Publications by authors named "Jacqueline Palace"

224 Publications

Objective biomarkers for clinical relapse in multiple sclerosis: a metabolomics approach.

Brain Commun 2021 12;3(4):fcab240. Epub 2021 Oct 12.

Department of Pharmacology, University of Oxford, Oxford OX1 3QT, UK.

Accurate determination of relapses in multiple sclerosis is important for diagnosis, classification of clinical course and therapeutic decision making. The identification of biofluid markers for multiple sclerosis relapses would add to our current diagnostic armamentarium and increase our understanding of the biology underlying the clinical expression of inflammation in multiple sclerosis. However, there is presently no biofluid marker capable of objectively determining multiple sclerosis relapses although some, in particular neurofilament-light chain, have shown promise. In this study, we sought to determine if metabolic perturbations are present during multiple sclerosis relapses, and, if so, identify candidate metabolite biomarkers and evaluate their discriminatory abilities at both group and individual levels, in comparison with neurofilament-light chain. High-resolution global and targeted H nuclear magnetic resonance metabolomics as well as neurofilament-light chain measurements were performed on the serum in four groups of relapsing-remitting multiple sclerosis patients, stratified by time since relapse onset: (i) in relapse (R); (ii) last relapse (LR) ≥ 1 month (M) to < 6 M ago; (iii) LR ≥ 6 M to < 24 M ago; and (iv) LR ≥ 24 M ago. Two hundred and one relapsing-remitting multiple sclerosis patients were recruited: R ( = 38), LR 1-6 M ( = 28), LR 6-24 M ( = 34), LR ≥ 24 M ( = 101). Using supervised multivariate analysis, we found that the global metabolomics profile of R patients was significantly perturbed compared to LR ≥ 24 M patients. Identified discriminatory metabolites were then quantified using targeted metabolomics. Lysine and asparagine (higher in R), as well as, isoleucine and leucine (lower in R), were shortlisted as potential metabolite biomarkers. ANOVA of these metabolites revealed significant differences across the four patient groups, with a clear trend with time since relapse onset. Multivariable receiver operating characteristics analysis of these four metabolites in discriminating R versus LR ≥ 24 M showed an area under the curve of 0.758, while the area under the curve for serum neurofilament-light chain was 0.575. Within individual patients with paired relapse-remission samples, all four metabolites were significantly different in relapse versus remission, with the direction of change consistent with that observed at group level, while neurofilament-light chain was not discriminatory. The perturbations in the identified metabolites point towards energy deficiency and immune activation in multiple sclerosis relapses, and the measurement of these metabolites, either singly or in combination, are useful as biomarkers to differentiate relapse from remission at both group and individual levels.
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http://dx.doi.org/10.1093/braincomms/fcab240DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8568847PMC
October 2021

Astrocytic outer retinal layer thinning is not a feature in AQP4-IgG seropositive neuromyelitis optica spectrum disorders.

J Neurol Neurosurg Psychiatry 2021 Oct 28. Epub 2021 Oct 28.

Neuro-Opthalmology Division, Department of Opthalmology, Rabin Medical Center, Petah Tikva, Israel.

Background: Patients with anti-aquaporin-4 antibody seropositive (AQP4-IgG+) neuromyelitis optica spectrum disorders (NMOSDs) frequently suffer from optic neuritis (ON) leading to severe retinal neuroaxonal damage. Further, the relationship of this retinal damage to a primary astrocytopathy in NMOSD is uncertain. Primary astrocytopathy has been suggested to cause ON-independent retinal damage and contribute to changes particularly in the outer plexiform layer (OPL) and outer nuclear layer (ONL), as reported in some earlier studies. However, these were limited in their sample size and contradictory as to the localisation. This study assesses outer retinal layer changes using optical coherence tomography (OCT) in a multicentre cross-sectional cohort.

Method: 197 patients who were AQP4-IgG+ and 32 myelin-oligodendrocyte-glycoprotein antibody seropositive (MOG-IgG+) patients were enrolled in this study along with 75 healthy controls. Participants underwent neurological examination and OCT with central postprocessing conducted at a single site.

Results: No significant thinning of OPL (25.02±2.03 µm) or ONL (61.63±7.04 µm) were observed in patients who were AQP4-IgG+ compared with patients who were MOG-IgG+ with comparable neuroaxonal damage (OPL: 25.10±2.00 µm; ONL: 64.71±7.87 µm) or healthy controls (OPL: 24.58±1.64 µm; ONL: 63.59±5.78 µm). Eyes of patients who were AQP4-IgG+ (19.84±5.09 µm, p=0.027) and MOG-IgG+ (19.82±4.78 µm, p=0.004) with a history of ON showed parafoveal OPL thinning compared with healthy controls (20.99±5.14 µm); this was not observed elsewhere.

Conclusion: The results suggest that outer retinal layer loss is not a consistent component of retinal astrocytic damage in AQP4-IgG+ NMOSD. Longitudinal studies are necessary to determine if OPL and ONL are damaged in late disease due to retrograde trans-synaptic axonal degeneration and whether outer retinal dysfunction occurs despite any measurable structural correlates.
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http://dx.doi.org/10.1136/jnnp-2021-327412DOI Listing
October 2021

Increasing role of imaging in differentiating MS from non-MS and defining indeterminate borderline cases.

Neurol Neurochir Pol 2021 Oct 19. Epub 2021 Oct 19.

Nuffield Department of Clinical Neurosciences, University of Oxford, United Kingdom.

Multiple sclerosis (MS) is a heterogenous condition with differences between patients regarding disease presentation, imaging features, disease activity, prognosis and treatment responses. Following the discovery of new biomarkers, the concept of MS has evolved, with syndromes previously considered to be its variants now recognised as separate entities, including aquaporin-4 (AQP4)-antibody (Ab) neuromyelits optica spectrum disorders (NMOSD), and myelin oligodendrocyte glycoprotein (MOG)-Ab disease (MOGAD). In line with their distinct pathology, the newly emerging conditions have imaging characteristics which are dissimilar to typical MS. Progress in reclassifying such demyelinating CNS conditions has highlighted the challenge in meaningful categorisation of atypical presentations at the borders of MS, such as antibody-negative neuromyelitis optica-like syndromes, tumefactive demyelinating lesions, or Balo's concentric sclerosis. In this review, we discuss the increasing role of imaging in distinguishing MS from non-MS CNS inflammatory/demyelinating conditions and defining undetermined borderline cases. This progress relies both on better characterisation of imaging features of these conditions on conventional imaging in terms of their appearance and location, as well as on the implementation of novel image acquisition and/or post-processing techniques allowing for more in-depth lesion assessment, including the presence of a central vein sign or paramagnetic rim.
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http://dx.doi.org/10.5603/PJNNS.a2021.0077DOI Listing
October 2021

Myasthenia gravis: do not forget the patient perspective.

Neuromuscul Disord 2021 Oct 8. Epub 2021 Oct 8.

Nuffield Department of Clinical Neurosciences, University of Oxford, Hospitals Trust, Oxford, England.

