Publications by authors named "Patrick Waters"

172 Publications

Comparison of Spinal Cord Magnetic Resonance Imaging Features Among Children With Acquired Demyelinating Syndromes.

JAMA Netw Open 2021 Oct 1;4(10):e2128871. Epub 2021 Oct 1.

Division of Child Neurology, Department of Neurology, The Children's Hospital of Philadelphia, Perelman School of Medicine, University of Pennsylvania, Philadelphia.

Importance: The recognition of magnetic resonance imaging (MRI) features associated with distinct causes of myelitis in children is essential to guide investigations and support diagnostic categorization.

Objective: To determine the clinical and MRI features and outcomes associated with spinal cord involvement in pediatric myelin oligodendrocyte glycoprotein antibody-associated disease (MOGAD), multiple sclerosis (MS), and seronegative monophasic myelitis.

Design, Setting, And Participants: In this cohort study, participants were recruited between 2004 and 2017 through the multicenter Canadian Pediatric Demyelinating Disease Study, which enrolled youth younger than 18 years presenting within 90 days of an acquired demyelinating syndrome. Of the 430 participants recruited, those with lesions on available spine MRI and anti-MOG testing performed on archived samples obtained close to clinical presentation were selected. Participants with poor-quality images and final diagnoses of nondemyelinating disease, anti-aquaporin 4 antibody positivity, and relapsing seronegative myelitis were excluded. Data analysis was performed from December 2019 to November 2020.

Main Outcomes And Measures: Spinal cord involvement was evaluated on 324 MRI sequences, with reviewers blinded to clinical, serological, and brain MRI findings. Associated clinical features and disability scores at 5 years of follow-up were retrieved. Results were compared between groups.

Results: A total of 107 participants (median [IQR] age at onset, 11.14 [5.59-13.39] years; 55 girls [51%]) were included in the analyses; 40 children had MOGAD, 21 had MS, and 46 had seronegative myelitis. Longitudinally extensive lesions were very common among children with MOGAD (30 of 40 children [75%]), less common among those with seronegative myelitis (20 of 46 children [43%]), and rare in children with MS (1 of 21 children [5%]). Axial gray matter T2-hyperintensity (ie, the H-sign) was observed in 22 of 35 children (63%) with MOGAD, in 14 of 42 children (33%) with seronegative myelitis, and in none of those with MS. The presence of leptomeningeal enhancement was highly suggestive for MOGAD (22 of 32 children [69%] with MOGAD vs 10 of 38 children [26%] with seronegative myelitis and 1 of 15 children [7%] with MS). Children with MOGAD were more likely to have complete lesion resolution on serial images (14 of 21 children [67%]) compared with those with MS (0 of 13 children).

Conclusions And Relevance: These findings suggest that several features may help identify children at presentation who are more likely to have myelitis associated with MOGAD. Prominent involvement of gray matter and leptomeningeal enhancement are common in pediatric MOGAD, although the pathological underpinning of these observations requires further study.
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http://dx.doi.org/10.1001/jamanetworkopen.2021.28871DOI Listing
October 2021

MRI Patterns Distinguish AQP4 Antibody Positive Neuromyelitis Optica Spectrum Disorder From Multiple Sclerosis.

Front Neurol 2021 9;12:722237. Epub 2021 Sep 9.

Menzies Health Institute Queensland, Gold Coast, Griffith University, Southport, QLD, Australia.

Neuromyelitis optica spectrum disorder (NMOSD) and multiple sclerosis (MS) are inflammatory diseases of the CNS. Overlap in the clinical and MRI features of NMOSD and MS means that distinguishing these conditions can be difficult. With the aim of evaluating the diagnostic utility of MRI features in distinguishing NMOSD from MS, we have conducted a cross-sectional analysis of imaging data and developed predictive models to distinguish the two conditions. NMOSD and MS MRI lesions were identified and defined through a literature search. Aquaporin-4 (AQP4) antibody positive NMOSD cases and age- and sex-matched MS cases were collected. MRI of orbits, brain and spine were reported by at least two blinded reviewers. MRI brain or spine was available for 166/168 (99%) of cases. Longitudinally extensive (OR = 203), "bright spotty" (OR = 93.8), whole (axial; OR = 57.8) or gadolinium (Gd) enhancing (OR = 28.6) spinal cord lesions, bilateral (OR = 31.3) or Gd-enhancing (OR = 15.4) optic nerve lesions, and nucleus tractus solitarius (OR = 19.2), periaqueductal (OR = 16.8) or hypothalamic (OR = 7.2) brain lesions were associated with NMOSD. Ovoid (OR = 0.029), Dawson's fingers (OR = 0.031), pyramidal corpus callosum (OR = 0.058), periventricular (OR = 0.136), temporal lobe (OR = 0.137) and T1 black holes (OR = 0.154) brain lesions were associated with MS. A score-based algorithm and a decision tree determined by machine learning accurately predicted more than 85% of both diagnoses using first available imaging alone. We have confirmed NMOSD and MS specific MRI features and combined these in predictive models that can accurately identify more than 85% of cases as either AQP4 seropositive NMOSD or MS.
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http://dx.doi.org/10.3389/fneur.2021.722237DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8458658PMC
September 2021

Myelin-oligodendrocyte glycoprotein antibody-associated disease.

Lancet Neurol 2021 09;20(9):762-772

Brain Institute of Rio Grande do Sul and School of Medicine, Pontifical Catholic University of Rio Grande do Sul, Porto Alegre, Brazil.

Myelin-oligodendrocyte glycoprotein antibody-associated disease (MOGAD) is a recently identified autoimmune disorder that presents in both adults and children as CNS demyelination. Although there are clinical phenotypic overlaps between MOGAD, multiple sclerosis, and aquaporin-4 antibody-associated neuromyelitis optica spectrum disorder (NMOSD) cumulative biological, clinical, and pathological evidence discriminates between these conditions. Patients should not be diagnosed with multiple sclerosis or NMOSD if they have anti-MOG antibodies in their serum. However, many questions related to the clinical characterisation of MOGAD and pathogenetic role of MOG antibodies are still unanswered. Furthermore, therapy is mainly based on standard protocols for aquaporin-4 antibody-associated NMOSD and multiple sclerosis, and more evidence is needed regarding how and when to treat patients with MOGAD.
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http://dx.doi.org/10.1016/S1474-4422(21)00218-0DOI Listing
September 2021

Leucine-Rich Glioma-Inactivated 1 versus Contactin-Associated Protein-like 2 Antibody Neuropathic Pain: Clinical and Biological Comparisons.

Ann Neurol 2021 Oct 30;90(4):683-690. Epub 2021 Aug 30.

Oxford Autoimmune Neurology Group, Nuffield Department of Clinical Neurosciences, John Radcliffe Hospital, University of Oxford, Oxford, UK.

