increasing prevalence of neurological disability among the rising aging population. Translational research focusing on disorders of the central nervous system (CNS) poses distinct challenges due to the limited accessibility of CNS tissue pre-mortem. Nevertheless, technological breakthroughs, including single-cell and single-nucleus methodologies, offer unprecedented insights into CNS pathophysiology using minimal input such as cerebrospinal fluid (CSF) cells and brain biopsies. Moreover, assays designed to detect factors that are released by CNS resident cells and diffuse into the CSF and/or bloodstream (such as neurofilament light chain [NfL], glial fibrillar acidic protein [GFAP] and amyloid beta peptides), and systemic factors that cross the blood-brain barrier to target CNS-specific molecules (e.g., autoantibodies that bind either the NMDA receptor [NMDAR] or myelin oligodendrocyte glycoprotein [MOG]), are increasingly deployed in clinical research and practice. This review provides an overview of current biobanking practices in neurological disorders and discusses ongoing challenges to biomarker discovery. Additionally, it outlines a rapid consenting and processing pipeline ensuring fresh paired blood and CSF specimens for single-cell sequencing that might more accurately reflect in vivo pathways. In summary, augmenting biobank rigor and establishing innovative research pipelines using patient samples will undoubtedly accelerate biomarker discovery in neurological disorders.
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Affiliation(s)
- Joseph S. Miller
- Heritage College of Osteopathic Medicine, Ohio University, Dublin, OH, United States
- Department of Neurology, College of Medicine, The Ohio State University, Columbus, OH, United States
| | - Michael Rose
- Department of Neurology, College of Medicine, The Ohio State University, Columbus, OH, United States
- Neuroscience Research Institute, College of Medicine, The Ohio State University, Columbus, OH, United States
| | - Jonathan Roell
- Department of Neurology, College of Medicine, The Ohio State University, Columbus, OH, United States
- Neuroscience Research Institute, College of Medicine, The Ohio State University, Columbus, OH, United States
| | - Samruddhi Ubhe
- Department of Neurology, College of Medicine, The Ohio State University, Columbus, OH, United States
- Neuroscience Research Institute, College of Medicine, The Ohio State University, Columbus, OH, United States
| | - Tom Liu
- Department of Neurology, College of Medicine, The Ohio State University, Columbus, OH, United States
- Neuroscience Research Institute, College of Medicine, The Ohio State University, Columbus, OH, United States
| | - Benjamin M. Segal
- Department of Neurology, College of Medicine, The Ohio State University, Columbus, OH, United States
- Neuroscience Research Institute, College of Medicine, The Ohio State University, Columbus, OH, United States
| | - Erica H. Bell
- Department of Neurology, College of Medicine, The Ohio State University, Columbus, OH, United States
- Neuroscience Research Institute, College of Medicine, The Ohio State University, Columbus, OH, United States
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29
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Shen MH. Utility of Oligoclonal Band Testing in Differentiating Immune-Mediated From Infectious Central Nervous System Disorders. J Craniofac Surg 2024:00001665-990000000-02281. [PMID: 39693629 DOI: 10.1097/scs.0000000000011014] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/21/2024] [Accepted: 11/26/2024] [Indexed: 12/20/2024] Open
Abstract
OBJECTIVE This study aimed to evaluate the clinical utility of oligoclonal bands (OCB) in differentiating between immune and infectious diseases of the central nervous system (CNS). METHODS The study enrolled patients hospitalized with suspected autoimmune or infectious CNS disorders between 2021 and 2023. Patients were categorized into diagnostic groups: multiple sclerosis (MS), neuromyelitis optica spectrum disorders (NMOSD), autoimmune encephalitis (AE), and viral encephalitis (VE). Relevant clinical and laboratory data were collected and subjected to comparative analysis. RESULTS Comparative analysis among the 4 groups revealed that the immunoglobulin G (IgG) index of patients in the MS group was significantly higher than that of patients in the NMOSD and VE groups (P < 0.05). The 24-hour intrathecal synthesis rate of IgG also differed significantly between the MS and NMOSD groups, the NMOSD and AE groups, as well as the AE and VE groups (P < 0.05). The positive rate of OCB was significantly higher in the MS group than in the other 3 groups (P < 0.05). Functional abilities, measured by scores of the Modified Rankin Scale (mRS) and the Expanded Disability Status Scale (EDSS), were higher in the immune group than in the infection group at 1-week, 1-month, 6-month, and 1-year post-treatment. Among patients with immune diseases, those who were OCB-positive showed significantly smaller ΔmRS and ΔEDSS at 1-month, 6-month, and 1-year post-treatment compared with patients who were OCB-negative (P < 0.05). CONCLUSION The IgG index and 24-hour intrathecal synthesis rate of IgG served as valuable early indicators for distinguishing between CNS immune and infectious diseases. Positive OCB findings were more common in patients with MS and often associated with poor prognosis and increased risk of disease recurrence.
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Affiliation(s)
- Min-Hui Shen
- Department of Neurology, Jiaxing Second Hospital, Jiaxing, China
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30
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Michalski K, Abdulla T, Kleeman S, Schmidl L, Gómez R, Simorowski N, Vallese F, Prüss H, Heckmann M, Geis C, Furukawa H. Structural and functional mechanisms of anti-NMDAR autoimmune encephalitis. Nat Struct Mol Biol 2024; 31:1975-1986. [PMID: 39227719 PMCID: PMC11921143 DOI: 10.1038/s41594-024-01386-4] [Citation(s) in RCA: 2] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/24/2023] [Accepted: 08/07/2024] [Indexed: 09/05/2024]
Abstract
Autoantibodies against neuronal membrane proteins can manifest in autoimmune encephalitis, inducing seizures, cognitive dysfunction and psychosis. Anti-N-methyl-D-aspartate receptor (NMDAR) encephalitis is the most dominant autoimmune encephalitis; however, insights into how autoantibodies recognize and alter receptor functions remain limited. Here we determined structures of human and rat NMDARs bound to three distinct patient-derived antibodies using single-particle electron cryo-microscopy. These antibodies bind different regions within the amino-terminal domain of the GluN1 subunit. Through electrophysiology, we show that all three autoantibodies acutely and directly reduced NMDAR channel functions in primary neurons. Antibodies show different stoichiometry of binding and antibody-receptor complex formation, which in one antibody, 003-102, also results in reduced synaptic localization of NMDARs. These studies demonstrate mechanisms of diverse epitope recognition and direct channel regulation of anti-NMDAR autoantibodies underlying autoimmune encephalitis.
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Affiliation(s)
- Kevin Michalski
- W.M. Keck Structural Biology Laboratory, Cold Spring Harbor Laboratory, Cold Spring Harbor, NY, USA
| | - Taha Abdulla
- Section Translational Neuroimmunology, Department of Neurology, Jena University Hospital, Jena, Germany
| | - Sam Kleeman
- W.M. Keck Structural Biology Laboratory, Cold Spring Harbor Laboratory, Cold Spring Harbor, NY, USA
- School of Biological Sciences, Cold Spring Harbor Laboratory, Cold Spring Harbor, NY, USA
| | - Lars Schmidl
- Section Translational Neuroimmunology, Department of Neurology, Jena University Hospital, Jena, Germany
| | - Ricardo Gómez
- W.M. Keck Structural Biology Laboratory, Cold Spring Harbor Laboratory, Cold Spring Harbor, NY, USA
| | - Noriko Simorowski
- W.M. Keck Structural Biology Laboratory, Cold Spring Harbor Laboratory, Cold Spring Harbor, NY, USA
| | - Francesca Vallese
- Department of Anesthesiology, Columbia University Irving Medical Center, New York, NY, USA
| | - Harald Prüss
- Department of Neurology and Experimental Neurology, Charité-Universitätsmedizin Berlin, Berlin, Germany
| | - Manfred Heckmann
- Department of Neurophysiology, Institute of Physiology, University of Würzburg, Würzburg, Germany
| | - Christian Geis
- Section Translational Neuroimmunology, Department of Neurology, Jena University Hospital, Jena, Germany
| | - Hiro Furukawa
- W.M. Keck Structural Biology Laboratory, Cold Spring Harbor Laboratory, Cold Spring Harbor, NY, USA.
- School of Biological Sciences, Cold Spring Harbor Laboratory, Cold Spring Harbor, NY, USA.
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31
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Jamet Z, Villega F, Groc L. Diverse anti-NMDAR autoantibodies from individuals with encephalitis. Nat Struct Mol Biol 2024; 31:1821-1823. [PMID: 39604561 DOI: 10.1038/s41594-024-01435-y] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/29/2024]
Affiliation(s)
- Zoe Jamet
- University of Bordeaux, CNRS, Interdisciplinary Institute for Neuroscience, IINS, UMR 5297, Bordeaux, France
| | - Frederic Villega
- University of Bordeaux, CNRS, Interdisciplinary Institute for Neuroscience, IINS, UMR 5297, Bordeaux, France
- Department of Pediatric Neurology, CIC-1401, University Children's Hospital of Bordeaux, Bordeaux, France
| | - Laurent Groc
- University of Bordeaux, CNRS, Interdisciplinary Institute for Neuroscience, IINS, UMR 5297, Bordeaux, France.
