Publications by authors named "Maria Isabel Leite"

74 Publications

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

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

Ann Clin Transl Neurol 2021 May 15. 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
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

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

Eur J Neurol 2021 Jul 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

MuSK Antibody-Associated Myasthenia Gravis With SARS-CoV-2 Infection: A Case Report.

Ann Intern Med 2021 Jun 12;174(6):872-873. Epub 2021 Jan 12.

Imperial College Healthcare NHS Trust, London, United Kingdom.

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http://dx.doi.org/10.7326/L20-1298DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7808439PMC
June 2021

Worldwide Incidence and Prevalence of Neuromyelitis Optica: A Systematic Review.

Neurology 2021 01 11;96(2):59-77. Epub 2020 Dec 11.

From the Department of Neurology (V.P., Z.I.), Odense University Hospital; Danish Multiple Sclerosis Center (M.M.), Copenhagen University Hospital, Rigshospitalet, Denmark; Department of Neurology (O.A.), Medical Faculty, Heinrich-Heine University, Düsseldorf, Germany; Department of Neurology (T.B.), Medical University of Vienna, Austria; Menzies Health Institute Queensland (S.A.B.), Griffith University, Gold Coast; Department of Neurology (S.A.B.), Gold Coast University Hospital, Australia; Department of Neurology (P.C.), Fort-de-France University Hospital Center, Pierre Zobda Quitman Hospital, Fort-de-France, Martinique, France; Department of Neurology (A.J.), The Walton Centre, Liverpool, UK; Cleveland Clinic (A.J.), Abu Dhabi, United Arab Emirates; Departments of Neurology (J.K., J.P.), Neurological Institute, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan; Nuffield Department of Clinical Neurosciences (M.I.L., J.P.), John Radcliffe Hospital, University of Oxford, UK; Service de Neurologie (R.M.), Sclérose en Plaques, Pathologies de la Myéline et Neuro-Inflammation, et Centre de Référence des Maladies Inflammatoires Rares du Cerveau et de la Moelle (MIRCEM), Hôpital Neurologique Pierre Wertheimer, Hospices Civils de Lyon, Bron, France; Department of Neurology (K.M.), Kindai University Graduate School of Medicine, Osaka, Japan; Center of Neuroimmunology (A.S., M.S.), Service of Neurology, Hospital Clínic of Barcelona, Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Universitat de Barcelona, Spain; Department of Neurology (O.S.), Karolinska University Hospital and Department of Clinical Neuroscience, Karolinska Institutet, Stockholm, Sweden; Institute of Clinical Research (Z.I.), University of Southern Denmark, Odense, Denmark; and Institute of Molecular Medicine (Z.I.), University of Southern Denmark, Odense.

Objective: Since the last epidemiologic review of neuromyelitis optica/neuromyelitis optica spectrum disorder (NMO/NMOSD), 22 additional studies have been conducted. We systematically review the worldwide prevalence, incidence, and basic demographic characteristics of NMOSD and provide a critical overview of studies.

Methods: PubMed, Ovid MEDLINE, and Embase using Medical Subject Headings and keyword search terms and reference lists of retrieved articles were searched from 1999 until August 2019. We collected data on the country; region; methods of case assessment and aquaporin-4 antibody (AQP4-Ab) test; study period; limitations; incidence (per 100,000 person-years); prevalence (per 100,000 persons); and age-, sex-, and ethnic group-specific incidence or prevalence.

Results: We identified 33 relevant articles. The results indicated the highest estimates of incidence and prevalence of NMOSD in Afro-Caribbean region (0.73/100 000 person-years [95% CI: 0.45-1.01] and 10/100 000 persons [95% CI: 6.8-13.2]). The lowest incidence and prevalence of NMOSD were found in Australia and New Zealand (0.037/100 000 person-years [95% CI: 0.036-0.038] and 0.7/100,000 persons [95% CI: 0.66-0.74]). There was prominent female predominance in adults and the AQP4-Ab-seropositive subpopulation. The incidence and prevalence peaked in middle-aged adults. African ethnicity had the highest incidence and prevalence of NMOSD, whereas White ethnicity had the lowest. No remarkable trend of incidence was described over time.