Pain is a under-recognized association of leucine-rich glioma-inactivated 1 (LGI1) and contactin-associated protein-like 2 (CASPR2) antibodies. Of 147 patients with these autoantibodies, pain was experienced by 17 of 33 (52%) with CASPR2- versus 20 of 108 (19%) with LGI1 antibodies (p = 0.0005), and identified as neuropathic in 89% versus 58% of these, respectively. Typically, in both cohorts, normal nerve conduction studies and reduced intraepidermal nerve fiber densities were observed in the sampled patient subsets. In LGI1 antibody patients, pain responded to immunotherapy (p = 0.008), often rapidly, with greater residual patient-rated impairment observed in CASPR2 antibody patients (p = 0.019). Serum CASPR2 antibodies, but not LGI1 antibodies, bound in vitro to unmyelinated human sensory neurons and rodent dorsal root ganglia, suggesting pathophysiological differences that may underlie our clinical observations. ANN NEUROL 2021;90:683-690.
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http://dx.doi.org/10.1002/ana.26189DOI Listing
October 2021

Progressive encephalomyelitis with rigidity: A Taiwanese case and review of literature.

Clin Neurol Neurosurg 2021 Sep 13;208:106807. Epub 2021 Jul 13.

Department of Neurology, Shin Kong Wu Ho-Su Memorial Hospital, No. 95, Wenchang Road, Shilin District, Taipei, Taiwan. Electronic address:

Introduction: Progressive encephalomyelitis with rigidity and myoclonus (PERM) is a rare disorder. However, the outcome is still variable with different serological and tumor associations, and the elements to good response with less relapse is yet to be elucidated.

Method: We present a case and obtain a literature review of patients with PERM and make comparisons based on different serological groups. We also analyze patients with idiopathic PERM that had detailed medical records.

Results: 81 patients were collected and analyzed. The largest group were glycine receptor-antibody (GlyR-Ab)-positive (70%), and the seropositive-GlyR-Ab-negative group had better response to immunotherapy. Malignancy can occur up to 2 years from the presentation of PERM. Among the 18 cases with detailed records, the patients who had good outcome initiate immunotherapy within 2 months from presentation. 9 of the 12 patients who experienced no relapse had non-steroid immunotherapy. The maximal interval time of relapse was 24 months.

Conclusion: We recommend tumor surveillance up to 2 years in patients with PERM and early administration of immunotherapies and maintain with non-steroid immunotherapy with or without oral corticosteroid for a minimum of 2 years to reduce the risk of relapse in GlyR-Ab-positive patients.
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http://dx.doi.org/10.1016/j.clineuro.2021.106807DOI Listing
September 2021

Frequency of MOG-IgG in cerebrospinal fluid versus serum.

J Neurol Neurosurg Psychiatry 2021 Jul 14. Epub 2021 Jul 14.

Oxford Autoimmune Neurology Group, University of Oxford, Oxford, Oxfordshire, UK

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http://dx.doi.org/10.1136/jnnp-2021-326779DOI Listing
July 2021

NMOSD and MS prevalence in the Indigenous populations of Australia and New Zealand.

J Neurol 2021 Jul 2. Epub 2021 Jul 2.

Menzies Health Institute Queensland, School of Medicine, Griffith University, Gold Coast Campus, Brisbane, QLD, 4222, Australia.

Background: We studied the prevalence of neuromyelitis optica spectrum disorder (NMOSD) and multiple sclerosis (MS) in Indigenous populations of Australia and New Zealand with the aim of assessing potential differences.

Methods: Cases of possible NMOSD and MS were collected from Australia and New Zealand. Clinical details, MR imaging, and serologic results were used to apply 2015 IPND diagnostic criteria for NMOSD and 2010 McDonald criteria for MS. Frequencies of self-determined ethnic ancestry were calculated for confirmed NMOSD, suspected NMOSD, and MS. Prevalence rates for NMOSD and MS according to ancestry were compared.

Results: There were 75 cases with NMOSD, 89 with suspected NMSOD, and 101 with MS. NMOSD cases were more likely to have Asian, Indigenous, or Other ancestry compared to suspected NMOSD or MS. There were no differences in the clinical phenotype of NMOSD seen in Indigenous compared to European ancestry populations. Per 100,000, the prevalence estimate for NMOSD in people with Māori ancestry was 1.50 (95% CI 0.52-2.49) which was similar to those with Asian ancestry 1.57 (95% CI 1.15-1.98). NMOSD prevalence in Australian Aboriginal and Torres Strait Islander populations was 0.38 (95% CI 0.00-0.80) per 100,000.

Conclusion: The prevalence of NMOSD in the Māori population is similar to South East Asian countries, reflecting their historical origins. The prevalence of MS in this group is intermediate between those with South East Asian and European ancestry living in New Zealand. Both NMOSD and particularly MS appear to be uncommon in the Indigenous populations of Australia.
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http://dx.doi.org/10.1007/s00415-021-10665-9DOI Listing
July 2021

Differential Binding of Autoantibodies to MOG Isoforms in Inflammatory Demyelinating Diseases.

Neurol Neuroimmunol Neuroinflamm 2021 07 15;8(5). Epub 2021 Jun 15.

From the Clinical Department of Neurology (K.S., P.P., M.L., B.S., H.H., F.D.P., M.R.), Medical University of Innsbruck, Austria; Euroimmun Medizinische Labordiagnostika AG (S. Mindorf, N.R., C.P.), Lübeck, Germany; Institute for Quality Assurance (ifQ) affiliated to Euroimmun (M.P.), Lübeck, Germany; Department of Pediatrics (E.-M.W.), Olgahospital/Klinikum Stuttgart, Germany; Department of Pediatrics I (C.L., M.B.), Medical University of Innsbruck, Austria; Neurology Unit (S. Mariotto, S.F.), Department of Neuroscience, Biomedicine, and Movement Sciences, University of Verona, Italy; Neuroimmunology and Multiple Sclerosis Unit (A.S.), Service of Neurology, Hospital Clinic, Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Universitat de Barcelona, Spain; Beaumont Hospital (M.F.), Dublin, Ireland; Oxford Autoimmune Neurology Group (M.I.S.L., S.R.I., J.P., P.W.), Nuffield Department of Clinical Neurosciences, University of Oxford, UK; Neuroimmunology and MS Research (A.L.), Department of Neurology, University Hospital Zurich & University of Zurich, Switzerland; Institute of Clinical Neuroimmunology (T.K.), Biomedical Center and University Hospital, Ludwig-Maximilians University, Munich, Germany; Department of Neurology (S.V., R.M.), Hospices civils de Lyon, Hôpital neurologique Pierre Wertheimer, France; Paediatric Neurology (K.R.), Witten/Herdecke University, Children's Hospital Datteln, Germany; Department of Neurology (T.B.), Medical University of Vienna, Austria; and Division of Neuropathology and Neurochemistry (R.H.), Department of Neurology, Medical University of Vienna, Austria.

Objective: To analyze serum immunoglobulin G (IgG) antibodies to major isoforms of myelin oligodendrocyte glycoprotein (MOG-alpha 1-3 and beta 1-3) in patients with inflammatory demyelinating diseases.