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32
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Amiri H, Karimi M, Shariatmadari F. Late relapse of anti-N-methyl-D-aspartate receptor (NMDAR) encephalitis: a case report. J Med Case Rep 2024; 18:575. [PMID: 39609922 PMCID: PMC11605960 DOI: 10.1186/s13256-024-04886-5] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/07/2024] [Accepted: 10/01/2024] [Indexed: 11/30/2024] Open
Abstract
BACKGROUND Anti-N-methyl-D-aspartate receptor encephalitis is a sporadic autoimmune disorder of the brain that presents in a variety of neuropsychiatric manifestations, including seizures, psychosis, and alterations in behavior. N-methyl-D-aspartate receptor is primarily seen in young females. Although this disease can be treated, it can relapse in rare cases. Relapsing typically occurs within the early years following the initial episode and is exceedingly rare after 5 years. CASE PRESENTATION In this case study, we report on a 16-year-old Iranian female experiencing a relapse of anti-N-methyl-D-aspartate receptor encephalitis 8 years after her initial diagnosis. She was admitted to the hospital with dysphasia (a speech disorder) and dyslexia (reading and writing impairment). A thorough clinical evaluation revealed the presence of anti-glutamate receptor type N-methyl-D-aspartate receptor antibodies in her serum and cerebrospinal fluid, confirming the diagnosis. Following treatment with immunotherapy and plasmapheresis, she made a complete recovery. CONCLUSION This case of relapsing anti-N-methyl-D-aspartate receptor encephalitis, occurring more than 5 years after the initial episode, is exceptionally rare. This late relapse underscores the importance of long-term follow-up for patients with this condition.
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Affiliation(s)
- Hamidreza Amiri
- Student Research Committee, Arak University of Medical Sciences, Arak, Iran
| | - Mehdi Karimi
- Faculty of Medicine, Bogomolets National Medical University, Kyiv, Ukraine.
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Greco G, Risi M, Masciocchi S, Businaro P, Rigoni E, Zardini E, Scaranzin S, Morandi C, Diamanti L, Foiadelli T, Giannoccaro MP, Morelli L, Liguori R, Barone P, Tozzo A, Passarini A, Gelibter S, Patti F, Banfi P, Simone AM, Bisecco A, Ruggieri M, Maimone D, Bruno G, Siliquini S, Bova S, Di Filippo M, Lanzillo R, Gallo A, Colombo E, Franciotta D, Gastaldi M. Clinical, prognostic and pathophysiological implications of MOG-IgG detection in the CSF: the importance of intrathecal MOG-IgG synthesis. J Neurol Neurosurg Psychiatry 2024; 95:1176-1186. [PMID: 38844341 DOI: 10.1136/jnnp-2024-333554] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/02/2024] [Accepted: 05/17/2024] [Indexed: 11/20/2024]
Abstract
BACKGROUND Cerebrospinal fluid myelin oligodendrocyte glycoprotein IgG (CSF MOG-IgG) are found in a proportion of patients with MOG antibody-associated disorder (MOGAD) and have been associated with severe disease presentations. However, most studies did not systematically investigate the role of MOG-IgG intrathecal synthesis (ITS). METHODS We retrospectively studied 960 consecutive patients with paired serum and CSF samples screened for MOG-IgG using a live cell-based assays. MOG-IgG-specific antibody index (AIMOG) was systematically calculated using serum and CSF titres to assess MOG-IgG ITS, and clinical features were compared between MOG-IgG CSF+/CSF- and ITS+/ITS- patients. RESULTS MOG-IgG were found in 55/960 patients (5.7%; serum+/CSF-: 58.2%, serum+/CSF+: 34.5%; serum-/CSF+: 7.3%). Serum/CSF MOG-IgG titres showed a moderate correlation in patients without ITS (ρ=0.47 (CI 0.18 to 0.68), p<0.001), but not in those with ITS (ρ=0.14 (CI -0.46 to -0.65), p=0.65). There were no clinical-paraclinical differences between MOG-IgG CSF+ vs CSF- patients. Conversely, patients with MOG-IgG ITS showed pyramidal symptoms (73% vs 32%, p=0.03), spinal cord involvement (82% vs 39%, p=0.02) and severe outcome at follow-up (36% vs 5%, p=0.02) more frequently than those without MOG-IgG ITS. A multivariate logistic regression model indicated that MOG-IgG ITS was an independent predictor of a poor outcome (OR: 14.93 (CI 1.40 to 19.1); p=0.03). AIMOG correlated with Expanded Disability Status Scale (EDSS) scores at disease nadir and at last follow-up (p=0.02 and p=0.01). CONCLUSIONS Consistently with physiopathology, MOG-IgG ITS is a promising prognostic factor in MOGAD, and its calculation could enhance the clinical relevance of CSF MOG-IgG testing, making a case for its introduction in clinical practice.
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Affiliation(s)
- Giacomo Greco
- Department of Brain and Behavioural Sciences, University of Pavia, Pavia, Italy
- Multiple Sclerosis Centre, IRCCS Mondino Foundation, Pavia, Italy
| | - Mario Risi
- Department of Advanced Medical and Surgical Sciences, University of Campania Luigi Vanvitelli, Napoli, Italy
| | - Stefano Masciocchi
- Department of Brain and Behavioural Sciences, University of Pavia, Pavia, Italy
- Neuroimmunology Laboratory, IRCCS Mondino Foundation, Pavia, Italy
| | - Pietro Businaro
- Department of Brain and Behavioural Sciences, University of Pavia, Pavia, Italy
- Neuroimmunology Laboratory, IRCCS Mondino Foundation, Pavia, Italy
| | - Eleonora Rigoni
- Multiple Sclerosis Centre, IRCCS Mondino Foundation, Pavia, Italy
| | - Elisabetta Zardini
- Department of Brain and Behavioural Sciences, University of Pavia, Pavia, Italy
- Neuroimmunology Laboratory, IRCCS Mondino Foundation, Pavia, Italy
| | - Silvia Scaranzin
- Neuroimmunology Laboratory, IRCCS Mondino Foundation, Pavia, Italy
| | - Chiara Morandi
- Neuroimmunology Laboratory, IRCCS Mondino Foundation, Pavia, Italy
| | - Luca Diamanti
- Neuroncology and Neuroinflammation Unit, IRCCS Mondino Foundation, Pavia, Italy
| | - Thomas Foiadelli
- Clinica Pediatrica, Fondazione IRCCS Policlinico San Matteo, University of Pavia, Pavia, Italy
| | - Maria Pia Giannoccaro
- Department of Biomedical and Neuromotor Sciences, University of Bologna, Bologna, Italy
- IRCCS Istituto Delle Scienze Neurologiche di Bologna, Bologna, Italy
| | - Luana Morelli
- IRCCS Istituto Delle Scienze Neurologiche di Bologna, Bologna, Italy
| | - Rocco Liguori
- Department of Biomedical and Neuromotor Sciences, University of Bologna, Bologna, Italy
- IRCCS Istituto Delle Scienze Neurologiche di Bologna, Bologna, Italy
| | - Paolo Barone
- Neurology Unit, University Hospital 'San Giovanni di Dio e Ruggi d'Aragona', Salerno, Italy
| | - Alessandra Tozzo
- Department of Pediatric Neuroscience, Foundation IRCCS Carlo Besta Neurological Institute, Milano, Italy
| | - Alice Passarini
- Child Neuropsychiatry Unit, ASST Grande Ospedale Metropolitano Niguarda, Milano, Italy
| | - Stefano Gelibter
- Department of Neurosciences, Neurology and Stroke Unit, ASST Grande Ospedale Metropolitano Niguarda, Milano, Italy
| | - Francesco Patti
- University of Catania, Department of Surgical and Medical Sciences and Advanced Technologies 'G.F. Ingrassia', Catania, Italy
- UOS Sclerosi Multipla, Gaspare Rodolico Hospital, Catania, Italy
| | - Paola Banfi
- Neurology and Stroke Unit, Ospedale di Circolo/Fondazione Macchi, ASST Sette Laghi, Varese, Italy
| | | | - Alvino Bisecco
- Department of Advanced Medical and Surgical Sciences, University of Campania Luigi Vanvitelli, Napoli, Italy
| | - Martino Ruggieri
- Department of Clinical and Experimental Medicine, Section of Pediatrics and Child Neuropsychiatry, University of Catania, Catania, Italy
| | - Davide Maimone
- Centro Sclerosi Multipla, UOC Neurologia, Azienda Ospedaliera ARNAS Garibaldi, Catania, Italy
| | - Giorgia Bruno
- Department of Advanced Medical and Surgical Sciences, University of Campania Luigi Vanvitelli, Napoli, Italy
- Pediatric Neurology Unit, Department of Neurosciences, Santobono Pausilipon Azienda Ospedaliera Pediatrica, Napoli, Italy
| | - Sabrina Siliquini
- Child Neurology and Psychiatry Unit, 'G. Salesi' Children's Hospital, Azienda Ospedaliero Universitaria delle Marche, Ancona, Italy
| | - Stefania Bova
- Pediatric Neurology Unit, Buzzi Children's Hospital, Milano, Italy
| | - Massimiliano Di Filippo
- Section of Neurology, University of Perugia, Department of Medicine and Surgery, Perugia, Italy
| | - Roberta Lanzillo
- Department of Neurosciences and Reproductive and Odontostomatological Sciences, University of Naples Federico II, Napoli, Italy
| | - Antonio Gallo
- Department of Advanced Medical and Surgical Sciences, University of Campania Luigi Vanvitelli, Napoli, Italy
| | - Elena Colombo
- Multiple Sclerosis Centre, IRCCS Mondino Foundation, Pavia, Italy
| | - Diego Franciotta
- Neuroimmunology Laboratory, IRCCS Mondino Foundation, Pavia, Italy
| | - Matteo Gastaldi
- Neuroimmunology Laboratory, IRCCS Mondino Foundation, Pavia, Italy
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Lai R, Wu Z, Wang H, Feng L, Sun X, Shen C, Feng H, Zhou H. Ofatumumab treatment for severe refractory anti-NMDAR encephalitis: A case series. J Neuroimmunol 2024; 396:578458. [PMID: 39277986 DOI: 10.1016/j.jneuroim.2024.578458] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/20/2024] [Revised: 08/22/2024] [Accepted: 09/10/2024] [Indexed: 09/17/2024]
Abstract
Rituximab is recommended as the preferred second-line immunotherapy for autoimmune encephalitis (AE). However, Ofatumumab (OFA), a novel fully human anti-CD20 antibody, has been reported infrequently in patients with AE. Among the various forms of AE, anti-N-methyl-d-aspartate receptor (anti-NMDAR) encephalitis is the most common and severe. This study presents three cases of severe anti-NMDAR encephalitis treated with OFA following the failure of first-line immunotherapy. The results indicated that the patients experienced no significant adverse reactions after receiving OFA, and their clinical symptoms improved markedly within one week of treatment. One month post-treatment with OFA, scores on the Glasgow Coma Scale (GCS) and the Barthel Index of Activities of Daily Living (Barthel-ADL) increased, while scores on the modified Rankin Scale (mRS), Clinical Assessment Scale in Autoimmune Encephalitis (CASE), and Paroxysmal Sympathetic Hyperactivity Assessment Measure (PSH-AM) decreased. During the three-month and six-month follow-up periods, patients exhibited further symptomatic improvement, suggesting that OFA is a safe and effective treatment option for anti-NMDAR encephalitis. These findings propose a novel therapeutic strategy for severe refractory anti-NMDAR encephalitis.