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http://dx.doi.org/10.1016/j.nmd.2021.07.396DOI Listing
October 2021

Characterizing 1-year development of cervical cord atrophy across different MS phenotypes: A voxel-wise, multicentre analysis.

Mult Scler 2021 Oct 4:13524585211045545. Epub 2021 Oct 4.

Neuroimaging Research Unit, Division of Neuroscience, Neurology Unit, IRCCS San Raffaele Scientific Institute, Milan, Italy; Vita-Salute San Raffaele University, Milan, Italy.

Background: Spatio-temporal evolution of cord atrophy in multiple sclerosis (MS) has not been investigated yet.

Objective: To evaluate voxel-wise distribution and 1-year changes of cervical cord atrophy in a multicentre MS cohort.

Methods: Baseline and 1-year 3D T1-weighted cervical cord scans and clinical evaluations of 54 healthy controls (HC) and 113 MS patients (14 clinically isolated syndromes (CIS), 77 relapsing-remitting (RR), 22 progressive (P)) were used to investigate voxel-wise cord volume loss in patients versus HC, 1-year volume changes and clinical correlations (SPM12).

Results: MS patients exhibited baseline cord atrophy versus HC at anterior and posterior/lateral C1/C2 and C4-C6 ( < 0.05, corrected). While CIS patients showed baseline volume increase at C4 versus HC ( < 0.001, uncorrected), RRMS exhibited posterior/lateral C1/C2 atrophy versus CIS, and PMS showed widespread cord atrophy versus RRMS ( < 0.05, corrected). At 1 year, 13 patients had clinically worsened. Cord atrophy progressed in MS, driven by RRMS, at posterior/lateral C2 and C3-C6 ( < 0.05, corrected). CIS patients showed no volume changes, while PMS showed circumscribed atrophy progression. Baseline cord atrophy at posterior/lateral C1/C2 and C3-C6 correlated with concomitant and 1-year disability ( = -0.40/-0.62, < 0.05, corrected).

Conclusions: Voxel-wise analysis characterized spinal cord neurodegeneration over 1 year across MS phenotypes and helped to explain baseline and 1-year disability.
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http://dx.doi.org/10.1177/13524585211045545DOI Listing
October 2021

Early predictors of disability of paediatric-onset AQP4-IgG-seropositive neuromyelitis optica spectrum disorders.

J Neurol Neurosurg Psychiatry 2021 Sep 28. Epub 2021 Sep 28.

Nuffield Department of Clinical Neuroscience, University of Oxford, Oxford, UK

Objective: To describe onset clinical features predicting time to first relapse and time to long-term visual, motor and cognitive disabilities in paediatric-onset aquaporin-4 antibody (AQP4-IgG) neuromyelitis optica spectrum disorders (NMOSDs).

Methods: In this retrospective UK multicentre cohort study, we recorded clinical data of paediatric-onset AQP4-IgG NMOSD. Univariate and exploratory multivariable Cox proportional hazard models were used to identify long-term predictors of permanent visual disability, Expanded Disability Status Scale (EDSS) score of 4 and cognitive impairment.

Results: We included 49 paediatric-onset AQP4-IgG patients (38.8% white, 34.7% black, 20.4% Asians and 6.1% mixed), mean onset age of 12±4.1 years, and 87.7% were female. Multifocal onset presentation occurred in 26.5% of patients, and optic nerve (47%), area postrema/brainstem (48.9%) and encephalon (28.6%) were the most involved areas. Overall, 52.3% of children had their first relapse within 1 year from disease onset. Children with onset age <12 years were more likely to have an earlier first relapse (p=0.030), despite showing no difference in time to immunosuppression compared with those aged 12-18 years at onset. At the cohort median disease duration of 79 months, 34.3% had developed permanent visual disability, 20.7% EDSS score 4 and 25.8% cognitive impairment. Visual disability was associated with white race (p=0.032) and optic neuritis presentations (p=0.002). Cognitive impairment was predicted by cerebral syndrome presentations (p=0.048), particularly if resistant to steroids (p=0.034).

Conclusions: Age at onset, race, onset symptoms and resistance to acute therapy at onset attack predict first relapse and long-term disabilities. The recognition of these predictors may help to power future paediatric clinical trials and to direct early therapeutic decisions in AQP4-IgG NMOSD.
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http://dx.doi.org/10.1136/jnnp-2021-327206DOI Listing
September 2021

Retinal Optical Coherence Tomography in Neuromyelitis Optica.

Neurol Neuroimmunol Neuroinflamm 2021 11 15;8(6). Epub 2021 Sep 15.

From the Experimental and Clinical Research Center (F.C.O., Svenja Specovius, H.G.Z., C.C., S.M., C.B., A.U.B., F.P.), Max Delbrück Center for Molecular Medicine and Charité-Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Germany: NeuroCure Clinical Research Center (F.C.O., Svenja Specovius, H.G.Z., C.C., S.M., C.B., A.U.B., F.P.), Charité-Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität zu Berlin, Germany; Department of Neurology (F.C.O., A.J.G.), University of California San Francisco, CA; Department of Pediatrics (L.C.), University of Utah, Salt Lake City; CIEM MS Research Center (M.A.L.P., M.A.F.), University of Minas Gerais, Medical School, Belo Horizonte, Brazil; Department of Neurology (H.J.K., J.-W.H.), National Cancer Center, Goyang, Republic of Korea; Department of Neurology (J.P., A.R.-F., M.I.L.), and Department of Ophthalmology (Srilakshmi Sharma), and Department of Ophthalmology (Srilakshmi Sharma), Oxford University Hospitals, National Health Service Trust, UK; Kashani MS Center (F.A.), School of Advanced Technologies in Medicine and Medical Image and Signal Processing Research Center (R.K.), Department of Ophthalmology, Isfahan Eye Research Center (A.D., Mohsen Pourazizi), Isfahan University of Medical Sciences, Iran; Department of Neurology (L.P., A.D'C.), KS Hegde Medical Academy, Nitte University, Mangalore, India; Department of Neurology (O.A., Marius Ringelstein, P.A.), Medical Faculty, Heinrich Heine University Düsseldorf, Germany; Swedish Neuroscience Institute Neuro-Ophthalmology (E.M., C.T.), Seattle, WA; Experimental Neurophysiology Unit (L.L., Marco Pisa, Marta Radaelli), Institute of Experimental Neurology (INSPE) Scientific Institute Hospital San Raffaele and University Vita-Salute San Raffaele, Milan, Italy; Hospital Clinic of Barcelona-Institut d'Investigacions (E.H.M.-L.), Biomèdiques August Pi Sunyer, (IDIBAPS), Spain; Sackler School of Medicine (H.S.-K.), Tel Aviv University, Israel; Neuro-Ophthalmology Division (H.S.-K.), Department of Ophthalmology, Rabin Medical Center, Petah Tikva, Israel; Division of Neurology (Sasitorn Siritho), Department of Medicine, Siriraj Hospital and Bumrungrad International Hospital, Bangkok, Thailand; Neurology Service (J.d.S., Thomas Senger), University Hospital of Strasbourg, France; Institute of Clinical Neuroimmunology (J.H.), Biomedical Center and University Hospital, Ludwig-Maximilians Universitaet Muenchen, Munich, Germany; Neurology (R.M., A.C.C.), Multiple Sclerosis, Myelin Disorders and Neuroinflammation, Pierre Wertheimer Neurological Hospital, Hospices Civils de Lyon, France; Centre d'Esclerosi Múltiple de Catalunya (Cemcat) (A.C.C.), Department of Neurology/Neuroimmunology, Hospital Universitari Vall d'Hebron, Universitat Autònoma de Barcelona, Spain; Department of Neurology and Neurosurgery (D.B., I.M.T.), Escola Paulista de Medicina, Universidade Federal de São Paulo, Brazil; Departments of Neurology (N.A.), Slagelse Hospitals, Institute of Regional Health Research, University of Southern Denmark, Odense; Institute of Regional Health Research (N.A., K.S.), University of Southern Denmark, Odense; Department of Neurology (A.A., U.T.), and Department of Ophthalmology (R.Y.), Cerrahpasa Medical Faculty, Istanbul University, Turkey; The Walton Centre for Neurology and Neurosurgery (A.J., S.H.), Liverpool, UK; The Cleveland Clinic Abu Dhabi (A.J.), United Arab Emirates; NYU Multiple Sclerosis Comprehensive Care Center (Z.R., A.R.), Department of Neurology, NYU School of Medicine, New York; Department of Neurology (Y.M.-D.), University of Michigan Medical School, Ann Arbor; Department of Neurology (I.S.C.), Hospital Clínico de Maracaibo, Venezuela; Moorfield's Eye Hospital (A.P.), University College London, UK; Department of Medicine (M.R.Y.), Los Angeles Biomedical Research Institute at Harbor-University of California at Los Angeles (UCLA) Medical Center, Torrance, CA, United States of America; Department of Medicine (M.R.Y.), David Geffen School of Medicine at UCLA, Los Angeles, CA, United States of America; Departments of Ophthalmology and Visual Sciences (Terry Smith), Kellogg Eye Center, University of Michigan Medical School, Ann Arbor, United States of America; Division of Metabolism (Terry Smith), Endocrine and Diabetes, Department of Internal Medicine, University of Michigan Medical School, Ann Arbor; Department of Neurology (A.U.B.), University of California, Irvine; and Department of Neurology (F.P.), Charité-Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Germany.