Methods: Retrospective case-control study using 378 serum samples from patients with multiple sclerosis (MS), patients with non-MS demyelinating disease, and healthy controls with MOG alpha-1-IgG positive (n = 202) or negative serostatus (n = 176). Samples were analyzed for their reactivity to human, mouse, and rat MOG isoforms with and without mutations in the extracellular MOG Ig domain (MOG-ecIgD), soluble MOG-ecIgD, and myelin from multiple species using live cell-based, tissue immunofluorescence assays and ELISA.

Results: The strongest IgG reactivities were directed against the longest MOG isoforms alpha-1 (the currently used standard test for MOG-IgG) and beta-1, whereas the other isoforms were less frequently recognized. Using principal component analysis, we identified 3 different binding patterns associated with non-MS disease: (1) isolated reactivity to MOG-alpha-1/beta-1 (n = 73), (2) binding to MOG-alpha-1/beta-1 and at least one other alpha, but no beta isoform (n = 64), and (3) reactivity to all 6 MOG isoforms (n = 65). The remaining samples were negative (n = 176) for MOG-IgG. These MOG isoform binding patterns were associated with a non-MS demyelinating disease, but there were no differences in clinical phenotypes or disease course. The 3 MOG isoform patterns had distinct immunologic characteristics such as differential binding to soluble MOG-ecIgD, sensitivity to MOG mutations, and binding to human MOG in ELISA.

Conclusions: The novel finding of differential MOG isoform binding patterns could inform future studies on the refinement of MOG-IgG assays and the pathophysiologic role of MOG-IgG.
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http://dx.doi.org/10.1212/NXI.0000000000001027DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8207634PMC
July 2021

Intrathecal Production of MOG-IgG: Highlighting the Need for CSF Testing in Clinical Practice.

Neurology 2021 07 12;97(1):12-13. Epub 2021 May 12.

From the Queen Square MS Centre (Y.H.), UCL Queen Square Institute of Neurology, Faculty of Brain Sciences, University College London; Department of Neurology (Y.H.), Great Ormond Street Hospital for Children, London, UK; Department of Neurology (W.K.), David Geffen School of Medicine at UCLA, Los Angeles, CA; and Nuffield Department of Clinical Neurosciences (P.W.), John Radcliffe Hospital, Oxford, UK.

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http://dx.doi.org/10.1212/WNL.0000000000012177DOI Listing
July 2021

Myelin Oligodendrocyte Glycoprotein (MOG) Antibody Positive Patients in a Multi-Ethnic Canadian Cohort.

Front Neurol 2020 12;11:525933. Epub 2021 Jan 12.

UBC MS/NMO Clinic, University of British Columbia, Vancouver, BC, Canada.

Myelin oligodendrocyte glycoprotein (MOG) antibody-associated disease is a recently described central nervous system (CNS) inflammatory disorder with phenotypic overlap with Neuromyelitis Optica Spectrum Disorder (NMOSD). NMOSD seronegative patients, and those with limited forms of the disorder, become suspects for MOG antibody-associated disease. We describe a multi-ethnic population with MOG antibody seropositivity from the University of British Columbia MS/NMO clinic. AQP4-antibody seronegative patients presenting 2005-2016 with CNS inflammatory disease suspicious for NMOSD, as well as 20 MS controls, were retrospectively tested for MOG-IgG1 antibodies by live cell-based assay at Oxford Autoimmune Neurology Diagnostic Laboratory (UK) and by a commercial fixed cell-based assay at MitogenDx (Calgary, Canada). Additional MOG seropositive cases were identified through routine clinical interaction (2016-2018) using one of these laboratories. Clinical data was reviewed retrospectively. Retrospective testing identified 21 MOG seropositives (14 by live assay only, 3 by fixed assay only and 4 by both) representing 14% of the "NMOSD suspects" cohort. One multiple sclerosis (MS) control serum was MOG seropositive. Twenty additional MOG positive cases were identified prospectively. Of 42 patients (27 female), median disease onset age was 29 years (range 3-62; 9 pediatric cases), 20 (47%) were non-Caucasian, and 3 (7%) had comorbid autoimmune disease. Most common onset phenotypes were optic neuritis (23, 55%; 8 bilateral) and myelitis (9, 21%; 6 longitudinally extensive) Three of the patients in our cohort experienced cortical encephalitis; two presented with seizures. Onset was moderate-severe in 64%, but 74% had good response to initial steroid therapy. Cumulative relapse probability for the MOG positive group at 1 year was 0.428 and at 4 years was 0.628. Most had abnormal brain imaging, including cortical encephalitis and poorly demarcated subcortical and infratentorial lesions. Few "classic MS" lesions were seen. Optic nerve lesions (frequently bilateral) were long and predominantly anterior, but 5 extended to the chiasm. Spinal cord lesions were long and short, with involvement of multiple spinal regions simultaneously, including the conus medullaris. Our MOG seropositive patients display phenotypes similar to previous descriptions, including cortical lesions with seizures and conus medullaris involvement. Many patients relapsed, predominantly in a different CNS location from onset. Serologic data from two different cell-based antibody assays highlight the discrepancies between live and fixed testing for MOG antibodies.
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http://dx.doi.org/10.3389/fneur.2020.525933DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7835710PMC
January 2021

Case Report: Myelin Oligodendrocyte Glycoprotein Antibody-Associated Relapse With COVID-19.

Front Neurol 2020 25;11:598531. Epub 2020 Nov 25.

Department of Neurology, Walton Centre NHS Foundation Trust, Liverpool, United Kingdom.

A 39-year-old lady with relapsing myelin oligodendrocyte glycoprotein antibody (MOG-IgG) associated disease developed coryzal symptoms, malaise, sweating, and postural dizziness. Six days later she presented with painful progressive right visual loss consistent with optic neuritis. COVID-19 was confirmed by nasopharyngeal swab and MOG-IgG serological reversion was noted. Visual function improved following steroids and plasma exchange. This case highlights a possible causal association between inflammation due to COVID-19 and a relapse of MOG-IgG associated disease. It also highlights the clinical relevance of reporting MOG-IgG titers in MOG-IgG associated disease.
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http://dx.doi.org/10.3389/fneur.2020.598531DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7724101PMC
November 2020

Overlapping central and peripheral nervous system syndromes in MOG antibody-associated disorders.

Neurol Neuroimmunol Neuroinflamm 2021 01 3;8(1). Epub 2020 Dec 3.