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Affiliation(s)
- Rong Lai
- Department of Neurology, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, People's Republic of China; Guangdong Provincial Key Laboratory of Diagnosis and Treatment of Major Neurological Diseases, National Key Clinical Department and Key Discipline of Neurology, Guangzhou, People's Republic of China
| | - Zichao Wu
- Department of Neurology, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, People's Republic of China; Guangdong Provincial Key Laboratory of Diagnosis and Treatment of Major Neurological Diseases, National Key Clinical Department and Key Discipline of Neurology, Guangzhou, People's Republic of China
| | - Haiyan Wang
- Department of Neurology, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, People's Republic of China; Guangdong Provincial Key Laboratory of Diagnosis and Treatment of Major Neurological Diseases, National Key Clinical Department and Key Discipline of Neurology, Guangzhou, People's Republic of China
| | - Li Feng
- Department of Neurology, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, People's Republic of China; Guangdong Provincial Key Laboratory of Diagnosis and Treatment of Major Neurological Diseases, National Key Clinical Department and Key Discipline of Neurology, Guangzhou, People's Republic of China
| | - Xunsha Sun
- Department of Neurology, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, People's Republic of China; Guangdong Provincial Key Laboratory of Diagnosis and Treatment of Major Neurological Diseases, National Key Clinical Department and Key Discipline of Neurology, Guangzhou, People's Republic of China
| | - Cunzhou Shen
- Department of Neurology, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, People's Republic of China; Guangdong Provincial Key Laboratory of Diagnosis and Treatment of Major Neurological Diseases, National Key Clinical Department and Key Discipline of Neurology, Guangzhou, People's Republic of China
| | - Huiyu Feng
- Department of Neurology, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, People's Republic of China; Guangdong Provincial Key Laboratory of Diagnosis and Treatment of Major Neurological Diseases, National Key Clinical Department and Key Discipline of Neurology, Guangzhou, People's Republic of China
| | - Hongyan Zhou
- Department of Neurology, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, People's Republic of China; Guangdong Provincial Key Laboratory of Diagnosis and Treatment of Major Neurological Diseases, National Key Clinical Department and Key Discipline of Neurology, Guangzhou, People's Republic of China.
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Guasp M, Dalmau J. Predicting the future of autoimmune encephalitides. Rev Neurol (Paris) 2024; 180:862-875. [PMID: 39277478 DOI: 10.1016/j.neurol.2024.08.003] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/14/2024] [Revised: 07/25/2024] [Accepted: 08/02/2024] [Indexed: 09/17/2024]
Abstract
The concept that many neurologic and psychiatric disorders of unknown cause are immune-mediated has evolved fast during the past 20 years. The main contribution to the expansion of this field has been the discovery of antibodies that attack neuronal or glial cell-surface proteins or receptors, directly modifying their structure and function. These antibodies facilitate the diagnosis and prompt treatment of patients who often improve with immunotherapy. The identification of this group of diseases, collectively named "autoimmune encephalitides", was preceded by many years of investigations on other autoimmune CNS disorders in which the antibodies are against intracellular proteins, occur more frequently with cancer, and associate with cytotoxic T-cell responses that are less responsive to immunotherapy. Here, we first trace the recent history of the autoimmune encephalitides and address how to assess the clinical value and implement in our practice the rapid pace of autoantibody discovery. In addition, we review recent developments in the post-acute stage of the two main autoimmune encephalitides (NMDAR and LGI1) focusing on symptoms that are frequently overlooked or missed, and therefore undertreated. Because a better understanding of the pathophysiology of these diseases relies on animal models, we examine currently available studies, recognizing the existing needs for better and all-inclusive neuro-immunobiological models. Finally, we assess the status of biomarkers of disease outcome, clinical scales, current treatment strategies, and emerging therapies including CAR T-cell technology. Altogether, this overview is intended to identify gaps of knowledge and provide suggestions for improvement and insights for future research.
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Affiliation(s)
- M Guasp
- Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS)-CaixaResearch Institute, Barcelona, Spain; Hospital Clínic de Barcelona, Universitat de Barcelona, Barcelona, Spain; Centro de Investigación Biomédica en Red, Enfermedades Raras (CIBERER), Madrid, Spain
| | - J Dalmau
- Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS)-CaixaResearch Institute, Barcelona, Spain; Hospital Clínic de Barcelona, Universitat de Barcelona, Barcelona, Spain; Centro de Investigación Biomédica en Red, Enfermedades Raras (CIBERER), Madrid, Spain; Department of Neurology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.
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Cai L, Li G, Abdulaziz AT, Gong X, Liu X, Kong X, Guo K, Li A, Li J, Zhou D, Hong Z. Efficacy and safety of different oral prednisone tapering courses in adult anti-NMDAR encephalitis: A multicenter prospective cohort study. Epilepsia 2024; 65:3199-3215. [PMID: 39324872 DOI: 10.1111/epi.18107] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/12/2024] [Revised: 08/16/2024] [Accepted: 08/16/2024] [Indexed: 09/27/2024]
Abstract
OBJECTIVE In adult anti-N-methyl-d-aspartate receptor (NMDAR) encephalitis, corticosteroids are commonly used as first-line treatment. However, the optimal oral prednisone tapering (OPT) following intravenous methylprednisolone pulse therapy remains unclear. We aim to compare the efficacy and safety of different OPT courses in anti-NMDAR encephalitis. METHODS The CHASE study, a multicenter prospective observational cohort study, enrolled patients with autoimmune encephalitis from October 2011 to March 2023. Patients were grouped based on oral prednisone tapering course: ≤3 months (Group ≤3 month), 3-6 months (Group 3-6 months, including 3 months), and >6 months (Group > 6 months). Kaplan-Meier plots were used to analyze time to relapse and time to total recovery within 2 years. RESULTS Among 666 screened patients, 171 (median [IQR] age 27 [21.0-36.5] years, 55.0% female) met selection criteria. Responders at 3 months were prevalent in Group ≤3 months (OR 7.251 [95% CI 2.252 to 23.344] and Group 3-6 months (OR, 3.857 [95% CI 1.107 to 13.440] than in Group >6 months. Clinical Assessment Scale for Autoimmune Encephalitis (CASE) scores at 12 months were higher in Group >6 months than in Group ≤3 months and Group 3-6 months (β, -2.329 [95% CI -3.784 to -.875]; β, -2.871 [95% CI -4.490, -1.253]). CASE seizures subscore was higher in Group >6 months than in Group 3-6 months (β, -.452 [95% CI -.788 to -.116]). No significant difference in seizure freedom rates among the groups. Adverse events were higher in Group 3-6 months and Group >6 months than in Group ≤3 months (OR 6.045 [95% CI 2.352 to 15.538]; OR 6.782 [95% CI 1.911 to 24.073]). SIGNIFICANCE Longer oral prednisone courses for adult patients with anti-NMDAR encephalitis did not show superior effects compared to shorter courses in improving modified Rankin Scale (mRS) scores and CASE scores, reducing the risk of relapse within 2 years, or achieving seizure freedom. Instead, extended prednisone courses may lead to more side effects- particularly weight gain. This outcome recommends evaluating the possibility of shortening the duration of oral prednisone after a thorough patient assessment.