Background And Objectives: To determine optic nerve and retinal damage in aquaporin-4 antibody (AQP4-IgG)-seropositive neuromyelitis optica spectrum disorders (NMOSD) in a large international cohort after previous studies have been limited by small and heterogeneous cohorts.

Methods: The cross-sectional Collaborative Retrospective Study on retinal optical coherence tomography (OCT) in neuromyelitis optica collected retrospective data from 22 centers. Of 653 screened participants, we included 283 AQP4-IgG-seropositive patients with NMOSD and 72 healthy controls (HCs). Participants underwent OCT with central reading including quality control and intraretinal segmentation. The primary outcome was thickness of combined ganglion cell and inner plexiform (GCIP) layer; secondary outcomes were thickness of peripapillary retinal nerve fiber layer (pRNFL) and visual acuity (VA).

Results: Eyes with ON (NMOSD-ON, N = 260) or without ON (NMOSD-NON, N = 241) were assessed compared with HCs (N = 136). In NMOSD-ON, GCIP layer (57.4 ± 12.2 μm) was reduced compared with HC (GCIP layer: 81.4 ± 5.7 μm, < 0.001). GCIP layer loss (-22.7 μm) after the first ON was higher than after the next (-3.5 μm) and subsequent episodes. pRNFL observations were similar. NMOSD-NON exhibited reduced GCIP layer but not pRNFL compared with HC. VA was greatly reduced in NMOSD-ON compared with HC eyes, but did not differ between NMOSD-NON and HC.

Discussion: Our results emphasize that attack prevention is key to avoid severe neuroaxonal damage and vision loss caused by ON in NMOSD. Therapies ameliorating attack-related damage, especially during a first attack, are an unmet clinical need. Mild signs of neuroaxonal changes without apparent vision loss in ON-unaffected eyes might be solely due to contralateral ON attacks and do not suggest clinically relevant progression but need further investigation.
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http://dx.doi.org/10.1212/NXI.0000000000001068DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8448522PMC
November 2021

Eculizumab monotherapy for NMOSD: Data from PREVENT and its open-label extension.

Mult Scler 2021 Sep 9:13524585211038291. Epub 2021 Sep 9.

Department of Neurology, Mayo Clinic, Scottsdale, AZ, USA.

During PREVENT (a phase 3, randomized, double-blind, placebo-controlled, time-to-event study) and its open-label extension (interim analysis), 33 adults with aquaporin-4 immunoglobulin G-positive neuromyelitis optica spectrum disorder (AQP4-IgG + NMOSD) received eculizumab monotherapy for a median of 2.8 years (range, 14 weeks-5.2 years). At 192 weeks (~4 years), 96% of these patients were free from adjudicated relapses (Kaplan-Meier analysis; 95% confidence interval, 75.7-99.4). During PREVENT, 95% (20/21) of patients receiving eculizumab monotherapy had no disability worsening. Eculizumab monotherapy provides effective long-term relapse prevention, relieving the chronic immunosuppression burden in patients with AQP4-IgG + NMOSD. ClinicalTrials.gov; PREVENT: NCT01892345; open-label extension: NCT02003144.
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http://dx.doi.org/10.1177/13524585211038291DOI Listing
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

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

Patient-reported burden of symptoms in neuromyelitis optica: A secondary analysis on pain and quality of life.

J Neurol Sci 2021 09 19;428:117546. Epub 2021 Jun 19.

Department of Immunology, National Institute of Neuroscience, National Center of Neurology and Psychiatry, Tokyo, Japan.

Introduction: Relapses of neuromyelitis optica spectrum disorder (NMOSD) result in cumulative neurologic disabilities, are unpredictable, and are interspersed with remissions. Pain in NMOSD is often severe and intractable, with a significant impact on patient quality of life (QoL). We performed a more detailed analysis of previously published survey data on the association of pain and QoL, comparing patients who were seropositive and seronegative for antibodies against aquaporin-4 (AQP4-IgG).

Methods: We conducted a secondary analysis of questionnaire data from 193 NMOSD patients across North America. The study population was predominantly female (88.6%) and aged 19-76 years. Results were reported for three groups: AQP4-IgG-seropositive (61.1%), AQP4-IgG-seronegative and the total cohort including patients with unknown serostatus. We measured the strength of associations and interactions between pain and variables including QoL, patient satisfaction, frequency of hospital visits, and number of relapses versus other symptoms.

Results: Pain severity was the strongest negative predictor of QoL. In the total and AQP4-IgG-seropositive groups, pain was the most common symptom that patients wanted their physician to be concerned about; in the AQP4-IgG-seronegative group, this was fatigue. For all patients, frequent hospital visits and relapses were associated with more severe pain, but not frequency of NMOSD specialist visits. Patients without recent relapse still commonly reported moderate or severe pain (>25%).