From the Inflammatory Neuropathy Group (S. Rinaldi, A.D., J.F.), Nuffield Department of Clinical Neurosciences, John Radcliffe Hospital; University of Oxford; Department of Neurology (S. Rinaldi, S.R.I.), Oxford University Hospitals NHS Foundation Trust, UK; Department of Neurology (H.N.B., M.H.B.), Royal Prince Alfred Hospital, Sydney; Brain and Mind Centre (H.N.B., T.A.H., M.H.B., S.W.R., F.B., R.C.D.), University of Sydney; Department of Neurology (J.W.), St George Hospital, Sydney; Department of Neurology (T.A.H., S.W.R., S. Ramanathan), Concord Repatriation General Hospital, Sydney; Menzies Institute of Health Queensland (S.A.B.), Griffith University; Department of Neurology (S.A.B.), Gold Coast University Hospital, Australia; Autoimmune Neurology Group (P.W., S.R.I., S. Ramanathan), Nuffield Department of Clinical Neuroscience, John Radcliffe Hospital; University of Oxford, UK; Brain Autoimmunity and Clinical Neuroimmunology Groups (F.B., R.C.D., S. Ramanathan), Kids Neuroscience Centre, Kids Research at the Children's Hospital at Westmead, Sydney; Faculty of Medicine and Health (F.B., R.C.D., S. Ramanathan), University of Sydney; School of Medical Sciences (F.B.), Discipline of Applied Medical Science, Faculty of Medicine and Health, University of Sydney, Australia; and TY Nelson Department of Paediatric Neurology (R.C.D.), Children's Hospital at Westmead, Sydney, Australia.

Objective: Antibodies to myelin oligodendrocyte glycoprotein (MOG) are associated with CNS demyelination inclusive of optic neuritis (ON) and transverse myelitis (TM). To examine whether peripheral nervous system (PNS) involvement is associated with MOG antibody-associated disorders (MOGAD), we performed detailed characterization of an Australasian MOGAD cohort.

Methods: Using a live cell-based assay, we diagnosed 271 adults with MOGAD (2013-2018) and performed detailed clinical and immunologic characterization on those with likely PNS involvement.

Results: We identified 19 adults with MOGAD and PNS involvement without prior TM. All patients had CNS involvement including ON (bilateral [n = 3], unilateral [n = 3], and recurrent [n = 7]), a cortical lesion (n = 1), meningoencephalitis (n = 1), and subsequent TM (n = 4). Clinical phenotyping and neurophysiology were consistent with acute inflammatory demyelinating polyneuropathy (n = 1), myeloradiculitis (n = 3), multifocal motor neuropathy (n = 1), brachial neuritis (n = 2), migrant sensory neuritis (n = 3), and paresthesia and/or radicular limb pain (n = 10). Onset MRI spine was consistent with myeloradiculitis with nerve root enhancement in 3/19 and normal in 16/19. Immunotherapy resulted in partial/complete PNS symptom resolution in 12/15 (80%) (steroids and/or IV immunoglobulin n = 9, rituximab n = 2, and plasmapheresis n = 1). We identified serum antibodies targeting neurofascin 155, contactin-associated protein 2, or GM1 in 4/16 patients with MOGAD PNS compared with 0/30 controls ( = 0.01). There was no binding to novel cell surface antigens using an in vitro myelinating sensory neuronal coculture model.

Conclusions: Myeloradiculitis, combined central and peripheral demyelination syndromes, and inflammatory neuropathies may be associated with MOGAD and may be immunotherapy responsive. We identified a subgroup who may have pathology mediated by coexistent autoantibodies.
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http://dx.doi.org/10.1212/NXI.0000000000000924DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7803332PMC
January 2021

Clinical features which predict neuronal surface autoantibodies in new-onset focal epilepsy: implications for immunotherapies.

J Neurol Neurosurg Psychiatry 2021 03 20;92(3):291-294. Epub 2020 Nov 20.

Oxford Autoimmune Neurology Group, Nuffield Department of Clinical Neurosciences, University of Oxford, Oxford, UK

Objective: To generate a score which clinically identifies surface-directed autoantibodies in adults with new-onset focal epilepsy, and evaluate the value of immunotherapy in this clinical setting.

Methods: Prospective clinical and autoantibody evaluations in a cohort of 219 consecutive patients with new-onset focal epilepsy.

Results: 10.5% (23/219) of people with new-onset focal epilepsy had detectable serum autoantibodies to known or novel cell surface antigenic targets. 9/23 with autoantibodies were diagnosed with encephalitis, by contrast to 0/196 without autoantibodies (p<0.0001). Multivariate analysis identified six features which predicted autoantibody positivity (area under the curve=0.83): age ≥54 years, ictal piloerection, lowered self-reported mood, reduced attention, MRI limbic system changes and the absence of conventional epilepsy risk factors. 11/14 (79%) patients with detectable autoantibodies, but without encephalitis, showed excellent long-term outcomes (modified Rankin Score=0) despite no immunotherapy. These outcomes were superior to those of immunotherapy-treated patients with confirmed autoantibody-mediated encephalitis (p<0.05).

Conclusions: Seizure semiology, cognitive and mood phenotypes, alongside inflammatory investigation findings, aid the identification of surface autoantibodies among unselected people with new-onset focal epilepsy. The excellent immunotherapy-independent outcomes of autoantibody-positive patients without encephalitis suggests immunotherapy administration should be guided by clinical features of encephalitis, rather than autoantibody positivity. Our findings suggest that, in this cohort, immunotherapy-responsive seizure syndromes with autoantibodies largely fall under the umbrella of autoimmune encephalitis.
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http://dx.doi.org/10.1136/jnnp-2020-325011DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7892387PMC
March 2021

Silent New Brain MRI Lesions in Children with MOG-Antibody Associated Disease.

Ann Neurol 2021 02 30;89(2):408-413. Epub 2020 Nov 30.

Center for Neuroinflammation and Neurotherapeutics, and Multiple Sclerosis Division, Department of Neurology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA.

Anti-myelin oligodendrocyte glycoprotein immunoglobulin G (MOG-IgG) antibodies are associated clinically with either a monophasic or relapsing disease course. We investigated the frequency and clinical importance of acquired asymptomatic brain magnetic resonance imaging (MRI) lesions in a prospective incident cohort of 74 MOG-IgG positive children with serial MRI scans over a median of 5 years from presentation. Silent new lesions were detected in 14% of MOG-IgG positive participants, most commonly within the first months post-onset, with a positive predictive value for clinically relapsing disease of only 20%. Detection of asymptomatic lesions alone need not prompt initiation of chronic immunotherapy. ANN NEUROL 2021;89:408-413.
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http://dx.doi.org/10.1002/ana.25957DOI Listing
February 2021

Autoantibodies in Japanese patients with ocular myasthenia gravis.

Muscle Nerve 2021 02 12;63(2):262-267. Epub 2020 Nov 12.

Department of Neurology, Nagasaki Kawatana Medical Center, Nagasaki, Japan.

Introduction: The majority of patients with myasthenia gravis (MG) initially present with ocular symptoms, but it is difficult to predict which cases will remain as ocular MG (OMG) or will progress to generalized MG. Herein we evaluated the serologic profile of Japanese OMG and its relationship with clinical features.

Methods: Seventy-three patients with OMG from five Japanese myasthenia gravis (MG) centers were enrolled. Live cell-based assays (CBAs) were used to determine the presence of autoantibodies (Abs) to clustered adult (2α, β, δ, ε) and fetal (2α, β, δ, γ) acetylcholine receptor (AChR) isoforms, muscle-specific receptor tyrosine kinase (MuSK), and lipoprotein receptor-related protein-4 (LRP4).