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Affiliation(s)
- Linjun Cai
- Department of Neurology, West China Hospital of Sichuan University, Chengdu, Sichuan, China
| | - Gaowei Li
- Department of Neurosurgery, West China Hospital, Sichuan University, Chengdu, Sichuan, China
| | - Ammar T Abdulaziz
- Department of Neurology, West China Hospital of Sichuan University, Chengdu, Sichuan, China
| | - Xue Gong
- Department of Neurology, West China Hospital of Sichuan University, Chengdu, Sichuan, China
| | - Xu Liu
- Department of Neurology, West China Hospital of Sichuan University, Chengdu, Sichuan, China
| | - Xueying Kong
- Department of Neurology, West China Hospital of Sichuan University, Chengdu, Sichuan, China
| | - Kundian Guo
- Department of Neurology, West China Hospital of Sichuan University, Chengdu, Sichuan, China
| | - Aiqing Li
- Department of Neurology, West China Hospital of Sichuan University, Chengdu, Sichuan, China
| | - Jinmei Li
- Department of Neurology, West China Hospital of Sichuan University, Chengdu, Sichuan, China
| | - Dong Zhou
- Department of Neurology, West China Hospital of Sichuan University, Chengdu, Sichuan, China
- Institute of Brain Science and Brain-Inspired Technology of West China Hospital, Sichuan University, Chengdu, Sichuan, China
- Department of Neurology, West China Tianfu Hospital of Sichuan University, Chengdu, Sichuan, China
- Department of Neurology, Chengdu Shangjin Nanfu Hospital, Chengdu, Sichuan, China
| | - Zhen Hong
- Department of Neurology, West China Hospital of Sichuan University, Chengdu, Sichuan, China
- Institute of Brain Science and Brain-Inspired Technology of West China Hospital, Sichuan University, Chengdu, Sichuan, China
- Department of Neurology, Chengdu Shangjin Nanfu Hospital, Chengdu, Sichuan, China
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Desbaillets NP, Hottinger AF. Cancer Therapy-Induced Encephalitis. Cancers (Basel) 2024; 16:3571. [PMID: 39518012 PMCID: PMC11545540 DOI: 10.3390/cancers16213571] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/30/2024] [Revised: 10/17/2024] [Accepted: 10/19/2024] [Indexed: 11/16/2024] Open
Abstract
Encephalitis associated with cancer therapies is a rare but serious complication that can significantly impact patients' quality of life and it requires prompt identification and management. Over the past two decades, immunotherapy-particularly immune checkpoint inhibitors-has become a cornerstone of cancer treatment, with up to half of metastatic cancer patients in economically developed countries now receiving these therapies. The widespread adoption of immunotherapy has led to improved survival rates and long-term remissions, even in patients with advanced metastatic disease. However, as immune modulators, these therapies can trigger a range of immune-related adverse events, including a variety of novel neurological toxicities. Among these, encephalitis is of particular concern due to its potential severity, which can compromise treatment outcomes. This review aims to provide a comprehensive overview of the literature on this condition, highlighting optimal diagnostic strategies and management approaches to mitigate the risk of significant morbidity, while also comparing encephalitis induced by immunotherapy with that caused by traditional chemotherapies and targeted oncologic treatments.
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Affiliation(s)
- Nicolas P. Desbaillets
- Department of Oncology, Centre Hospitalier Universitaire Vaudois (CHUV), Lausanne University, 1011 Lausanne, Switzerland
- Lundin Family Brain Tumor Research Centre, Centre Hospitalier Universitaire Vaudois (CHUV), Lausanne University, 1011 Lausanne, Switzerland
| | - Andreas F. Hottinger
- Department of Oncology, Centre Hospitalier Universitaire Vaudois (CHUV), Lausanne University, 1011 Lausanne, Switzerland
- Lundin Family Brain Tumor Research Centre, Centre Hospitalier Universitaire Vaudois (CHUV), Lausanne University, 1011 Lausanne, Switzerland
- Department of Clinical Neurosciences, Centre Hospitalier Universitaire Vaudois (CHUV), Lausanne University, 1011 Lausanne, Switzerland
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Xue H, Hu J, Chen Y, Huang W, Liu H, Xu H, Shi M. Anti-NMDAR encephalitis with delayed ovarian teratoma in a young woman: a case report with 5 years of follow-up. BMC Neurol 2024; 24:377. [PMID: 39375580 PMCID: PMC11460029 DOI: 10.1186/s12883-024-03891-x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/01/2024] [Accepted: 09/30/2024] [Indexed: 10/09/2024] Open
Abstract
BACKGROUND Anti-N-methyl-D-aspartate receptor (NMDAR) encephalitis is an autoimmune disorder with a variety of clinical manifestations. It has been established that anti-NMDAR encephalitis may be related to ovarian teratoma in female patients. However, a considerable number of patients have no obvious evidence of ovarian teratoma during the onset of the disease. CASE A 25-year-old previously-healthy female experienced a series of acute symptoms within two days, including confusion, disorientation, short-term memory loss, auditory hallucinations, abnormal behavior, refractory status epilepticus, etc. Her brain MRI and abdominal imaging showed no definite abnormality while her electroencephalogram exhibited the presence of low to moderate amplitude sharp, spike, and multi-spike waves. Serum and cerebrospinal fluid tests yielded positive results for anti-NMDAR antibodies. However, an ultrasound scan failed to identify an ovarian teratoma. Consequently, the diagnosis of anti-NMDAR encephalitis without teratoma was made after 4 days onset. After the plasma exchange and immunoglobulin therapy, her neurological symptoms improved and obtained a clinical cure. In the next eight months of follow-up, the patient accidentally touched a lump in the lower abdomen without any symptoms, and abdominal ultrasound and CT scan revealed a left ovarian tumor. Then she underwent left ovarian teratoma resection surgery and histopathology showed a mature cystic teratoma with neural components. The patient continued to receive five years of follow-up, and her condition remained stable without any recurrence, except that there had been a low titer of anti-NMDAR antibody in her serum. CONCLUSION Our case demonstrated the importance of long-term follow-up for female patients with anti-NMDAR encephalitis, since anti-NMDAR encephalitis-associated ovarian teratomas may develop in a delayed manner, even without any symptoms.
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Affiliation(s)
- Hailong Xue
- Department of Neurology, 987th Hospital of PLA Joint Service Support Force, No. 45 Dongfeng Street, Baoji, Shaanxi Province, 721015, China
| | - Junhao Hu
- Department of Neurology, 987th Hospital of PLA Joint Service Support Force, No. 45 Dongfeng Street, Baoji, Shaanxi Province, 721015, China
- Department of Neurology, Xijing Hospital, Air Force Medical University, No. 15 Changle West Street, Xi'an, Shaanxi Province, 710032, China
| | - Yingge Chen
- Department of Neurology, 987th Hospital of PLA Joint Service Support Force, No. 45 Dongfeng Street, Baoji, Shaanxi Province, 721015, China
| | - Wenbin Huang
- Department of Neurology, 987th Hospital of PLA Joint Service Support Force, No. 45 Dongfeng Street, Baoji, Shaanxi Province, 721015, China
| | - Haoling Liu
- Department of Neurology, 987th Hospital of PLA Joint Service Support Force, No. 45 Dongfeng Street, Baoji, Shaanxi Province, 721015, China
| | - Hongli Xu
- Department of Neurology, 987th Hospital of PLA Joint Service Support Force, No. 45 Dongfeng Street, Baoji, Shaanxi Province, 721015, China
| | - Ming Shi
- Department of Neurology, Xijing Hospital, Air Force Medical University, No. 15 Changle West Street, Xi'an, Shaanxi Province, 710032, China.
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Chen J, Qin M, Xiang X, Guo X, Nie L, Mao L. Lymphocytes in autoimmune encephalitis: Pathogenesis and therapeutic target. Neurobiol Dis 2024; 200:106632. [PMID: 39117118 DOI: 10.1016/j.nbd.2024.106632] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/18/2024] [Revised: 08/04/2024] [Accepted: 08/04/2024] [Indexed: 08/10/2024] Open
Abstract
Autoimmune encephalitis (AE) is an inflammatory disease of the central nervous system characterized by the production of various autoimmune antibodies targeting neuronal proteins. The pathogenesis of AE remains elusive. Accumulating evidence suggests that lymphocytes, particularly B and T lymphocytes, play an integral role in the development of AE. In the last two decades, autoimmune neural antibodies have taken center stage in diagnosing AE. Recently, increasing evidence has highlighted the importance of T lymphocytes in the onset of AE. CD4+ T cells are thought to influence disease progression by secreting associated cytokines, whereas CD8+ T cells exert a cytotoxic role, causing irreversible damage to neurons mainly in patients with paraneoplastic AE. Conventionally, the first-line treatments for AE include intravenous steroids, intravenous immunoglobulin, and plasma exchange to remove pathogenic autoantibodies. However, a minority of patients are insensitive to conventional first-line treatment protocols and suffer from disease relapse, a condition referred to as refractory AE. In recent years, new treatments, such as rituximab or CAAR-T, which target pathogenic lymphocytes in patients with AE, have offered new therapeutic options for refractory AE. This review aims to describe the current knowledge about the function of B and T lymphocytes in the pathophysiology of AE and to summarize and update the immunotherapy options for treating this disease.
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Affiliation(s)
- Jiaojiao Chen
- Department of Neurology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China
| | - Mengting Qin
- Department of Neurology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China
| | - Xuying Xiang
- Department of Neurology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China
| | - Xiaoqing Guo
- Department of Neurology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China
| | - Lei Nie
- Department of Neurology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China
| | - Ling Mao
- Department of Neurology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China.
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Bokhari SFH, I Kh Almadhoun MK, Khan MU, Ahmad S, Awan M, Imran MM, Bashir M, Tariq MR, Imran M, Khalid MO. Emerging Biomarkers for the Early Detection of Autoimmune Encephalitis: A Narrative Review. Cureus 2024; 16:e69038. [PMID: 39391424 PMCID: PMC11464805 DOI: 10.7759/cureus.69038] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 09/09/2024] [Indexed: 10/12/2024] Open
Abstract
Autoimmune encephalitis (AE) is a rare yet critical neurological disorder characterized by inflammation of the brain, typically triggered by an abnormal immune response. The early detection and diagnosis of AE are crucial for effective treatment and improved patient outcomes. However, the diagnostic process is often complicated by the diverse clinical presentations of AE, which can mimic other neurological and psychiatric conditions. Currently, diagnosis relies on a combination of clinical evaluation, neuroimaging, cerebrospinal fluid analysis, and the detection of specific autoantibodies. Despite advances in these areas, challenges remain, particularly in cases where patients are seronegative or present with nonspecific symptoms. This narrative review provides a comprehensive overview of emerging biomarkers for the early detection of AE, highlighting their potential to enhance diagnostic accuracy and speed. We explore a variety of biomarkers, including novel autoantibodies, inflammatory markers, cytokines, and neuronal damage indicators, and discuss their clinical implications. This review emphasizes the need for biomarkers that are not only sensitive and specific but also accessible and rapid to facilitate earlier diagnosis and treatment. By synthesizing current research, this review aims to contribute to the ongoing efforts to refine the diagnostic approach to AE, ultimately improving outcomes for patients affected by this challenging condition.