Conclusion: NMOSD is a rare disease worldwide. Variations in prevalence and incidence have been described among different geographic areas and ethnicities. These are only partially explained by different study methods and NMO/NMOSD definitions, highlighting the need for specifically designed epidemiologic studies to identify genetic effects and etiologic factors.
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http://dx.doi.org/10.1212/WNL.0000000000011153DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7905781PMC
January 2021

Cohort profile: a collaborative multicentre study of retinal optical coherence tomography in 539 patients with neuromyelitis optica spectrum disorders (CROCTINO).

BMJ Open 2020 10 29;10(10):e035397. Epub 2020 Oct 29.

Neurological Department and Institute of Experimental Neurology (INSPE) Scientific Institute, Hospital San Raffaele; and University Vita-Salute San Raffaele, Milan, Italy.

Purpose: Optical coherence tomography (OCT) captures retinal damage in neuromyelitis optica spectrum disorders (NMOSD). Previous studies investigating OCT in NMOSD have been limited by the rareness and heterogeneity of the disease. The goal of this study was to establish an image repository platform, which will facilitate neuroimaging studies in NMOSD. Here we summarise the profile of the Collaborative OCT in NMOSD repository as the initial effort in establishing this platform. This repository should prove invaluable for studies using OCT to investigate NMOSD.

Participants: The current cohort includes data from 539 patients with NMOSD and 114 healthy controls. These were collected at 22 participating centres from North and South America, Asia and Europe. The dataset consists of demographic details, diagnosis, antibody status, clinical disability, visual function, history of optic neuritis and other NMOSD defining attacks, and OCT source data from three different OCT devices.

Findings To Date: The cohort informs similar demographic and clinical characteristics as those of previously published NMOSD cohorts. The image repository platform and centre network continue to be available for future prospective neuroimaging studies in NMOSD. For the conduct of the study, we have refined OCT image quality criteria and developed a cross-device intraretinal segmentation pipeline.

Future Plans: We are pursuing several scientific projects based on the repository, such as analysing retinal layer thickness measurements, in this cohort in an attempt to identify differences between distinct disease phenotypes, demographics and ethnicities. The dataset will be available for further projects to interested, qualified parties, such as those using specialised image analysis or artificial intelligence applications.
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http://dx.doi.org/10.1136/bmjopen-2019-035397DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7597491PMC
October 2020

A clinico-neurophysiological study of urogenital dysfunction in MOG-antibody transverse myelitis.

Neurology 2020 11 12;95(21):e2924-e2934. Epub 2020 Oct 12.

From the National Hospital for Neurology and Neurosurgery (V.L., P.M., S.S., M.P., J.N.P.), UCL Institute of Neurology, Department of Uro-Neurology; Queen Square MS Centre (V.L.), UCL Institute of Neurology, Department of Neuroinflammation, Queen Square, London; and Nuffield Department of Clinical Neurosciences (R.E., C.S., M.I.L., J.P.), John Radcliffe Hospital, University of Oxford, UK.

Objective: To assess the clinical, urodynamic, and neurophysiologic features of patients with persisting bladder, bowel, and sexual dysfunction after transverse myelitis in myelin oligodendrocyte glycoprotein antibody (MOG-Ab) disease.

Methods: Patients with a history of MOG-Ab disease-related transverse myelitis seen prospectively in a tertiary center uro-neurology service between 2017 and 2019 were included. They received cross-sectional clinical assessment; completed standardized questionnaires on bladder, bowel, and sexual symptoms; and underwent urodynamic and pelvic neurophysiologic investigations.

Results: Twelve patients (9 male) were included with a total of 17 episodes of transverse myelitis. Mean age at first attack was 26 (SD 9) years, and median follow-up duration was 50 (interquartile range 32-87) months. Acute urinary retention requiring bladder catheterization occurred in 14 episodes and was the first symptom in 10 episodes. Patients with lesions affecting the conus medullaris required catheterization for significantly longer durations than those without a conus lesion (median difference 15.5 days, = 0.007). At follow-up, all patients had recovered full ambulatory function, but persisting bladder and bowel dysfunction moderately or severely affected quality of life in 55% and 36%, respectively, and 82% had sexual dysfunction. Pelvic neurophysiology demonstrated abnormal residual conus function in 6 patients. Urodynamic findings predominantly showed detrusor overactivity and/or detrusor-sphincter dyssynergia, indicative of a supraconal pattern of lower urinary tract dysfunction.