Conclusion: This study confirms the heavy burden of pain on NMOSD patients and its effect on QoL and healthcare utilization. Prevention or early treatment of relapses and more effective pain management may reduce this burden.
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http://dx.doi.org/10.1016/j.jns.2021.117546DOI Listing
September 2021

Asian and African/Caribbean AQP4-NMOSD patient outcomes according to self-identified race and place of residence.

Mult Scler Relat Disord 2021 Aug 15;53:103080. Epub 2021 Jun 15.

Nuffield Department of Clinical Neurosciences, West Wing, John Radcliffe Hospital, Oxford University Hospitals, Oxford OX3 9DU, United Kingdom. Electronic address:

Background: Neuromyelitis optica spectrum disorder (NMOSD) is an autoimmune astrocytopathy characterized by aquaporin-4 antibodies, whose prognosis is influenced by onset age, race, environmental exposures and immunosuppression. Distinguishing the contribution of environment from genetics is challenging. We aimed to compare neuromyelitis optica spectrum disorder (NMOSD) patient outcomes according to self-identified racial group and place of residence.

Methods: This retrospective analysis of prospectively collected data included non-white anti-aquaporin-4 antibody positive NMOSD patients under follow-up from 15 centers [United Kingdom, France, Germany, Denmark, Martinique, United States of America, Japan, South Korea, Singapore, Thailand, China (including Hong Kong) and India]. Racial groups were designated: African/Caribbean; South Asian; East Asian (including Southeast Asia). Patients from these racial groups residing outside Africa/Caribbean or Asia were compared with those living in the Caribbean or the Asian areas. Kaplan-Meier survival curves and Cox models were generated using time to sustained Expanded Disability Status Scale≥6.0 or death; time to sustained Kurtzke Visual Function Score≥3.0 or a composite endpoint of all three.

Results: Among 821 patients, African/Caribbean patients (n = 206) had the shortest time to immunosuppression and higher visual disability at onset. South Asian patients (n = 65) were younger, had lower visual disability at onset and higher mortality rate. East Asians (n = 550) had the lowest relapse rate and lowest accrued motor disability. Survival analysis of African/Caribbean outside Africa/Caribbean vs those in the Caribbean showed a significant difference in the composite endpoint (p = 0.024,log-rank test), not apparently related to treatment differences. No significant differences between native and those residing outside Asia were found for other racial groups.

Conclusion: This NMOSD study reports the effects of place of residence on the outcomes in different races. Place of residence may not be a significant driver of disability among Asian patients, while it may influence African/Caribbean patient outcomes. Validating these findings could help distinguish between genetic causes and potentially modifiable environmental factors.
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http://dx.doi.org/10.1016/j.msard.2021.103080DOI Listing
August 2021

Sarcoidosis and neuromyelitis optica in a patient with optic neuritis - a case report.

Ann Clin Transl Neurol 2021 08 24;8(8):1760-1763. Epub 2021 Jun 24.

Department of Neuroinflammation, UCL Queen Square Institute of Neurology, London, UK.

We present a case of atypical recurrent optic neuritis. A man in his 50s presented with right optic neuritis and profound visual loss, associated with elevated inflammatory markers. Lymph-node biopsy was consistent with sarcoidosis. Aquaporin-4 antibodies were also present. Three months following corticosteroid treatment, his right optic neuritis relapsed, again with raised inflammatory markers. He was started on azathioprine and prednisolone with good effect. A dual diagnosis of sarcoidosis and neuromyelitis optica with aquaporin-4 antibodies is very rare. Long-term immunosuppression is required. The case highlights the importance of identifying the features and cause of atypical optic neuritis.
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http://dx.doi.org/10.1002/acn3.51413DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8351381PMC
August 2021

2021 MAGNIMS-CMSC-NAIMS consensus recommendations on the use of MRI in patients with multiple sclerosis.

Lancet Neurol 2021 08 14;20(8):653-670. Epub 2021 Jun 14.

Section of Neuroradiology, Department of Radiology, Hospital Universitari Vall d'Hebron, Universitat Autònoma de Barcelona, Barcelona, Spain. Electronic address:

The 2015 Magnetic Resonance Imaging in Multiple Sclerosis and 2016 Consortium of Multiple Sclerosis Centres guidelines on the use of MRI in diagnosis and monitoring of multiple sclerosis made an important step towards appropriate use of MRI in routine clinical practice. Since their promulgation, there have been substantial relevant advances in knowledge, including the 2017 revisions of the McDonald diagnostic criteria, renewed safety concerns regarding intravenous gadolinium-based contrast agents, and the value of spinal cord MRI for diagnostic, prognostic, and monitoring purposes. These developments suggest a changing role of MRI for the management of patients with multiple sclerosis. This 2021 revision of the previous guidelines on MRI use for patients with multiple sclerosis merges recommendations from the Magnetic Resonance Imaging in Multiple Sclerosis study group, Consortium of Multiple Sclerosis Centres, and North American Imaging in Multiple Sclerosis Cooperative, and translates research findings into clinical practice to improve the use of MRI for diagnosis, prognosis, and monitoring of individuals with multiple sclerosis. We recommend changes in MRI acquisition protocols, such as emphasising the value of three dimensional-fluid-attenuated inversion recovery as the core brain pulse sequence to improve diagnostic accuracy and ability to identify new lesions to monitor treatment effectiveness, and we provide recommendations for the judicious use of gadolinium-based contrast agents for specific clinical purposes. Additionally, we extend the recommendations to the use of MRI in patients with multiple sclerosis in childhood, during pregnancy, and in the post-partum period. Finally, we discuss promising MRI approaches that might deserve introduction into clinical practice in the near future.
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http://dx.doi.org/10.1016/S1474-4422(21)00095-8DOI Listing
August 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

COVID-19 in a Cohort of Patients with Congenital Myasthenic Syndrome.

J Neuromuscul Dis 2021 ;8(6):1003-1005

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

Congenital Myasthenic Syndromes (CMS) are a rare group of genetic disorders of neuromuscular transmission. Some subtypes of CMS can be associated with respiratory and bulbar weakness and these patients may therefore be at high risk of developing a severe disease from COVID-19. We screened 73 patients with genetically confirmed CMS who were attending the UK national referral centre for evidence of previous Severe Acute Respiratory Syndrome Corona Virus 2 infection and their clinical outcome. Of 73 patients, seven had history of confirmed COVID-19. None of the infected patients developed a severe disease, and there were no signals that CMS alone carries a high risk of severe disease from COVID-19.
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http://dx.doi.org/10.3233/JND-210699DOI Listing
November 2021

An In-vivo 1H-MRS short-echo time technique at 7T: Quantification of metabolites in chronic multiple sclerosis and neuromyelitis optica brain lesions and normal appearing brain tissue.

Neuroimage 2021 09 30;238:118225. Epub 2021 May 30.

Wellcome Centre for Integrative Neuroimaging, FMRIB, Nuffield Department of Clinical Neurosciences, University of Oxford, Oxford, OX3 9DU, United Kingdom; School of Health Sciences, Purdue University, 550 Stadium Mall Drive, West Lafayette, IN 47907, (765) 494-1419, United States; Weldon School of Biomedical Engineering, Purdue University, West Lafayette, IN, United States.