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Affiliation(s)
| | | | - Muhammad U Khan
- Medicine and Surgery, King Edward Medical University, Lahore, PAK
| | - Shahzad Ahmad
- Cardiac Surgery, Liaquat National Hospital, Karachi, PAK
| | - Manahil Awan
- Executive and Special Ward, Liaquat National Hospital, Karachi, PAK
| | | | - Muhammad Bashir
- Medicine and Surgery, Jinnah Medical and Dental College, Karachi, PAK
| | | | - Minahil Imran
- Medicine and Surgery, King Edward Medical University, Lahore, PAK
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Pavăl D, Gherghel-Pavăl N, Căpățînă OO, Stan A, Raduly L, Budișan L, Micluția IV. Neural Antibodies in First-episode Psychosis Patients with Warning Signs for Autoimmune Encephalitis. CLINICAL PSYCHOPHARMACOLOGY AND NEUROSCIENCE : THE OFFICIAL SCIENTIFIC JOURNAL OF THE KOREAN COLLEGE OF NEUROPSYCHOPHARMACOLOGY 2024; 22:520-530. [PMID: 39069692 PMCID: PMC11289598 DOI: 10.9758/cpn.24.1164] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 01/02/2024] [Revised: 02/28/2024] [Accepted: 03/20/2024] [Indexed: 07/30/2024]
Abstract
Objective : Autoimmune encephalitis (AE) remains an essential differential diagnosis in patients with first-episode psychosis (FEP). In this study, we aimed to assess to prevalence of AE in a cohort of FEP patients. Methods : We used a phenotype-driven algorithm to detect AE in patients with FEP. Initially, we screened patients for warning signs with a low or high pre-test probability for AE, defined as "yellow" and "red flags", respectively. In the next step, patients with red flags underwent cerebrospinal fluid analysis (including neural antibodies), while patients with yellow flags underwent tests for serum neural antibodies, electroencephalography, and brain magnetic resonance imaging. Results : We screened 78 patients with FEP and found that eight (10.3%) had at least one warning sign for AE: four (5.13%) patients had at least one red flag, while four (5.13%) had only yellow flags. Among these, two patients (2.56%) had anti-N-methyl-D-aspartate receptor encephalitis, while the remaining six (7.69%) received a primary psychiatric disorder diagnosis. Conclusion : Our study highlights the importance of considering AE in the differential diagnosis of FEP.
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Affiliation(s)
- Denis Pavăl
- Department of Psychiatry, Iuliu Hațieganu University of Medicine and Pharmacy, Cluj-Napoca, Romania
- Romanian Association for Autoimmune Encephalitis, Cluj-Napoca, Romania
| | | | - Octavia Oana Căpățînă
- Department of Psychiatry, Iuliu Hațieganu University of Medicine and Pharmacy, Cluj-Napoca, Romania
- Romanian Association for Autoimmune Encephalitis, Cluj-Napoca, Romania
| | - Adina Stan
- Department of Neurology, Iuliu Hațieganu University of Medicine and Pharmacy, Cluj-Napoca, Romania
| | - Lajos Raduly
- Research Center for Functional Genomics, Biomedicine and Translational Medicine, Iuliu Hațieganu University of Medicine and Pharmacy, Cluj-Napoca, Romania
| | - Liviuța Budișan
- Research Center for Functional Genomics, Biomedicine and Translational Medicine, Iuliu Hațieganu University of Medicine and Pharmacy, Cluj-Napoca, Romania
| | - Ioana Valentina Micluția
- Department of Psychiatry, Iuliu Hațieganu University of Medicine and Pharmacy, Cluj-Napoca, Romania
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Søgaard A, Poulsen CA, Belhouche NZ, Thybo A, Hovet STF, Larsen L, Nilsson C, Blaabjerg M, Nissen MS. Post-Herpetic Anti-NMDAR Encephalitis in Denmark: Current Status and Future Challenges. Biomedicines 2024; 12:1953. [PMID: 39335467 PMCID: PMC11429063 DOI: 10.3390/biomedicines12091953] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/28/2024] [Revised: 08/18/2024] [Accepted: 08/22/2024] [Indexed: 09/30/2024] Open
Abstract
It is well known that N-methyl-D-aspartate receptor encephalitis (NMDARE) can be triggered by infectious encephalitis such as herpes simplex virus 1 encephalitis (HSE). However, the incidence of post-HSE NMDARE in Denmark is unknown. We reviewed literature cases and compared these to retrospectively identified cases of post-HSE NMDARE in Denmark, using a national cohort database of autoimmune encephalitis (AE) and two regional databases of infectious encephalitis patients. We identified 80 post-HSE NMDARE cases in the literature, 66% being children, who more often presented movement disorders, decreased consciousness, and sleep disturbances compared to adults. Eight patients with post-HSE NMDARE were identified from the national cohort database of AE, none being children. Forty-four HSE patients were identified from the regional infectious encephalitis databases. Of these, 16 (36%) fulfilled the Graus criteria for probable/definite NMDARE, and eight (18%) presented a prolonged/relapsing disease course. Ten (23%) were tested for AE during hospitalization. Six (14%) had leftover cerebrospinal fluid available for retrospective autoantibody testing. One out of these six patients (17%) harbored NMDARE antibodies. Thus, in total, nine post-HSE NMDARE patients have been identified in Denmark from 2009 to 2021. Comparing the adult Danish patients to the literature, Danish patients were older, but the clinical phenotype and paraclinical findings were similar. Overall, the incidence of adult post-HSE NMDARE in the Region of Southern Denmark was 0.17 per million people per year and only 7% of adult HSE patients in the region were diagnosed with post-HSE NMDARE. Our findings suggest that adult patients are still underdiagnosed and the absence of pediatric cases diagnosed with post-HSE NMDARE in Denmark is highly concerning.
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Affiliation(s)
- Anna Søgaard
- Department of Clinical Research, University of Southern Denmark, 5230 Odense, Denmark
| | | | | | - Alberte Thybo
- Department of Clinical Research, University of Southern Denmark, 5230 Odense, Denmark
| | - Siv Tonje Faret Hovet
- Department of Clinical Research, University of Southern Denmark, 5230 Odense, Denmark
| | - Lykke Larsen
- Department of Clinical Research, University of Southern Denmark, 5230 Odense, Denmark
- Department of Infectious Medicine, Odense University Hospital, 5000 Odense, Denmark
| | - Christine Nilsson
- Department of Clinical Research, University of Southern Denmark, 5230 Odense, Denmark
- Department of Clinical Immunology, Odense University Hospital, 5000 Odense, Denmark
| | - Morten Blaabjerg
- Department of Clinical Research, University of Southern Denmark, 5230 Odense, Denmark
- Department of Neurology, Odense University Hospital, 5000 Odense, Denmark
| | - Mette Scheller Nissen
- Department of Clinical Research, University of Southern Denmark, 5230 Odense, Denmark
- Department of Neurology, Odense University Hospital, 5000 Odense, Denmark
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Lee ST, Abboud H, Irani SR, Nakajima H, Piquet AL, Pittock SJ, Yeh EA, Wang J, Rajan S, Overell J, Smith J, St Lambert J, El-Khairi M, Gafarova M, Gelfand JM. Innovation and optimization in autoimmune encephalitis trials: the design and rationale for the Phase 3, randomized study of satralizumab in patients with NMDAR-IgG-antibody-positive or LGI1-IgG-antibody-positive autoimmune encephalitis (CIELO). Front Neurol 2024; 15:1437913. [PMID: 39193150 PMCID: PMC11348855 DOI: 10.3389/fneur.2024.1437913] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/24/2024] [Accepted: 07/15/2024] [Indexed: 08/29/2024] Open
Abstract
Background Autoimmune encephalitis (AIE) encompasses a spectrum of rare autoimmune-mediated neurological disorders, which are characterized by brain inflammation and dysfunction. Autoantibodies targeting the N-methyl-d-aspartic acid receptor (NMDAR) and leucine-rich glioma-inactivated 1 (LGI1) are the most common subtypes of antibody-positive AIE. Currently, there are no approved therapies for AIE. Interleukin-6 (IL-6) signaling plays a role in the pathophysiology of AIE. Satralizumab, a humanized, monoclonal recycling antibody that specifically targets the IL-6 receptor and inhibits IL-6 signaling, has demonstrated efficacy and safety in another autoantibody-mediated neuroinflammatory disease, aquaporin-4 immunoglobulin G antibody-positive neuromyelitis optica spectrum disorder, and has the potential to be an evidence-based disease modifying treatment in AIE. Objectives CIELO will evaluate the efficacy, safety, pharmacodynamics, and pharmacokinetics of satralizumab compared with placebo in patients with NMDAR-immunoglobulin G antibody-positive (IgG+) or LGI1-IgG+ AIE. Study design CIELO (NCT05503264) is a prospective, Phase 3, randomized, double-blind, multicenter, basket study that will enroll approximately 152 participants with NMDAR-IgG+ or LGI1-IgG+ AIE. Prior to enrollment, participants will have received acute first-line therapy. Part 1 of the study will consist of a 52-week primary treatment period, where participants will receive subcutaneous placebo or satralizumab at Weeks 0, 2, 4, and every 4 weeks thereafter. Participants may continue to receive background immunosuppressive therapy, symptomatic treatment, and rescue therapy throughout the study. Following Part 1, participants can enter an optional extension period (Part 2) to continue the randomized, double-blind study drug, start open-label satralizumab, or stop study treatment and continue with follow-up assessments. Endpoints The primary efficacy endpoint is the proportion of participants with a ≥1-point improvement in the modified Rankin Scale (mRS) score from study baseline and no use of rescue therapy at Week 24. Secondary efficacy assessments include mRS, Clinical Assessment Scale of Autoimmune Encephalitis (CASE), time to rescue therapy, sustained seizure cessation and no rescue therapy, Montreal Cognitive Assessment, and Rey Auditory Verbal Learning Test (RAVLT) measures. Safety, pharmacokinetics, pharmacodynamics, exploratory efficacy, and biomarker endpoints will be captured. Conclusion The innovative basket study design of CIELO offers the opportunity to yield prospective, robust evidence, which may contribute to the development of evidence-based treatment recommendations for satralizumab in AIE.