Results: Thirty-four of 73 (46.5%) serum samples were positive for Abs against both the adult-type and fetal-type AChR, as expected, but 7 (9.6%) and 2 (2.7%) were positive only for fetal or adult AChR-Abs, respectively. Four (5.4%) samples were positive for MuSK-Abs, but two of these also contained antibodies to fetal AChR or LRP4. Twenty-six (35.6%) samples were seronegative.

Discussion: Abs against fetal-specific AChR, MuSK, and LRP4 are found in some patients with OMG. Future studies attempting to predict conversion from ocular symptoms to generalized MG may benefit from measurement of these antibodies.
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http://dx.doi.org/10.1002/mus.27103DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7983878PMC
February 2021

Detection of MOG-IgG by cell-based assay: moving from discovery to clinical practice.

Neurol Sci 2021 Jan 15;42(1):73-80. Epub 2020 Oct 15.

Neuroinflammation and Neuroimmunology Lab, Brain Institute of Rio Grande do Sul, Porto Alegre, Brazil.

Myelin oligodendrocyte glycoprotein (MOG) is a unique CNS-specific mammalian protein that is expressed on the surface of compact myelin and oligodendrocyte cell bodies. MOG is an accessible target for autoantibodies, associated with immune-mediated demyelination in the central nervous system. The identification of MOG reactive immunoglobulin G antibodies (MOG-IgG) helps to distinguish a subgroup of patients from multiple sclerosis and other CNS disorders, reducing the risk of clinical misdiagnosis. The development of the cell-based assays (CBA) improved the detection of clinically meaningful MOG-IgG binding to conformational MOG expressed in the cell membrane surface. In this review, we describe factors that impact on the results of CBA, such as MOG conformation, protein glycosylation, addition of fluorescent tags, serum dilution, secondary antibodies, and data interpretation.
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http://dx.doi.org/10.1007/s10072-020-04828-1DOI Listing
January 2021

Absence of Neuronal Autoantibodies in Neuropsychiatric Systemic Lupus Erythematosus.

Ann Neurol 2020 12 6;88(6):1244-1250. Epub 2020 Oct 6.

Oxford Autoimmune Neurology Group, Nuffield Department of Clinical Neurosciences, University of Oxford, Oxford, UK.

This study aimed to characterise both neuronal autoantibodies and levels of interferon α, two proposed causative agents in neuropsychiatric systemic lupus erythematosus (NPSLE). Cerebrospinal fluid (CSF) and plasma from 35 patients with systemic lupus erythematosus (SLE; 15 with NPSLE) showed no antibodies against natively expressed N-methyl-D-aspartate receptors (NMDARs), or the surface of live hippocampal neurons. By comparison to controls (n = 104), patients with SLE had antibodies that bound to a peptide representing the extracellular domain of NMDARs (p < 0.0001), however, binding was retained against both rearranged peptides and no peptide (r = 0.85 and r = 0.79, respectively, p < 0.0001). In summary, neuronal-surface reactive antibodies were not detected in NPSLE. Further, while interferon α levels were higher in SLE (p < 0.0001), they lacked specificity for NPSLE. Our findings mandate a search for novel biomarkers in this condition. ANN NEUROL 2020;88:1244-1250.
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http://dx.doi.org/10.1002/ana.25908DOI Listing
December 2020

Cell-based assays for the detection of MOG antibodies: a comparative study.

J Neurol 2020 Dec 4;267(12):3555-3564. Epub 2020 Jul 4.

Neuroimmunology Laboratory, IRCCS Mondino Foundation, Pavia, Italy.

Background: The detection of antibodies to myelin oligodendrocyte glycoprotein (MOG) is fundamental for the identification of MOG antibody-associated disorders (MOGAD), and the differential diagnosis of acquired demyelinating syndromes of the CNS, among which multiple sclerosis (MS). We compared the diagnostic performance of four cell-based assays (CBAs) for their detection.

Methods: Consecutive sera from 204 patients with 'possible MOGAD' (55), MS (112), and other neurological disorders (OND, 37) were tested for MOG-IgG with a live-CBA with anti-heavy-and-light chain secondary-antibody (LCBA-IgG), and a live-CBA for IgG (LCBA-IgG). A subgroup of 71 patients was additionally tested with a live-CBA with anti-Fcγ secondary-antibody (LCBA-IgG), and a commercial fixed-CBA with anti-Fcγ secondary-antibody (FCBA-IgG) RESULTS: Fifty-seven/204 patients (27.9%) were MOG-IgG-positive. Sensitivity was 89.1% (CI:77.8-95.9) and specificity 93.3% (CI:88.0-96.7) for LCBA-IgG, and 74.6% (CI:61.0-85.3) and 100% (CI:97.6-100) for LCBA-IgG. Eighteen of 57 (31%) samples showed discrepant results (all negative on LCBA-IgG); of these, three with 'possible MOGAD' showed high-titer MOG-IgG (≥ 1:640), and positivity for MOG-IgG, whereas 15/18 had low-titer MOG-IgG (1:160/1:320) and mixed diagnoses (5 'possible MOGAD', 6 MS, 4 OND). In the subgroup analysis, sensitivity was 92.3% (CI:79.1-98.4) and specificity 97.0% (CI:83.8-99.9) for LCBA-IgG, and 87.2% (CI:72.6-95.7) and 97.0% (CI:83.8-99.9) for FCBA-IgG.

Conclusions: LCBA-IgG showed the highest specificity but can miss MOG-IgG reactivities, whose meaning warrants further investigations. Titration of samples tested with LCBA-IgG/ IgG is important for meaningful interpretation of the results. In the subgroup analysis, LCBA-IgG yielded the highest accuracy, and FCBA-IgG good specificity, but it was at risk of false-negative results.
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http://dx.doi.org/10.1007/s00415-020-10024-0DOI Listing
December 2020

Relapse Patterns in NMOSD: Evidence for Earlier Occurrence of Optic Neuritis and Possible Seasonal Variation.

Front Neurol 2020 16;11:537. Epub 2020 Jun 16.

Westmead Clinical School, Westmead Hospital, University of Sydney, Westmead, NSW, Australia.

Neuromyelitis optica spectrum disorders (NMOSD) and multiple sclerosis (MS) show overlap in their clinical features. We performed an analysis of relapses with the aim of determining differences between the two conditions. Cases of NMOSD and age- and sex-matched MS controls were collected from across Australia and New Zealand. Demographic and clinical information, including relapse histories, were recorded using a standard questionnaire. There were 75 cases of NMOSD and 101 MS controls. There were 328 relapses in the NMOSD cases and 375 in MS controls. Spinal cord and optic neuritis attacks were the most common relapses in both NMOSD and MS. Optic neuritis ( < 0.001) and area postrema relapses ( = 0.002) were more common in NMOSD and other brainstem attacks were more common in MS ( < 0.001). Prior to age 30 years, attacks of optic neuritis were more common in NMOSD than transverse myelitis. After 30 this pattern was reversed. Relapses in NMOSD were more likely to be treated with acute immunotherapies and were less likely to recover completely. Analysis by month of relapse in NMOSD showed a trend toward reduced risk of relapse in February to April compared to a peak in November to January ( = 0.065). Optic neuritis and transverse myelitis are the most common types of relapse in NMOSD and MS. Optic neuritis tends to occur more frequently in NMOSD prior to the age of 30, with transverse myelitis being more common thereafter. Relapses in NMOSD were more severe. A seasonal bias for relapses in spring-summer may exist in NMOSD.
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http://dx.doi.org/10.3389/fneur.2020.00537DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7308484PMC
June 2020

Stop testing for autoantibodies to the VGKC-complex: only request LGI1 and CASPR2.