Magnetic Resonance Spectroscopy (MRS) allows for the non-invasive quantification of neurochemicals and has the potential to differentiate between the pathologically distinct diseases, multiple sclerosis (MS) and AQP4Ab-positive neuromyelitis optica spectrum disorder (AQP4Ab-NMOSD). In this study we characterised the metabolite profiles of brain lesions in 11 MS and 4 AQP4Ab-NMOSD patients using an optimised MRS methodology at ultra-high field strength (7T) incorporating correction for T2 water relaxation differences between lesioned and normal tissue. MS metabolite results were in keeping with the existing literature: total N-acetylaspartate (NAA) was lower in lesions compared to normal appearing brain white matter (NAWM) with reciprocal findings for myo-Inositol. An unexpected subtlety revealed by our technique was that total NAA differences were likely driven by NAA-glutamate (NAAG), a ubiquitous CNS molecule with functions quite distinct from NAA though commonly quantified together with NAA in MRS studies as total NAA. Surprisingly, AQP4Ab-NMOSD showed no significant differences for total NAA, NAA, NAAG or myo-Inositol between lesion and NAWM sites, nor were there any differences between MS and AQP4Ab-NMOSD for a priori hypotheses. Post-hoc testing revealed a significant correlation between NAWM Ins:NAA and disability (as measured by EDSS) for disease groups combined, driven by the AP4Ab-NMOSD group. Utilising an optimised MRS methodology, our study highlights some under-explored subtleties in MRS profiles, such as the absence of myo-Inositol concentration differences in AQP4Ab-NMOSD brain lesions versus NAWM and the potential influence of NAAG differences between lesions and normal appearing white matter in MS.
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http://dx.doi.org/10.1016/j.neuroimage.2021.118225DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7611458PMC
September 2021

Contrasting the brain imaging features of MOG-antibody disease, with AQP4-antibody NMOSD and multiple sclerosis.

Mult Scler 2021 May 28:13524585211018987. Epub 2021 May 28.

Nuffield Department of Clinical Neurosciences, John Radcliffe Hospital, University of Oxford, Oxford, UK/Oxford University Hospital NHS Foundation Trust, Oxford, UK.

Background: Identifying magnetic resonance imaging (MRI) markers in myelin-oligodendrocytes-glycoprotein antibody-associated disease (MOGAD), neuromyelitis optica spectrum disorder-aquaporin-4 positive (NMOSD-AQP4) and multiple sclerosis (MS) is essential for establishing objective outcome measures.

Objectives: To quantify imaging patterns of central nervous system (CNS) damage in MOGAD during the remission stage, and to compare it with NMOSD-AQP4 and MS.

Methods: 20 MOGAD, 19 NMOSD-AQP4, 18 MS in remission with brain or spinal cord involvement and 18 healthy controls (HC) were recruited. Volumetrics, lesions and cortical lesions, diffusion-imaging measures, were analysed.

Results: Deep grey matter volumes were lower in MOGAD ( = 0.02) and MS ( = 0.0001), compared to HC and were strongly correlated with current lesion volume (MOGAD  = -0.93,  < 0.001, MS  = -0.65,  = 0.0034). Cortical/juxtacortical lesions were seen in a minority of MOGAD, in a majority of MS and in none of NMOSD-AQP4. Non-lesional tissue fractional anisotropy (FA) was only reduced in MS ( = 0.01), although focal reductions were noted in NMOSD-AQP4, reflecting mainly optic nerve and corticospinal tract pathways.

Conclusion: MOGAD patients are left with grey matter damage, and this may be related to persistent white matter lesions. NMOSD-AQP4 patients showed a relative sparing of deep grey matter volumes, but reduced non-lesional tissue FA. Observations from our study can be used to identify new markers of damage for future multicentre studies.
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http://dx.doi.org/10.1177/13524585211018987DOI Listing
May 2021

Elucidating distinct clinico-radiologic signatures in the borderland between neuromyelitis optica and multiple sclerosis.

J Neurol 2021 May 27. Epub 2021 May 27.

Department of Clinical Neurology, Nuffield Department of Clinical Neuroscienes, University of Oxford, Oxford, UK.

Background: Separating antibody-negative neuromyelitis optica spectrum disorders (NMOSD) from multiple sclerosis (MS) in borderline cases is extremely challenging due to lack of biomarkers. Elucidating different pathologies within the likely heterogenous antibody-negative NMOSD/MS overlap syndrome is, therefore, a major unmet need which would help avoid disability from inappropriate treatment.

Objective: In this study we aimed to identify distinct subgroups within the antibody-negative NMOSD/MS overlap syndrome.

Methods: Twenty-five relapsing antibody-negative patients with NMOSD features underwent a prospective brain and spinal cord MRI. Subgroups were identified by an unsupervised algorithm based on pre-selected NMOSD/MS discriminators.

Results: Four subgroups were identified. Patients from Group 1 termed "MS-like" (n = 6) often had central vein sign and cortical lesions (83% and 67%, respectively). All patients from Group 2 ("spinal MS-like", 8) had short-segment myelitis and no MS-like brain lesions. Group 3 ("classic NMO-like", 6) had high percentage of bilateral optic neuritis and longitudinally extensive transverse myelitis (LETM, 80% and 60%, respectively) and normal brain appearance (100%). Group 4 ("NMO-like with brain involvement", 5) typically had a history of NMOSD-like brain lesions and LETM. When compared with other groups, Group 4 had significantly decreased fractional anisotropy in non-lesioned tracts (0.46 vs. 0.49, p = 0.003) and decreased thalamus volume (0.84 vs. 0.98, p = 0.04).

Conclusions: NMOSD/MS cohort contains distinct subgroups likely corresponding to different pathologies and requiring tailored treatment. We propose that non-conventional MRI might help optimise diagnosis in these challenging patients.
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http://dx.doi.org/10.1007/s00415-021-10619-1DOI Listing
May 2021

Integrative biochemical, proteomics and metabolomics cerebrospinal fluid biomarkers predict clinical conversion to multiple sclerosis.

Brain Commun 2021 19;3(2):fcab084. Epub 2021 Apr 19.

Department of Pharmacology, University of Oxford, Oxford OX1 3QT, UK.

Eighty-five percent of multiple sclerosis cases begin with a discrete attack termed clinically isolated syndrome, but 37% of clinically isolated syndrome patients do not experience a relapse within 20 years of onset. Thus, the identification of biomarkers able to differentiate between individuals who are most likely to have a second clinical attack from those who remain in the clinically isolated syndrome stage is essential to apply a personalized medicine approach. We sought to identify biomarkers from biochemical, metabolic and proteomic screens that predict clinically defined conversion from clinically isolated syndrome to multiple sclerosis and generate a multi-omics-based algorithm with higher prognostic accuracy than any currently available test. An integrative multi-variate approach was applied to the analysis of cerebrospinal fluid samples taken from 54 individuals at the point of clinically isolated syndrome with 2-10 years of subsequent follow-up enabling stratification into clinical converters and non-converters. Leukocyte counts were significantly elevated at onset in the clinical converters and predict the occurrence of a second attack with 70% accuracy. Myo-inositol levels were significantly increased in clinical converters while glucose levels were decreased, predicting transition to multiple sclerosis with accuracies of 72% and 63%, respectively. Proteomics analysis identified 89 novel gene products related to conversion. The identified biochemical and protein biomarkers were combined to produce an algorithm with predictive accuracy of 83% for the transition to clinically defined multiple sclerosis, outperforming any individual biomarker in isolation including oligoclonal bands. The identified protein biomarkers are consistent with an exaggerated immune response, perturbed energy metabolism and multiple sclerosis pathology in the clinical converter group. The new biomarkers presented provide novel insight into the molecular pathways promoting disease while the multi-omics algorithm provides a means to more accurately predict whether an individual is likely to convert to clinically defined multiple sclerosis.
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http://dx.doi.org/10.1093/braincomms/fcab084DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8111065PMC
April 2021

No strong HLA association with MOG antibody disease in the UK population.