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Affiliation(s)
- Soon-Tae Lee
- Department of Neurology, Seoul National University Hospital, Seoul National University College of Medicine, Seoul, Republic of Korea
| | - Hesham Abboud
- Department of Neurology, University Hospitals Cleveland Medical Center, Cleveland, OH, United States
| | - Sarosh R. Irani
- Oxford Autoimmune Neurology Group, Nuffield Department of Clinical Neurosciences, University of Oxford, Oxford, United Kingdom
- Departments of Neurology and Neurosciences, Mayo Clinic, Jacksonville, FL, United States
| | - Hideto Nakajima
- Division of Neurology, Department of Medicine, Nihon University School of Medicine, Tokyo, Japan
| | - Amanda L. Piquet
- Department of Neurology, University of Colorado, Aurora, CO, United States
| | - Sean J. Pittock
- Department of Neurology, Mayo Clinic College of Medicine, Rochester, MN, United States
| | - E. Ann Yeh
- Division of Neurology, Department of Pediatrics, The Hospital for Sick Children, University of Toronto, Toronto, ON, Canada
| | - Jiawei Wang
- Department of Neurology, Beijing Tongren Hospital, Capital Medical University, Beijing, China
| | - Sharmila Rajan
- Product Development Neuroscience, Genentech, Inc., South San Francisco, CA, United States
| | - James Overell
- Product Development Neuroscience, F. Hoffmann-La Roche Ltd., Basel, Switzerland
| | - Jillian Smith
- Roche Products Ltd., Welwyn Garden City, United Kingdom
| | | | | | - Marina Gafarova
- Product Development Neuroscience, F. Hoffmann-La Roche Ltd., Basel, Switzerland
| | - Jeffrey M. Gelfand
- Department of Neurology, UCSF Weill Institute for Neurosciences, San Francisco, CA, United States
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Zhang J, Li Y, Liu L, Dai F, Peng Y, Ma Q, Li L, Hong Y, Liu A, Zhang X, Wang X, He J, Bu H, Guo Y, Jiang H, Cui S, Sun H, Wang J. Development of a short-term prognostic model for anti-N-methyl-D-aspartate receptor encephalitis in Chinese patients. BMC Neurol 2024; 24:276. [PMID: 39123191 PMCID: PMC11313159 DOI: 10.1186/s12883-024-03724-x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/01/2023] [Accepted: 06/12/2024] [Indexed: 08/12/2024] Open
Abstract
BACKGROUND Recognizing the predictors of poor short-term prognosis after first-line immunotherapy in patients with anti-N-methyl-D-aspartate receptor (anti-NMDAR) encephalitis is essential for individualized treatment strategy. The objective of this study was to ascertain the factors that forecast short-term prognosis in patients with anti-NMDAR encephalitis, develop a prognostic prediction model, and authenticate its efficacy in an external validation cohort. Further, all patients were followed-up long-term to assess the factors of long-term outcome and relapses. METHODS A prospective enrollment of patients diagnosed with anti-NMDAR encephalitis was conducted across five clinical centers in China from June 2014 to Mar 2022. The enrolled patients were divided into the derivation and validation sets based on enrollment time. The short-term prognostic model was visualized using a nomogram. Further, all patients were followed-up long-term to assess the factors of long-term outcome. RESULTS This study found that poor short-term prognosis was a risk factor for poor long-term outcome (6-month prognosis, OR 29.792, 95%CI 6.507-136.398, p < 0.001; 12-month prognosis, OR 15.756, 95%CI 3.384-73.075, p < 0.001; 24-month prognosis, OR 5.500, 95%CI 1.045-28.955, p = 0.044). Abnormal behavior or cognitive dysfunction (OR 8.57, 95%CI 1.48-49.79, p = 0.017), consciousness impairment (OR19.32, 95%CI 3.03-123.09, p = 0.002), autonomic dysfunction or central hypoventilation (OR 5.66, 95%CI 1.25-25.75, p = 0.025), CSF pleocytosis (OR 4.33, 95%CI 1.48-12.65, p = 0.007), abnormal EEG (OR 5.48, 95% CI 1.09-27.54, p = 0.039) were independent predictors for a poor short-term prognosis after first-line immunotherapy. A nomogram that incorporated those factors showed good discrimination and calibration abilities. The area under the curve (AUC) for the prognostic model were 0.866 (95%CI: 0.798-0.934) with a sensitivity of 0.761 and specificity of 0.869. CONCLUSION We established and validated a prognostic model that can provide individual prediction of short-term prognosis after first-line immunotherapy for patients with anti-NMDAR encephalitis. This practical prognostic model may help neurologists to predict the short-term prognosis early and potentially assist in adjusting appropriate treatment timely.
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Affiliation(s)
- Jingxiao Zhang
- Department of Neurology, Beijing Tongren Hospital, Capital Medical University, Beijing, China
| | - Yatong Li
- Department of Neurology, Beijing Tongren Hospital, Capital Medical University, Beijing, China
| | - Lei Liu
- Department of Neurology, Beijing Tongren Hospital, Capital Medical University, Beijing, China
| | - Feifei Dai
- Department of Neurology, Beijing Tongren Hospital, Capital Medical University, Beijing, China
| | - Yujing Peng
- Department of Neurology, Beijing Tongren Hospital, Capital Medical University, Beijing, China
| | - Qiuying Ma
- Department of Neurology, Beijing Tongren Hospital, Capital Medical University, Beijing, China
| | - Lin Li
- Department of Neurology, Beijing Tongren Hospital, Capital Medical University, Beijing, China
| | - Yu Hong
- Department of Neurology, Beijing Tongren Hospital, Capital Medical University, Beijing, China
| | - Aihua Liu
- Department of Neurology, Xuanwu Hospital, Capital Medical University, Beijing, China
| | - Xinghu Zhang
- Department of Neurology, Beijing Tiantan Hospital, Capital Medical University, Beijing, China
| | - Xiaohui Wang
- Beijing Children Hospital, Capital Medical University, Beijing, China
| | - Junying He
- Department of Neurology, the Second Hospital of Hebei Medical University, Shijiazhuang, China
| | - Hui Bu
- Department of Neurology, the Second Hospital of Hebei Medical University, Shijiazhuang, China
| | - Yanjun Guo
- Department of Neurology, Beijing Tongren Hospital, Capital Medical University, Beijing, China
| | - Hanqiu Jiang
- Department of Neurology, Beijing Tongren Hospital, Capital Medical University, Beijing, China
| | - Shilei Cui
- Department of Neurology, Beijing Tongren Hospital, Capital Medical University, Beijing, China
| | - Houliang Sun
- Department of Neurology, Beijing Tongren Hospital, Capital Medical University, Beijing, China
| | - Jiawei Wang
- Department of Neurology, Beijing Tongren Hospital, Capital Medical University, Beijing, China.
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Hacohen Y. Pediatric Autoimmune Neurologic Disorders. Continuum (Minneap Minn) 2024; 30:1160-1188. [PMID: 39088292 DOI: 10.1212/con.0000000000001464] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 08/03/2024]
Abstract
OBJECTIVE This article discusses common principles in diagnosing and managing autoimmune neurologic conditions in children. LATEST DEVELOPMENTS The key to improving outcomes in all patients with autoimmune neurologic diseases is making an early diagnosis, promptly initiating treatment, and identifying patients who will benefit from long-term maintenance treatment. Some neuroinflammatory syndromes can be diagnosed with an antibody biomarker (eg, aquaporin-4 antibodies, N-methyl-d-aspartate [NMDA] receptor antibodies), whereas others require clinical diagnostic criteria (eg, multiple sclerosis, opsoclonus-myoclonus syndrome). A proportion of children will be labeled as seronegative, and further investigations for other inflammatory or monogenetic etiologies need to be carried out in parallel with treating the central nervous system inflammation. Time to treatment and treatment escalation were shown to correlate with outcomes in many patients with these disorders. The choice and duration of treatment should be evaluated considering side effects and risks in the short and long terms. The presence of a highly inflammatory disease process in children supports the use of highly effective disease-modifying therapies in pediatrics. ESSENTIAL POINTS The phenotypes of pediatric autoimmune neurologic conditions may change across different age groups, as the brain is still actively developing. In general, the presentation in children is more inflammatory, but overall disability is lower, likely because of better neuroplasticity and repair. Convincing evidence has increasingly emerged to support the biological rationale that effective immunosuppressive therapies used in adult neuroimmunology are equally effective in children.
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Dwibedi B, Satapathy AK, Jain A, Champatiray JR, Dash M, Mishra B, Patra G, Prakash O, Abbas F, Purkait S. Prevalence & clinical outcome of autoimmune encephalitis versus viral encephalitis in children with acute encephalitis syndrome: A prospective observational study. Indian J Med Res 2024; 160:217-225. [PMID: 39513204 PMCID: PMC11544577 DOI: 10.25259/ijmr_2332_23] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/14/2023] [Accepted: 07/30/2024] [Indexed: 11/15/2024] Open
Abstract
Background & objectives Acute encephalitic syndrome (AES), encompasses a wide spectrum of potential causes, clinical presentations, and outcomes. While infectious encephalitis is generally considered more prevalent, autoimmune encephalitis is emerging as a significant aetiology. Neuronal autoantibodies have been identified independently or in association with acute viral encephalitis. The primary objective of this study was to ascertain the prevalence and clinical manifestation of autoimmune encephalitis as well as of coexisting viral markers in children with AES. Methods This study was a prospective observational investigation conducted in a hospital setting. It involved enrolling children with AES who were admitted to specific tertiary hospitals. Children were subjected to examinations to detect the presence of viral markers and neuronal autoantibodies in both their blood and cerebrospinal fluid (CSF). All the participants received treatment based on established guidelines and was followed for six months for outcome assessment. Results During the study period, 867 children with AES were examined. Among these cases, 37 children (4.2%) were diagnosed with autoimmune encephalitis, and all of them tested positive for anti-NMDAR (N-methyl-D-aspartate receptor) antibodies. Evidence of viral infection was seen in 409 (47.1%) of cases, out of which nearly 254 (29.2%) children had detectable HSV IgM antibodies. Among the 37 children with autoimmune encephalitis, 25 (67.5%) had evidence of a viral trigger, with eight of them tested positive for HSV IgM antibodies. The clinical presentation of autoimmune-associated AES was similar to those with viral aetiology. Interpretation & conclusions Autoimmune encephalitis triggered by neurotropic (HSV) viral infection was more prevalent in this study than in the earlier reports. Typically, these children show positive responses to immunosuppressive treatments if administered promptly. It is hence advisable to assess children who exhibit behavioural issues and movement disorders for possible autoimmune encephalitis.