Pract Neurol 2020 Oct 28;20(5):377-384. Epub 2020 Jun 28.

Oxford Autoimmune Neurology Group, Nuffield Department of Clinical Neurosciences, University of Oxford, Oxford, UK

Autoantibodies to leucine-rich glioma-inactivated 1 (LGI1) and contactin-associated protein like-2 (CASPR2) are associated with clinically distinctive syndromes that are highly immunotherapy responsive, such as limbic encephalitis, faciobrachial dystonic seizures, Morvan's syndrome and neuromyotonia. These autoantibodies target surface-exposed domains of LGI1 or CASPR2, and appear to be directly pathogenic. In contrast, voltage-gated potassium channel (VGKC) antibodies that lack LGI1 or CASPR2 reactivities ('double-negative') are common in healthy controls and have no consistent associations with distinct syndromes. These antibodies target intracellular epitopes and lack pathogenic potential. Moreover, the clinically important LGI1 and CASPR2 antibodies comprise only ~15% of VGKC-positive results, meaning that most VGKC-antibody positive results mislead rather than help. Further, initial VGKC testing misses some cases that have LGI1 and CASPR2 antibodies. These collective observations confirm that laboratories should stop testing for VGKC antibodies and instead, test only for LGI1 and CASPR2 antibodies. This change in practice will lead to significant patient benefit.
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http://dx.doi.org/10.1136/practneurol-2019-002494DOI Listing
October 2020

We need to talk about MOG.

Neurology 2020 07 17;95(2):55-56. Epub 2020 Jun 17.

From the Nuffield Department of Clinical Neurosciences, University of Oxford, UK.

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http://dx.doi.org/10.1212/WNL.0000000000009768DOI Listing
July 2020

Bone health in neuromyelitis optica: Bone mineral density and fractures.

Mult Scler Relat Disord 2020 Jul 28;42:102080. Epub 2020 Apr 28.

Department of Neurology, Seoul National University Bundang Hospital, Gyeonggi, Republic of Korea; Department of Neurology, Neuroscience Research Institute, Seoul National University College of Medicine, Seoul, Republic of Korea. Electronic address:

Background: The bone health in neuromyelitis optica spectrum disorder with aquaporin-4 immunoglobulin G antibodies (NMOSD-AQP4) have not been fully evaluated. To evaluate the prevalence of fractures and bone loss in patients with NMOSD-AQP4 compared to healthy controls and patients with multiple sclerosis (MS) and to identify the risk factors associated with fractures and low bone mineral density (BMD) in patients with NMOSD-AQP4.

Methods: Seventy-one patients with NMOSD-AQP4 were included. The two control groups consisted of 213 age-, sex-, menopause-, and body mass index (BMI)-matched healthy participants from the Korean National Health and Nutrition Examination Survey (healthy controls) and 41 patients with multiple sclerosis (disease controls). We collected demographic and clinical data related to bone health including BMD and FRAX score.

Results: Patients with NMOSD-AQP4 had a higher prevalence of fractures than the healthy control group (OR = 5.40, CI = 2.004-14.524, p = 0.001), with falling, but not steroid use, being associated with an increased risk of fractures after diagnosis with NMOSD-AQP4 (OR = 24.902, CI = 3.086-200.947, p = 0.003). They also had significantly lower BMD than controls (femur neck, p = 0.044; total hip, p < 0.001), which was more prominent in young participants. The BMD in the NMOSD-AQP4 group was associated with cumulative dose of oral steroids, age, sex, BMI, and partly with the prophylactic calcium supplements. Though the patients with NMOSD-AQP4 did not differ significantly from patients with MS in terms of fracture rate and BMD, they had higher risk of fractures as measured by the Fracture Risk Assessment Tool (for major osteoporotic fractures, (p = 0.001; for hip fractures, p = 0.018).

Conclusion: Patients with NMOSD-AQP4 had a significantly higher risk of fractures that could mostly be attributed to falling. Additionally, low BMD was observed in these patients; it was more prominent among young patients, associated with steroid use, and may partially prevented by the use of prophylactic calcium supplements.
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http://dx.doi.org/10.1016/j.msard.2020.102080DOI Listing
July 2020

Distinctive binding properties of human monoclonal LGI1 autoantibodies determine pathogenic mechanisms.

Brain 2020 06;143(6):1731-1745

Oxford Autoimmune Neurology Group, Nuffield Department of Clinical Neurosciences, University of Oxford, Oxford, UK.

Autoantibodies against leucine-rich glioma inactivated 1 (LGI1) are found in patients with limbic encephalitis and focal seizures. Here, we generate patient-derived monoclonal antibodies (mAbs) against LGI1. We explore their sequences and binding characteristics, plus their pathogenic potential using transfected HEK293T cells, rodent neuronal preparations, and behavioural and electrophysiological assessments in vivo after mAb injections into the rodent hippocampus. In live cell-based assays, LGI1 epitope recognition was examined with patient sera (n = 31), CSFs (n = 11), longitudinal serum samples (n = 15), and using mAbs (n = 14) generated from peripheral B cells of two patients. All sera and 9/11 CSFs bound both the leucine-rich repeat (LRR) and the epitempin repeat (EPTP) domains of LGI1, with stable ratios of LRR:EPTP antibody levels over time. By contrast, the mAbs derived from both patients recognized either the LRR or EPTP domain. mAbs against both domain specificities showed varied binding strengths, and marked genetic heterogeneity, with high mutation frequencies. LRR-specific mAbs recognized LGI1 docked to its interaction partners, ADAM22 and ADAM23, bound to rodent brain sections, and induced internalization of the LGI1-ADAM22/23 complex in both HEK293T cells and live hippocampal neurons. By contrast, few EPTP-specific mAbs bound to rodent brain sections or ADAM22/23-docked LGI1, but all inhibited the docking of LGI1 to ADAM22/23. After intrahippocampal injection, and by contrast to the LRR-directed mAbs, the EPTP-directed mAbs showed far less avid binding to brain tissue and were consistently detected in the serum. Post-injection, both domain-specific mAbs abrogated long-term potentiation induction, and LRR-directed antibodies with higher binding strengths induced memory impairment. Taken together, two largely dichotomous populations of LGI1 mAbs with distinct domain binding characteristics exist in the affinity matured peripheral autoantigen-specific memory pools of individuals, both of which have pathogenic potential. In human autoantibody-mediated diseases, the detailed characterization of patient mAbs provides a valuable method to dissect the molecular mechanisms within polyclonal populations.
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http://dx.doi.org/10.1093/brain/awaa104DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7296845PMC
June 2020

International multicenter examination of MOG antibody assays.