Ann Clin Transl Neurol 2021 07 15;8(7):1502-1507. Epub 2021 May 15.

Department of Clinical Neurology, John Radcliffe Hospital, Oxford, UK.

Improvements in assays for detecting serum antibodies against myelin oligodendrocyte glycoprotein (MOG) have led to the appreciation of MOG-antibody-associated disease (MOGAD) as a novel disorder. However, much remains unknown about its etiology. We performed human leukocyte antigen (HLA) analysis in 82 MOGAD patients of European ancestry in the UK population. No HLA class II associations were observed, thus questioning the mechanism of anti-MOG antibody generation. A weak protective association of HLA-C*03:04 was observed (OR = 0.26, 95% CI = 0.10-0.71, p  = 0.013), suggesting a need for continued efforts to better understand MOGAD genetics and pathophysiology.
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http://dx.doi.org/10.1002/acn3.51378DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8283171PMC
July 2021

Eculizumab in Asian patients with anti-aquaporin-IgG-positive neuromyelitis optica spectrum disorder: A subgroup analysis from the randomized phase 3 PREVENT trial and its open-label extension.

Mult Scler Relat Disord 2021 May 20;50:102849. Epub 2021 Feb 20.

Department of Neurology, Tohoku University Graduate School of Medicine, 1-1 Seiryomachi, Aobaku, Sendai, Miyagi 980-8574, Japan; Department of Multiple Sclerosis Therapeutics, Fukushima Medical University School of Medicine, 1 Hikariga-oka, Fukushima City, Fukushima 960-1295, Japan; Multiple Sclerosis and Neuromyelitis Optica Center, Southern TOHOKU Research Institute for Neuroscience (STRINS), Koriyama, 7-115, Yatsuyamada, Koriyama, Fukushima 963-8563, Japan. Electronic address:

Background Eculizumab, a terminal complement inhibitor, significantly reduced the risk of relapse compared with placebo in patients with anti-aquaporin-4 immunoglobulin G-positive (AQP4+) neuromyelitis optica spectrum disorder (NMOSD) in the PREVENT trial. We report efficacy and safety analyses in Asian patients in PREVENT and its open-label extension (OLE). Methods PREVENT was a double-blind, randomized, phase 3 trial. Patients with AQP4+ NMOSD were randomly assigned (2:1) to receive intravenous eculizumab (maintenance dose, 1200 mg/2 weeks) or placebo. Patients who completed PREVENT could receive eculizumab in an OLE. Analyses were performed in a prespecified subgroup of Asian patients. Results Of 143 patients enrolled, 52 (36.4%) were included in the Asian subgroup (eculizumab, n = 37; placebo, n = 15); 45 Asian patients received eculizumab in the OLE. Most Asian patients (86.5%) received concomitant immunosuppressive therapy. During PREVENT, one adjudicated relapse occurred in patients receiving eculizumab and six occurred in patients receiving placebo in the Asian subgroup (hazard ratio, 0.05; 95% confidence interval: 0.01-0.35; p = 0.0002). An estimated 95.2% of Asian patients remained relapse-free after 144 weeks of eculizumab treatment. Upper respiratory tract infections, headache, and nasopharyngitis were the most common adverse events with eculizumab in the Asian subgroup. Conclusion Eculizumab reduces the risk of relapse in Asian patients with AQP4+ NMOSD, with a benefit-risk profile similar to the overall PREVENT population. The benefits of eculizumab were maintained during long-term therapy. Clinical trial registration ClinicalTrials.gov identifiers: NCT01892345 (PREVENT); NCT02003144 (open-label extension).
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http://dx.doi.org/10.1016/j.msard.2021.102849DOI Listing
May 2021

Pregnancy in Patients With AQP4-Ab, MOG-Ab, or Double-Negative Neuromyelitis Optica Disorder.

Neurology 2021 04 24;96(15):e2006-e2015. Epub 2021 Feb 24.

From the Department of Neurology (N.C., C.A.D.R., J.D.S.), CHU de Strasbourg; Department of Neurology (B.B.), Rouen University Hospital; Department of Neurology (D.B.), CRC-SEP, CHU Toulouse; Service de Neurologie Sclérose en Plaques, Pathologies de La Myéline et Neuro-inflammation (R.M.), Hôpital Neurologique Pierre Wertheimer, Hospices Civils de Lyon, France; Department of Neurology (A.M.d.S., E.S.), Centro Hospitalar Universitario do Porto, Hospital de Santo Antonio, Oporto, Portugal; Department of Neurology (E.M., C.P.), Centre de Référence des Maladies Inflammatoires Rares du Cerveau et de la Moelle, Pitié-Salpétrière Hospital, Paris, France; and Department of Clinical Neurology (J.P., M.I.S.L.), John Radcliffe Hospital, Oxford University Hospitals Trust, UK.

Objective: To analyze the effects of pregnancy on neuromyelitis optica spectrum disorder (NMOSD) according to patients' serostatus and immunosuppressive therapy (IST).

Methods: We performed a retrospective multicenter international study on patients with NMOSD. Patients were tested for aquaporin-4 (AQP4) and myelin oligodendrocyte glycoprotein (MOG) antibodies (Ab). Informative pregnancies were reported when NMOSD onset occurred before or during pregnancy or up to 12 months postpartum. The mean annualized relapse rate (ARR) was calculated for the 12 months before conception, for each trimester of pregnancy, and postpartum. Events such as miscarriage, abortion, and preeclampsia were reported. IST was considered if taken in the 3 months before or during pregnancy.

Results: We included 89 pregnancies (46 with AQP4-Ab, 30 with MOG-Ab, and 13 without either Ab) in 58 patients with NMOSD. Compared to the prepregnancy period, the ARR was lower during pregnancy in each serostatus group and higher during the postpartum period in patients with AQP4-Ab ( < 0.01). Forty-eight percent (n = 31) of pregnancies occurred during IST and these patients presented fewer relapses during pregnancy and the 12 months postpartum than untreated patients (26% vs 53%, = 0.04). Miscarriages occurred in 10 (11%) pregnancies, and were mainly in patients with AQP4-Ab (with or without IST) and a previous history of miscarriage. Preeclampsia was reported in 2 (2%) patients who were AQP4-Ab-positive.