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Affiliation(s)
- Bhagirathi Dwibedi
- Department of Pediatrics, All India Institute of Medical Sciences, Bhubaneswar, India
| | - Amit Kumar Satapathy
- Department of Pediatrics, All India Institute of Medical Sciences, Bhubaneswar, India
| | - Amita Jain
- Department of Microbiology, King George's Medical University, Lucknow, Uttar Pradesh, India
| | - Jyoti Ranjan Champatiray
- Department of Pediatrics, Sardar Vallabhbhai Patel Post Graduate Institute of Paediatrics, Odisha, India
| | - Mrutunjay Dash
- Department of Paediatrics, Institute of Medical Sciences and Sum Hospital, Odisha, India
| | - Baijayantimala Mishra
- Department of Paediatrics, Institute of Medical Sciences and Sum Hospital, Odisha, India
| | - Gayatri Patra
- Department of Pediatrics, All India Institute of Medical Sciences, Bhubaneswar, India
| | - Om Prakash
- Department of Microbiology, King George's Medical University, Lucknow, Uttar Pradesh, India
| | - Faisal Abbas
- Department of Virology, King George's Medical University, Lucknow, Uttar Pradesh, India
| | - Suvendu Purkait
- Department of Pathology, All India Institute of Medical Sciences, Bhubaneswar, India
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Mathias A, Perriot S, Jones S, Canales M, Bernard-Valnet R, Gimenez M, Torcida N, Oberholster L, Hottinger AF, Zekeridou A, Theaudin M, Pot C, Du Pasquier R. Human stem cell-derived neurons and astrocytes to detect novel auto-reactive IgG response in immune-mediated neurological diseases. Front Immunol 2024; 15:1419712. [PMID: 39114659 PMCID: PMC11303155 DOI: 10.3389/fimmu.2024.1419712] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/18/2024] [Accepted: 07/11/2024] [Indexed: 08/10/2024] Open
Abstract
Background and objectives Up to 46% of patients with presumed autoimmune limbic encephalitis are seronegative for all currently known central nervous system (CNS) antigens. We developed a cell-based assay (CBA) to screen for novel neural antibodies in serum and cerebrospinal fluid (CSF) using neurons and astrocytes derived from human-induced pluripotent stem cells (hiPSCs). Methods Human iPSC-derived astrocytes or neurons were incubated with serum/CSF from 99 patients [42 with inflammatory neurological diseases (IND) and 57 with non-IND (NIND)]. The IND group included 11 patients with previously established neural antibodies, six with seronegative neuromyelitis optica spectrum disorder (NMOSD), 12 with suspected autoimmune encephalitis/paraneoplastic syndrome (AIE/PNS), and 13 with other IND (OIND). IgG binding to fixed CNS cells was detected using fluorescently-labeled antibodies and analyzed through automated fluorescence measures. IgG neuronal/astrocyte reactivity was further analyzed by flow cytometry. Peripheral blood mononuclear cells (PBMCs) were used as CNS-irrelevant control target cells. Reactivity profile was defined as positive using a Robust regression and Outlier removal test with a false discovery rate at 10% following each individual readout. Results Using our CBA, we detected antibodies recognizing hiPSC-derived neural cells in 19/99 subjects. Antibodies bound specifically to astrocytes in nine cases, to neurons in eight cases, and to both cell types in two cases, as confirmed by microscopy single-cell analyses. Highlighting the significance of our comprehensive 96-well CBA assay, neural-specific antibody binding was more frequent in IND (15 of 42) than in NIND patients (4 of 57) (Fisher's exact test, p = 0.0005). Two of four AQP4+ NMO and four of seven definite AIE/PNS with intracellular-reactive antibodies [1 GFAP astrocytopathy, 2 Hu+, 1 Ri+ AIE/PNS)], as identified in diagnostic laboratories, were also positive with our CBA. Most interestingly, we showed antibody-reactivity in two of six seronegative NMOSD, six of 12 probable AIE/PNS, and one of 13 OIND. Flow cytometry using hiPSC-derived CNS cells or PBMC-detected antibody binding in 13 versus zero patients, respectively, establishing the specificity of the detected antibodies for neural tissue. Conclusion Our unique hiPSC-based CBA allows for the testing of novel neuron-/astrocyte-reactive antibodies in patients with suspected immune-mediated neurological syndromes, and negative testing in established routine laboratories, opening new perspectives in establishing a diagnosis of such complex diseases.
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Affiliation(s)
- Amandine Mathias
- Laboratories of Neuroimmunology, Neuroscience Research Center and Division of Neurology, Department of Clinical Neurosciences, Lausanne University Hospital and Lausanne University, Epalinges, Switzerland
| | - Sylvain Perriot
- Laboratories of Neuroimmunology, Neuroscience Research Center and Division of Neurology, Department of Clinical Neurosciences, Lausanne University Hospital and Lausanne University, Epalinges, Switzerland
| | - Samuel Jones
- Laboratories of Neuroimmunology, Neuroscience Research Center and Division of Neurology, Department of Clinical Neurosciences, Lausanne University Hospital and Lausanne University, Epalinges, Switzerland
| | - Mathieu Canales
- Laboratories of Neuroimmunology, Neuroscience Research Center and Division of Neurology, Department of Clinical Neurosciences, Lausanne University Hospital and Lausanne University, Epalinges, Switzerland
| | - Raphaël Bernard-Valnet
- Service of Neurology, Department of Clinical Neurosciences, Lausanne University Hospital and University of Lausanne, Lausanne, Switzerland
| | - Marie Gimenez
- Laboratories of Neuroimmunology, Neuroscience Research Center and Division of Neurology, Department of Clinical Neurosciences, Lausanne University Hospital and Lausanne University, Epalinges, Switzerland
| | - Nathan Torcida
- Laboratories of Neuroimmunology, Neuroscience Research Center and Division of Neurology, Department of Clinical Neurosciences, Lausanne University Hospital and Lausanne University, Epalinges, Switzerland
| | - Larise Oberholster
- Laboratories of Neuroimmunology, Neuroscience Research Center and Division of Neurology, Department of Clinical Neurosciences, Lausanne University Hospital and Lausanne University, Epalinges, Switzerland
| | - Andreas F. Hottinger
- Lundin Family Brain Tumor Research Centre, Department of Clinical Neurosciences and Oncology, Lausanne University Hospital and University of Lausanne, Lausanne, Switzerland
| | - Anastasia Zekeridou
- Department of Laboratory Medicine and Pathology and Department of Neurology, Center for MS and Autoimmune Neurology, Mayo Clinic, Rochester, MN, United States
| | - Marie Theaudin
- Service of Neurology, Department of Clinical Neurosciences, Lausanne University Hospital and University of Lausanne, Lausanne, Switzerland
| | - Caroline Pot
- Laboratories of Neuroimmunology, Neuroscience Research Center and Division of Neurology, Department of Clinical Neurosciences, Lausanne University Hospital and Lausanne University, Epalinges, Switzerland
- Service of Neurology, Department of Clinical Neurosciences, Lausanne University Hospital and University of Lausanne, Lausanne, Switzerland
| | - Renaud Du Pasquier
- Laboratories of Neuroimmunology, Neuroscience Research Center and Division of Neurology, Department of Clinical Neurosciences, Lausanne University Hospital and Lausanne University, Epalinges, Switzerland
- Service of Neurology, Department of Clinical Neurosciences, Lausanne University Hospital and University of Lausanne, Lausanne, Switzerland
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Dor A, Harrison C, Irani SR, Al-Diwani A, Grogan J, Manohar S. N-Methyl-D-Aspartate Receptor-Antibody Encephalitis Impairs Maintenance of Attention to Items in Working Memory. J Neurosci 2024; 44:e1500232024. [PMID: 38830760 PMCID: PMC11236588 DOI: 10.1523/jneurosci.1500-23.2024] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/07/2023] [Revised: 04/23/2024] [Accepted: 04/28/2024] [Indexed: 06/05/2024] Open
Abstract
NMDA receptors (NMDARs) may be crucial to working memory (WM). Computational models predict that they sustain neural firing and produce associative memory, which may underpin maintaining and binding information, respectively. We test this in patients with antibodies to NMDAR (n = 10, female) and compare them with healthy control participants (n = 55, 20 male, 35 female). Patients were tested after recovery with a task that separates two aspects of WM: sustaining attention and feature binding. Participants had to remember two colored arrows. Then attention was directed to one of them. After a variable delay, they reported the direction of either the same arrow (congruent cue) or of the other arrow (incongruent cue). We asked how congruency affected recall precision and measured types of error. Patients had difficulty in both sustaining attention to an item over time and feature binding. Controls were less precise after longer delays and incongruent cues. In contrast, patients did not benefit from congruent cues at longer delays [group × congruency (long condition); p = 0.041], indicating they could not sustain attention. Additionally, patients reported the wrong item (misbinding errors) more than controls after congruent cues [group × delay (congruent condition), main effect of group; p ≤ 0.001]. Our results suggest NMDARs are critical for both maintaining attention and feature binding.