Neurol Neuroimmunol Neuroinflamm 2020 03 5;7(2). Epub 2020 Feb 5.

From the Clinical Department of Neurology (M. Reindl, K.S., M. Ramberger, H.H.), Medical University of Innsbruck, Innsbruck, Austria; Oxford Autoimmune Neurology Group (M.W., M. Ramberger, M.I.L., J.P., S.R.I., P.W.), Nuffield Department of Clinical Neurosciences, University of Oxford, United Kingdom; Brain Autoimmunity Group (F.T., S.R., R.C.D., F.B.), Kids Neuroscience Centre at Kids Research at the Children's Hospital at Westmead, Brain and Mind Centre, University of Sydney, New South Wales, Australia; Department of Neurology (J.S., J.P.F., J.M., E.P.F., S.J.P.), Mayo Clinic, Rochester, MN; Euroimmun Medizinische Labordiagnostika AG (B.T., S.M., N.R., U.K., W.S., C.P.), Lübeck, Germany; Institute for Quality Assurance (ifQ) affiliated to Euroimmun (J.E., M.P.), Lübeck, Germany; Paediatric Neurology (K.R.), Witten/Herdecke University, Children's Hospital Datteln, Datteln, Germany; and Department of Neurology (T.B.), Medical University of Vienna, Austria.

Objective: To compare the reproducibility of 11 antibody assays for immunoglobulin (Ig) G and IgM myelin oligodendrocyte glycoprotein antibodies (MOG-IgG and MOG-IgM) from 5 international centers.

Methods: The following samples were analyzed: MOG-IgG clearly positive sera (n = 39), MOG-IgG low positive sera (n = 39), borderline negative sera (n = 13), clearly negative sera (n = 40), and healthy blood donors (n = 30). As technical controls, 18 replicates (9 MOG-IgG positive and 9 negative) were included. All samples and controls were recoded, aliquoted, and distributed to the 5 testing centers, which performed the following antibody assays: 5 live and 1 fixed immunofluorescence cell-based assays (CBA-IF, 5 MOG-IgG, and 1 MOG-IgM), 3 live flow cytometry cell-based assays (CBA-FACS, all MOG-IgG), and 2 ELISAs (both MOG-IgG).

Results: We found excellent agreement (96%) between the live CBAs for MOG-IgG for samples previously identified as clearly positive or negative from 4 different national testing centers. The agreement was lower with fixed CBA-IF (90%), and the ELISA showed no concordance with CBAs for detection of human MOG-IgG. All CBAs showed excellent interassay reproducibility. The agreement of MOG-IgG CBAs for borderline negative (77%) and particularly low positive (33%) samples was less good. Finally, most samples from healthy blood donors (97%) were negative for MOG-IgG in all CBAs.

Conclusions: Live MOG-IgG CBAs showed excellent agreement for high positive and negative samples at 3 international testing centers. Low positive samples were more frequently discordant than in a similar comparison of aquaporin-4 antibody assays. Further research is needed to improve international standardization for clinical care.
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http://dx.doi.org/10.1212/NXI.0000000000000674DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7051197PMC
March 2020

The clinical profile of NMOSD in Australia and New Zealand.

J Neurol 2020 May 31;267(5):1431-1443. Epub 2020 Jan 31.

Department of Neurology, Westmead Hospital, Westmead, NSW, 2145, Australia.

Neuromyelitis optica spectrum disorders (NMOSD) are an inflammation of the central nervous system associated with autoantibodies to aquaporin-4. We have undertaken a clinic-based survey of NMOSD in the Australia and New Zealand populations with the aim of characterising the clinical features and establishing the value of recently revised diagnostic criteria. Cases of possible NMOSD and age and sex-matched controls with multiple sclerosis (MS) were referred from centres across Australia and New Zealand. Cases were classified as NMOSD if they met the 2015 IPND criteria and remained as suspected NMOSD if they did not. Clinical and paraclinical data were compared across the three groups. NMOSD was confirmed in 75 cases and 89 had suspected NMOSD. There were 101 controls with MS. Age at onset, relapse rates and EDSS scores were significantly higher in NMOSD than in MS. Lesions and symptoms referable to the optic nerve were more common in NMOSD whereas brainstem, cerebellar and cerebral lesions were more common in MS. Longitudinally extensive spinal cord lesions were seen in 48/71 (68%) of cases with NMOSD. Elevations of CSF, white cell count and protein were more common in NMOSD. We have confirmed a clinical pattern of NMOSD that has been seen in several geographical regions. We have demonstrated the clinical utility of the current diagnostic criteria. Distinct patterns of disease are evident in NMOSD and MS, but there remains a large number of patients with NMOSD-like features who do not meet the current diagnostic criteria for NMOSD and remain a diagnostic challenge.
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http://dx.doi.org/10.1007/s00415-020-09716-4DOI Listing
May 2020

Refining cell-based assay to detect MOG-IgG in patients with central nervous system inflammatory diseases.

Mult Scler Relat Disord 2020 May 9;40:101939. Epub 2020 Jan 9.

Department of Neurology, Research Institute and Hospital of National Cancer Center, 323 Ilsan-ro, Ilsandong-gu, Goyang, Republic of Korea; Division of Clinical Research, National Cancer Center, Research institute, Goyang, Republic of Korea. Electronic address:

Background: Given that the spectrum of myelin oligodendrocyte glycoprotein immunoglobulin G (MOG-IgG) associated disease is yet to be fully defined, development of sensitive and highly specific assays to identify MOG-IgG is crucial to precisely define the clinical phenotypes, disease courses and prognosis to describe the full spectrum of MOG-IgG associated diseases. Here, we aim to validate a new in-house live cell-based assay (CBA) for screening MOG-IgG in patients with central nervous system inflammatory diseases.

Methods: We generated a full length MOG transfected HEK293 stable cell line using pIRES2-eGFP vector. Sera from 355 patients with central nervous system inflammatory diseases and 25 healthy individuals were evaluated for MOG-IgG seropositivity using in-house cell-based immunofluorescence assay (CBA-IF). The specificity of IgG (H + L) and IgG1-Fc secondary antibodies as well as IgM binding were determined by cell-based flow cytometry (CBA-FACS). The optimal cut-offs for determining seropositivity in CBA-FACS were calculated and the concordance of CBA-IF score and CBA-FACS was studied. The results of our CBA-IF were compared with the Oxford CBA-IF.

Results: 11.5% (41/355) of patients were seropositive for MOG-IgG and had clinical phenotypes that were within the known clinical spectrum of MOG-IgG associated diseases. No typical multiple sclerosis patients, aquaporin-4-IgG positive neuromyelitis optica spectrum disorder or healthy individuals were MOG-IgG seropositive. Using CBA-FACS, the anti-human IgG (H + L) was found to be comparable to IgG1-Fc antibody. No IgM binding was observed in all the samples tested. CBA-IF score and CBA-FACS yielded high correlation. The concordance of the NCC CBA-IF with the Oxford CBA-IF was 98%.