Conclusion: We found a rebound in the ARR during the first postpartum trimester that was higher than the prepregnancy period only in AQP4-Ab-positive patients. Taking IST just before or during pregnancy reduces the risk of relapses in these conditions.
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http://dx.doi.org/10.1212/WNL.0000000000011744DOI Listing
April 2021

Long-Term Safety and Efficacy of Eculizumab in Aquaporin-4 IgG-Positive NMOSD.

Ann Neurol 2021 06 27;89(6):1088-1098. Epub 2021 Feb 27.

Mayo Clinic, Rochester, MN.

Objective: During PREVENT (NCT01892345), eculizumab significantly reduced relapse risk versus placebo in patients with aquaporin-4 immunoglobulin G-positive neuromyelitis optica spectrum disorder (AQP4-IgG+ NMOSD). We report an interim analysis of PREVENT's ongoing open-label extension (OLE; NCT02003144) evaluating eculizumab's long-term safety and efficacy.

Methods: Patients who completed PREVENT could enroll in the OLE to receive eculizumab (maintenance dose = 1,200 mg/2 weeks, after a blinded induction phase). Safety and efficacy data from PREVENT and its OLE (interim data cut, July 31, 2019) were combined for this analysis.

Results: Across PREVENT and the OLE, 137 patients received eculizumab and were monitored for a median (range) of 133.3 weeks (5.1-276.9 weeks), for a combined total of 362.3 patient-years (PY). Treatment-related adverse event (AE) and serious adverse event (SAE) rates were 183.5 in 100 PY and 8.6 in 100 PY, respectively. Serious infection rates were 10.2 in 100 PY in eculizumab-treated patients versus 15.1 in 100 PY in the PREVENT placebo group. No patient developed a meningococcal infection. At 192 weeks (3.7 years), 94.4% (95% confidence interval [CI], 88.6-97.3) of patients remained adjudicated relapse-free. The adjudicated annualized relapse rate was 0.025 (95% CI = 0.013-0.048) in all eculizumab-treated patients versus 0.350 (95% CI = 0.199-0.616) in the PREVENT placebo group. During the OLE, 37% of patients (44 of 119 patients) stopped or decreased background immunosuppressive therapy use.

Interpretation: This analysis demonstrates that eculizumab's long-term safety profile in NMOSD is consistent with its established profile across other indications. This analysis also demonstrated the sustained ability of long-term eculizumab treatment to reduce relapse risk in patients with AQP4-IgG+ NMOSD. ANN NEUROL 2021;89:1088-1098.
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http://dx.doi.org/10.1002/ana.26049DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8248139PMC
June 2021

Foveal changes in aquaporin-4 antibody seropositive neuromyelitis optica spectrum disorder are independent of optic neuritis and not overtly progressive.

Eur J Neurol 2021 07 23;28(7):2280-2293. Epub 2021 Mar 23.

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

Background And Purpose: Foveal changes were reported in aquaporin-4 antibody (AQP4-Ab) seropositive neuromyelitis optica spectrum disorder (NMOSD) patients; however, it is unclear whether they are independent of optic neuritis (ON), stem from subclinical ON or crossover from ON in fellow eyes. Fovea morphometry and a statistical classification approach were used to investigate if foveal changes in NMOSD are independent of ON and progressive.

Methods: This was a retrospective longitudinal study of 27 AQP4-IgG + NMOSD patients (49 eyes; 15 ON eyes and 34 eyes without a history of ON [NON eyes]), follow-up median (first and third quartile) 2.32 (1.33-3.28), and 38 healthy controls (HCs) (76 eyes), follow-up median (first and third quartile) 1.95 (1.83-2.54). The peripapillary retinal nerve fibre layer thickness and the volume of combined ganglion cell and inner plexiform layer as measures of neuroaxonal damage from ON were determined by optical coherence tomography. Nineteen foveal morphometry parameters were extracted from macular optical coherence tomography volume scans. Data were analysed using orthogonal partial least squares discriminant analysis and linear mixed effects models.

Results: At baseline, foveal shape was significantly altered in ON eyes and NON eyes compared to HCs. Discriminatory analysis showed 81% accuracy distinguishing ON vs. HCs and 68% accuracy in NON vs. HCs. NON eyes were distinguished from HCs by foveal shape parameters indicating widening. Orthogonal partial least squares discriminant analysis discriminated ON vs. NON with 76% accuracy. In a follow-up of 2.4 (20.85) years, no significant time-dependent foveal changes were found.

Conclusion: The parafoveal area is altered in AQP4-Ab seropositive NMOSD patients suggesting independent neuroaxonal damage from subclinical ON. Longer follow-ups are needed to confirm the stability of the parafoveal structure over time.
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http://dx.doi.org/10.1111/ene.14766DOI Listing
July 2021

The influence of smoking on the pattern of disability and relapse risk in AQP4-positive Neuromyelitis Optica Spectrum Disorder, MOG-Ab Disease and Multiple Sclerosis.

Mult Scler Relat Disord 2021 Apr 19;49:102773. Epub 2021 Jan 19.

Nuffield Department of Clinical Neurosciences, John Radcliffe Hospital, University of Oxford, Oxford, UK; Department of Clinical Neurology, John Radcliffe Hospital, Oxford University Hospitals Trust, Oxford, UK. Electronic address:

Background: the role of smoking on clinical outcomes of central nervous system (CNS) inflammatory disorders is unclear. To assess the effect of smoking on relapses and disability in neuromyelitis optica with aquaporin-4-antibodies (NMOSD-AQP4-Ab), Myelin Oligodendrocyte Glycoprotein-antibodies associated disease (MOGAD) and relapsing remitting Multiple Sclerosis (MS) patients.

Methods: in a UK cohort of 101 NMOSD-AQP4-Ab, 70 MOGAD and 159 MS, and a Korean cohort of 97 NMOSD-AQ4-Ab, time to first relapse, annualised relapse rate, onset relapse severity and recovery, time to Expanded Disability Status Score(EDSS)/secondary progressive MS (SPMS) were compared between never-smokers and ever-smokers. All clinical data were collected under the local ethics between January 2017 and January 2019.

Results: Smoking did not affect the risk of relapse in any of the diseases. The risk of reaching EDSS 6.0 in the UK NMOSD-AQP4-Ab cohort was higher in ever smokers but this did not achieve significance (HR 2.12, p=0.068). When combining the UK and Korea NMOSD-AQP4-Ab cohorts, poorer recovery from the onset attack was significantly more frequent in the ever-smokers versus the never smokers (55% vs 38%, p=0.04). In the MS cohort the risk of reaching EDSS 6 and SPMS was significantly higher in the ever-smokers (HR=2.67, p=0.01 and HR=3.18, p=0.001). In MOGAD similar patterns were seen without reaching significance.

Conclusions: In NMOSD-AQP4-Ab smoking associates with worse disability not through an increased risk of relapses but through poor relapse recovery. As in MS, smoking cessation should be encouraged in NMOSD-AQP4-Ab.
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http://dx.doi.org/10.1016/j.msard.2021.102773DOI Listing
April 2021

Effects of immunotherapies and clinical outcomes in neurosarcoidosis: a retrospective cohort study.