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Affiliation(s)
- Afrose Dor
- Nuffield Department of Clinical Neurosciences, University of Oxford, Oxford OX3 9DU, United Kingdom
| | - Corin Harrison
- Department of Experimental Psychology, University of Oxford, Oxford OX2 6GG, United Kingdom
| | - Sarosh R Irani
- Nuffield Department of Clinical Neurosciences, University of Oxford, Oxford OX3 9DU, United Kingdom
| | - Adam Al-Diwani
- Nuffield Department of Clinical Neurosciences, University of Oxford, Oxford OX3 9DU, United Kingdom
- Department of Psychiatry, University of Oxford, Oxford OX3 7JX, United Kingdom
| | - John Grogan
- Trinity College Institute of Neuroscience, Trinity College Dublin, Dublin 2, Ireland
| | - Sanjay Manohar
- Nuffield Department of Clinical Neurosciences, University of Oxford, Oxford OX3 9DU, United Kingdom
- Department of Experimental Psychology, University of Oxford, Oxford OX2 6GG, United Kingdom
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Dai Y, Zhu Z, Tang Y, Xiao L, Liu X, Zhang M, Xiao B, Hu K, Long L, Xie Y, Hu S. The clinical and predictive value of 18F-FDG PET/CT metabolic patterns in a clinical Chinese cohort with autoimmune encephalitis. CNS Neurosci Ther 2024; 30:e14821. [PMID: 38948940 PMCID: PMC11215490 DOI: 10.1111/cns.14821] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/26/2024] [Revised: 05/29/2024] [Accepted: 06/14/2024] [Indexed: 07/02/2024] Open
Abstract
AIMS To investigate the diagnostic and predictive role of 18F-FDG PET/CT in patients with autoimmune encephalitis (AE) as a whole group. METHODS Thrty-five patients (20 females and 15 males) with AE were recruited. A voxel-to-voxel semi-quantitative analysis based on SPM12 was used to analyze 18F-FDG PET/CT imaging data compared to healthy controls. Further comparison was made in different prognostic groups categorized by modified Rankin Scale (mRS). RESULTS In total, 24 patients (68.6%) were tested positive neuronal antibodies in serum and/or CSF. Psychiatric symptoms and seizure attacks were major clinical symptoms. In the acute stage, 13 patients (37.1%) demonstrated abnormal brain MRI results, while 33 (94.3%) presented abnormal metabolism patterns. 18F-FDG PET/CT was more sensitive than MRI (p < 0.05). Patients with AE mainly presented mixed metabolism patterns compared to the matched controls, demonstrating hypermetabolism mainly in the cerebellum, BG, MTL, brainstem, insula, middle frontal gyrus, and relatively hypometabolism in the frontal cortex, occipital cortex, temporal gyrus, right parietal gyrus, left cingulate gyrus (p < 0.05, FWE corrected). After a median follow-up of 26 months, the multivariable analysis identified a decreased level of consciousness as an independent risk factor associated with poor outcome of AE (HR = 3.591, p = 0.016). Meanwhile, decreased metabolism of right superior frontal gyrus along with increased metabolism of the middle and upper brainstem was more evident in patients with poor outcome (p < 0.001, uncorrected). CONCLUSION 18F-FDG PET/CT was more sensitive than MRI to detect neuroimaging abnormalities of AE. A mixed metabolic pattern, characterized by large areas of cortical hypometabolism with focal hypermetabolism was a general metabolic pattern. Decreased metabolism of right superior frontal gyrus with increased metabolism of the middle and upper brainstem may predict poor long-term prognosis of AE.
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Affiliation(s)
- Yuwei Dai
- Department of Neurology, Xiangya HospitalCentral South UniversityChangshaHunanP.R. China
- National Clinical Research Center for Geriatric Diseases, Xiangya HospitalCentral South UniversityChangshaHunanP.R. China
- Clinical Research Center for Epileptic disease of Hunan ProvinceCentral South UniversityChangshaHunanP.R. China
| | - Zehua Zhu
- National Clinical Research Center for Geriatric Diseases, Xiangya HospitalCentral South UniversityChangshaHunanP.R. China
- Department of Nuclear Medicine, Xiangya HospitalCentral South UniversityChangshaHunanP.R. China
- Key Laboratory of Biological Nanotechnology of National Health Commission, Xiangya HospitalCentral South UniversityChangshaHunanP.R. China
- Division of Life Sciences and Medicine, Department of Nuclear Medicine, The First Affiliated Hospital of USTCUniversity of Science and Technology of ChinaHefeiAnhuiP.R. China
| | - Yongxiang Tang
- National Clinical Research Center for Geriatric Diseases, Xiangya HospitalCentral South UniversityChangshaHunanP.R. China
- Department of Nuclear Medicine, Xiangya HospitalCentral South UniversityChangshaHunanP.R. China
- Key Laboratory of Biological Nanotechnology of National Health Commission, Xiangya HospitalCentral South UniversityChangshaHunanP.R. China
| | - Ling Xiao
- National Clinical Research Center for Geriatric Diseases, Xiangya HospitalCentral South UniversityChangshaHunanP.R. China
- Department of Nuclear Medicine, Xiangya HospitalCentral South UniversityChangshaHunanP.R. China
- Key Laboratory of Biological Nanotechnology of National Health Commission, Xiangya HospitalCentral South UniversityChangshaHunanP.R. China
| | - Xianghe Liu
- Department of Neurology, Xiangya HospitalCentral South UniversityChangshaHunanP.R. China
- National Clinical Research Center for Geriatric Diseases, Xiangya HospitalCentral South UniversityChangshaHunanP.R. China
- Clinical Research Center for Epileptic disease of Hunan ProvinceCentral South UniversityChangshaHunanP.R. China
| | - Min Zhang
- Department of Neurology, Xiangya HospitalCentral South UniversityChangshaHunanP.R. China
- National Clinical Research Center for Geriatric Diseases, Xiangya HospitalCentral South UniversityChangshaHunanP.R. China
- Clinical Research Center for Epileptic disease of Hunan ProvinceCentral South UniversityChangshaHunanP.R. China
| | - Bo Xiao
- Department of Neurology, Xiangya HospitalCentral South UniversityChangshaHunanP.R. China
- National Clinical Research Center for Geriatric Diseases, Xiangya HospitalCentral South UniversityChangshaHunanP.R. China
- Clinical Research Center for Epileptic disease of Hunan ProvinceCentral South UniversityChangshaHunanP.R. China
| | - Kai Hu
- Department of Neurology, Xiangya HospitalCentral South UniversityChangshaHunanP.R. China
- National Clinical Research Center for Geriatric Diseases, Xiangya HospitalCentral South UniversityChangshaHunanP.R. China
- Clinical Research Center for Epileptic disease of Hunan ProvinceCentral South UniversityChangshaHunanP.R. China
| | - Lili Long
- Department of Neurology, Xiangya HospitalCentral South UniversityChangshaHunanP.R. China
- National Clinical Research Center for Geriatric Diseases, Xiangya HospitalCentral South UniversityChangshaHunanP.R. China
- Clinical Research Center for Epileptic disease of Hunan ProvinceCentral South UniversityChangshaHunanP.R. China
| | - Yuanyuan Xie
- Department of Neurology, Xiangya HospitalCentral South UniversityChangshaHunanP.R. China
- National Clinical Research Center for Geriatric Diseases, Xiangya HospitalCentral South UniversityChangshaHunanP.R. China
- Clinical Research Center for Epileptic disease of Hunan ProvinceCentral South UniversityChangshaHunanP.R. China
| | - Shuo Hu
- National Clinical Research Center for Geriatric Diseases, Xiangya HospitalCentral South UniversityChangshaHunanP.R. China
- Department of Nuclear Medicine, Xiangya HospitalCentral South UniversityChangshaHunanP.R. China
- Key Laboratory of Biological Nanotechnology of National Health Commission, Xiangya HospitalCentral South UniversityChangshaHunanP.R. China
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Balaji N, Ignatowicz A, Kalra A, Mansour R, Jadhav V. Anti-CASPR2 Antibody-Associated Autoimmune Encephalitis Presenting as Refractory Seizures. Cureus 2024; 16:e64317. [PMID: 39131008 PMCID: PMC11316415 DOI: 10.7759/cureus.64317] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 07/11/2024] [Indexed: 08/13/2024] Open
Abstract
Autoimmune encephalitis (AE) is a rare immune-mediated disorder comprised of non-infectious neuroinflammatory disease processes. Clinical presentation overlaps with a broad range of neurodegenerative disorders and infectious encephalitis; therefore, AE remains a diagnosis of exclusion. Patients may present with nonspecific symptoms such as psychiatric disturbances, cognitive deficits, seizures, movement disorders, and confusion. Prompt diagnosis and management are necessary for patients with AE to decrease mortality and improve quality of life. First-line therapy includes immunosuppression with corticosteroids, intravenous immunoglobulin, and plasmapheresis. We report the case of an 86-year-old female with a medical history of Parkinson's disease who presented with nonspecific seizure-like activity and was diagnosed with AE.
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Affiliation(s)
- Nivedha Balaji
- Internal Medicine, Northeast Georgia Medical Center Gainsville, Gainesville, USA
| | | | - Aarushi Kalra
- Internal Medicine, Northeast Georgia Medical Center Gainsville, Gainesville, USA
| | - Rami Mansour
- Internal Medicine, Philadelphia College of Osteopathic Medicine, Suwanee, USA
| | - Vaishali Jadhav
- Internal Medicine, Northeast Georgia Medical Center Gainsville, Gainesville, USA
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