Conclusion: We have developed MOG-IgG CBAs that have different characteristics and benefits but with high specificity and concordance. The complementary use of two methods and follow-up study with larger cohort will increase the clinical usefulness of MOG-IgG CBAs.
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http://dx.doi.org/10.1016/j.msard.2020.101939DOI Listing
May 2020

Randomized Placebo-Controlled Trial of Intravenous Immunoglobulin in Autoimmune LGI1/CASPR2 Epilepsy.

Ann Neurol 2020 02 14;87(2):313-323. Epub 2019 Dec 14.

Department of Neurology and Immunology, Mayo Clinic, Rochester, MN.

Objective: Drug-resistant seizures are common in patients with leucine-rich, glioma-inactivated 1 (LGI1)-IgG associated and contactin-associated protein-like 2 (CASPR2)-IgG associated encephalitis. We performed the first randomized double-blind placebo-controlled trial to evaluate efficacy of intravenous immunoglobulin (IVIG) in reducing seizure frequency.

Methods: Our enrollment goal was 30 LGI1/CASPR2-IgG-seropositive adult patients with ≥2 seizures per week. Patients were randomized to receive IVIG (0.5g/kg day 1, 1g/kg day 2, 0.6g/kg weeks 3 and 5) or volume-matched intravenous normal saline. Following the blinded phase, the nonresponders in the placebo group received IVIG. The primary clinical outcome was 50% reduction in seizure frequency from baseline to 5 weeks.

Results: After enrollment of 17 patients (LGI1-IgG, 14; CASPR2-IgG, 3) over 34 months, the study was terminated due to slow enrollment. Six of 8 patients in the IVIG group were responders, compared to 2 of 9 in the placebo group (p = 0.044, odds ratio = 10.5, 95% confidence interval = 1.1-98.9). For the LGI1-IgG seropositive subgroup, 6 of 8 patients in the IVIG group were responders, compared to zero of 6 in the placebo group. Two LGI1-IgG-seropositive patients receiving IVIG, but none receiving placebo, were seizure-free at the end of the blinded phase. Four of the 6 patients entering the open-label IVIG arm reported ≥50% reduction in seizure frequency. There were no correlations with LGI1/CASPR2-IgG1-4 subclasses.

Interpretation: Superiority of IVIG to placebo reached statistical significance for the primary endpoint for all patients and the subset with LGI1-IgG. These results have to be interpreted with the caveat that the study did not reach its originally selected sample size. ANN NEUROL 2020;87:313-323.
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http://dx.doi.org/10.1002/ana.25655DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7003900PMC
February 2020

Classifying the antibody-negative NMO syndromes: Clinical, imaging, and metabolomic modeling.

Neurol Neuroimmunol Neuroinflamm 2019 11 28;6(6):e626. Epub 2019 Oct 28.

From the Department of Pharmacology (T.Y, F.P., M.S., D.C.A.), University of Oxford, UK; Department of Neurology (T.Y.), National Neuroscience Institute, Singapore; Nuffield Department of Clinical Neurosciences (M.J., A.C., M.W., P.W., M.I.L., J.P.), John Radcliffe Hospital, University of Oxford, UK; Department of Chemistry, (T.D.W.C.), Chemistry Research Laboratory, University of Oxford, UK.

Objective: To determine whether unsupervised principal component analysis (PCA) of comprehensive clinico-radiologic data can identify phenotypic subgroups within antibody-negative patients with overlapping features of multiple sclerosis (MS) and neuromyelitis optica spectrum disorders (NMOSDs), and to validate the phenotypic classifications using high-resolution nuclear magnetic resonance (NMR) plasma metabolomics with inference to underlying pathologies.

Methods: Forty-one antibody-negative patients were recruited from the Oxford NMO Service. Thirty-six clinico-radiologic parameters, focusing on features known to distinguish NMOSD and MS, were collected to build an unbiased PCA model identifying phenotypic subgroups within antibody-negative patients. Metabolomics data from patients with relapsing-remitting MS (RRMS) (n = 34) and antibody-positive NMOSD (Ab-NMOSD) (aquaporin-4 antibody n = 54, myelin oligodendrocyte glycoprotein antibody n = 20) were used to identify discriminatory plasma metabolites separating RRMS and Ab-NMOSD.

Results: PCA of the 36 clinico-radiologic parameters revealed 3 phenotypic subgroups within antibody-negative patients: an MS-like subgroup, an NMOSD-like subgroup, and a low brain lesion subgroup. Supervised multivariate analysis of metabolomics data from patients with RRMS and Ab-NMOSD identified myoinositol and formate as the most discriminatory metabolites (both higher in RRMS). Within antibody-negative patients, myoinositol and formate were significantly higher in the MS-like vs NMOSD-like subgroup; myoinositol (mean [SD], 0.0023 [0.0002] vs 0.0019 [0.0003] arbitrary units [AU]; = 0.041); formate (0.0027 [0.0006] vs 0.0019 [0.0006] AU; = 0.010) (AU).

Conclusions: PCA identifies 3 phenotypic subgroups within antibody-negative patients and that the metabolite discriminators of RRMS and Ab-NMOSD suggest that these groupings have some pathogenic meaning. Thus, the identified clinico-radiologic discriminators may provide useful diagnostic clues when seeing antibody-negative patients in the clinic.
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http://dx.doi.org/10.1212/NXI.0000000000000626DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6865851PMC
November 2019

The autoantibody-mediated encephalitides: from clinical observations to molecular pathogenesis.

J Neurol 2021 May 26;268(5):1689-1707. Epub 2019 Oct 26.

Oxford Autoimmune Neurology Group, Nuffield Department of Clinical Neuroscience, John Radcliffe Hospital, Oxford, UK.

The autoimmune encephalitis (AE) syndromes have been characterised by the detection of autoantibodies in serum and/or cerebrospinal fluid which target the extracellular domains of specific neuroglial antigens. The clinical syndromes have phenotypes which are often highly characteristic of their associated antigen-specific autoantibody. For example, the constellation of psychiatric features and the multi-faceted movement disorder observed in patients with NMDAR antibodies are highly distinctive, as are the faciobrachial dystonic seizures observed in close association with LGI1 antibodies. These typically tight correlations may be conferred by the presence of autoantibodies which can directly access and modulate their antigens in vivo. AE remains an under-recognised clinical syndrome but one where early and accurate detection is critical as prompt initiation of immunotherapy is closely associated with improved outcomes. In this review of a rapidly emerging field, we outline molecular observations with translational value. We focus on contemporary methodologies of autoantibody detection, the evolution and distinctive nature of the clinical phenotypes, generalisable therapeutic paradigms, and finally discuss the likely mechanisms of autoimmunity in these patients which may inform future precision therapies.
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http://dx.doi.org/10.1007/s00415-019-09590-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8068716PMC
May 2021
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