J Neurol 2021 Jul 30;268(7):2466-2472. Epub 2021 Jan 30.

Oxford University Hospitals NHS Foundation Trust, Headley way, Headington, OX3 9DU, UK.

Introduction: Neurosarcoidosis is associated with a significant degree of morbidity and mortality and its treatments are varied and complex. There is a paucity of information in current literature on patterns of treatment and long term outcomes. This study aimed to evaluate the clinical outcomes and responses to immunosuppressive therapy in a large cohort of neurosarcoidosis patients .

Methods: We enrolled 80 patients with a diagnosis of neurosarcoidosis. Prescription patterns and clinical outcomes before and after treatment and differences between the treatment groups were compared using Kruskal-Wallis and Mann-Witney U tests.

Results: Patients with cranial mononeuropathy other than optic neuropathy were more likely to be treated with steroids alone whereas patients with other presentations were likely to require second and third level treatments. These included azathioprine, methotrexate, mycophenolate, infliximab, and cyclophosphamide often used in combination. Prednisolone alone at onset failed in 67% of patients but appeared most effective in those with isolated facial nerve palsy. Patients treated with prednisolone plus a standard immunosuppression first line generally did well except for those with brain parenchymal disease and /or hydrocephalus who responded better to the addition of infliximab, or cyclophosphamide. Triple therapy with prednisolone + azathioprine + infliximab was associated with significantly greater improvement on the Modified Rankin Scale than prednisolone alone whether used first line (p = 0.001 corrected) or subsequently (p = 0.021 corrected). Overall favourable outcomes in the form of improvement of MRS were reported in 87%, CONCLUSIONS: Our results provides evidence that early immunosuppressive treatments, with azathioprine, methotrexate and infliximab could effectively improve clinical outcomes in many patients with neurosarcoidosis.
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http://dx.doi.org/10.1007/s00415-021-10421-zDOI Listing
July 2021

Association of Gray Matter Atrophy Patterns With Clinical Phenotype and Progression in Multiple Sclerosis.

Neurology 2021 03 13;96(11):e1561-e1573. Epub 2021 Jan 13.

From the Neuroimaging Research Unit (M.A.R., P.V., A.M., P.P., M.F.), Division of Neuroscience, Neurology Unit (M.A.R., P.P., M.F.), Neurorehabilitation Unit, and Neurophysiology Service (M.F.), IRCCS San Raffaele Scientific Institute, Milan, Italy; Vita-Salute San Raffaele University (M.A.R., M.F.), Milan, Italy; Multiple Sclerosis Center (C.G., C.Z.), Department of Neurology, Neurocenter of Southern Switzerland, Civic Hospital; Faculty of Biomedical Sciences Università della Svizzera Italiana (C.G., C.Z.), Lugano, Switzerland; Section of Neuroradiology (A.R.), Department of Radiology, and Department of Neurology/Neuroimmunology (J.S.-G.), Multiple Sclerosis Center of Catalonia, Hospital Universitari Vall d'Hebron, Barcelona, Spain; NMR Research Unit (H.K., O.C.), Queen Square MS Centre, Department of Neuroinflammation, UCL Institute of Neurology, London; Nuffield Department of Clinical Neurosciences (L.M., J.P.), University of Oxford, UK; Department of Advanced Medical and Surgical Sciences (A.G., A.B.) and 3T MRI-Center (A.G., A.B.), University of Campania Luigi Vanvitelli, Naples, Italy; Institute of Neuroradiology at the Department of Radiology and Nuclear Medicine (C.L., B.B.), St. Josef Hospital, Ruhr University Bochum, Germany; Department of Radiology and Nuclear Medicine (F.B., H.V.), MS Center Amsterdam, Amsterdam Neuroscience Amsterdam UMC, location VUmc, the Netherlands; and Institutes of Neurology and Healthcare Engineering (F.B.), University College London, UK.

Objectives: Gay matter (GM) involvement is clinically relevant in multiple sclerosis (MS). Using source-based morphometry (SBM), we characterized GM atrophy and its 1-year evolution across different MS phenotypes.

Methods: Clinical and MRI data were obtained at 8 European sites from 170 healthy controls (HCs) and 398 patients with MS (34 with clinically isolated syndrome [CIS], 226 with relapsing-remitting MS [RRMS], 95 with secondary progressive MS [SPMS], and 43 with primary progressive MS [PPMS]). Fifty-seven HCs and 144 with MS underwent 1-year follow-up. Baseline GM loss, atrophy progression, and correlations with disability and 1-year clinical worsening were assessed.

Results: SBM identified 26 cerebellar, subcortical, sensory, motor, and cognitive GM components. GM atrophy was found in patients with MS vs HCs in almost all components ( range <0.001-0.04). Compared to HCs, patients with CIS showed circumscribed subcortical, cerebellar, temporal, and salience GM atrophy, while patients with RRMS exhibited widespread GM atrophy. Cerebellar, subcortical, sensorimotor, salience, and frontoparietal GM atrophy was found in patients with PPMS vs HCs and in patients with SPMS vs those with RRMS. At 1 year, 21 (15%) patients had clinically worsened. GM atrophy progressed in MS in subcortical, cerebellar, sensorimotor, and fronto-temporo-parietal components. Baseline higher disability was associated ( = 0.65) with baseline lower normalized brain volume (β = -0.13, = 0.001), greater sensorimotor GM atrophy (β = -0.12, = 0.002), and longer disease duration (β = 0.09, = 0.04). Baseline normalized GM volume (odds ratio 0.98, = 0.008) and cerebellar GM atrophy (odds ratio 0.40, = 0.01) independently predicted clinical worsening (area under the curve 0.83).

Conclusion: GM atrophy differed across disease phenotypes and progressed at 1 year in MS. In addition to global atrophy measures, sensorimotor and cerebellar GM atrophy explained baseline disability and clinical worsening.
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http://dx.doi.org/10.1212/WNL.0000000000011494DOI Listing
March 2021

'Cochlear-type' hearing loss as part of aquaporin-4 neuromyelitis optica spectrum disorder.

BMJ Case Rep 2021 Jan 11;14(1). Epub 2021 Jan 11.

Bodleian Library, University of Oxford, Oxford, UK

Neuromyelitis optica spectrum disorder is an inflammatory autoimmune central nervous system condition caused in the majority of cases by aquaporin-4 IgG antibodies. Aquaporin-4 is expressed in the cochlear and vestibular nuclei regions in the brainstem and a handful of cases of retro-cochlear type hearing loss have been documented in the literature. Aquaporin-4 has also been reported within the organ of Corti and the cristae and maculae of the vestibular apparatus. We present a case where there is evidence of peripheral (labyrinthine) rather than central pathology and propose this is due to autoimmune inflammation as part of neuromyelitis optica spectrum disorder. This is the first case in the literature suggesting a 'cochlear-type' hearing loss occurring as part of neuromyelitis optica spectrum disorder. It raises the possibility of peripheral relapses of neuromyelitis optica spectrum disorder going unnoticed, resulting in patient morbidity, and highlights the importance of research within this area.
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http://dx.doi.org/10.1136/bcr-2019-233468DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7802673PMC
January 2021
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