Conclusions: Persisting urogenital and bowel dysfunction is common despite motor recovery. Although a proportion of patients had neurophysiologic evidence of residual conus abnormalities at follow-up, predominant urodyamic findings suggest that ongoing lower urinary tract dysfunction results from supraconal injury.
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http://dx.doi.org/10.1212/WNL.0000000000011030DOI Listing
November 2020

State of the Art and Future Challenges in Multiple Sclerosis Research and Medical Management: An Insight into the 5th International Porto Congress of Multiple Sclerosis.

Neurol Ther 2020 Dec 14;9(2):281-300. Epub 2020 Jul 14.

Beijing Tiantan Hospital, Capital Medical University, Beijing, 100070, China.

The 5th International Porto Congress of Multiple Sclerosis took place between the 14th and 16th of February 2019 in Porto, Portugal. Its intensive programme covered a wide-range of themes-including many of the hot topics, challenges, pitfalls and yet unmet needs in the field of multiple sclerosis (MS)-led by a number of well-acknowledged world experts. This meeting review summarizes the talks that took place during the congress, which focussed on issues in MS as diverse as the development and challenges of progressive MS, epidemiology, differential diagnosis, medical management, molecular research and imaging tools.
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http://dx.doi.org/10.1007/s40120-020-00202-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7606370PMC
December 2020

Seasonal distribution of attacks in aquaporin-4 antibody disease and myelin-oligodendrocyte antibody disease.

J Neurol Sci 2020 Aug 7;415:116881. Epub 2020 May 7.

Nuffield Department of Clinical Neurosciences, John Radcliffe Hospital, University of Oxford, Oxford, United Kingdom. Electronic address:

Background: Seasonal variation in incidence and exacerbations has been reported for neuroinflammatory conditions such as multiple sclerosis and acute disseminated encephalomyelitis (ADEM). It is unknown whether seasonality also influences aquaporin-4 antibody (AQP4-Ab) disease and myelin-oligodendrocyte antibody (MOG-Ab) disease.

Objective: We examined the seasonal distribution of attacks in AQP4-Ab disease and MOG-Ab disease.

Methods: Observational study using data prospectively recorded from three cohorts in the United Kingdom.

Results: There was no clear seasonal variation in AQP4-Ab or MOG-Ab attacks for either the onset attack nor subsequent relapses. In both groups, the proportion of attacks manifesting with each of the main phenotypes (optic neuritis, transverse myelitis, ADEM/ADEM-like) appeared stable across the year. This study is the first to examine seasonal distribution of MOG-Ab attacks and the largest in AQP4-Ab disease so far.

Conclusion: Lack of seasonal distribution in AQP4-Ab and MOG-Ab disease may argue against environment factors playing a role in the aetiopathogenesis of these conditions.
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http://dx.doi.org/10.1016/j.jns.2020.116881DOI Listing
August 2020

Induction of aquaporin 4-reactive antibodies in Lewis rats immunized with aquaporin 4 mimotopes.

Acta Neuropathol Commun 2020 04 15;8(1):49. Epub 2020 Apr 15.

Department Neuroimmunology, Medical University Vienna, Center for Brain Research, Spitalgasse 4, A-1090, Vienna, Austria.

Most cases of neuromyelitis optica spectrum disorders (NMOSD) harbor pathogenic autoantibodies against the water channel aquaporin 4 (AQP4). Binding of these antibodies to AQP4 on astrocytes initiates damage to these cells, which culminates in the formation of large tissue destructive lesions in the central nervous system (CNS). Consequently, untreated patients may become permanently blind or paralyzed. Studies on the induction and breakage of tolerance to AQP4 could be of great benefit for NMOSD patients. So far, however, all attempts to create suitable animal models by active sensitization have failed. We addressed this challenge and identified peptides, which mimic the conformational AQP4 epitopes recognized by pathogenic antibodies of NMOSD patients. Here we show that these mimotopes can induce the production of AQP4-reactive antibodies in Lewis rats. Hence, our results provide a conceptual framework for the formation of such antibodies in NMOSD patients, and aid to improve immunization strategies for the creation of animal models suitable for tolerance studies in this devastating disease.
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http://dx.doi.org/10.1186/s40478-020-00920-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7160927PMC
April 2020

Factors associated with fatigue in CNS inflammatory diseases with AQP4 and MOG antibodies.

Ann Clin Transl Neurol 2020 03 18;7(3):375-383. Epub 2020 Mar 18.

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

Objective: Fatigue is a common and disabling symptom amongst people with multiple sclerosis, however it has not been compared across the central nervous system (CNS) inflammatory diseases associated with aquaporin-4 (AQP4) and myelin oligodendrocyte glycoprotein (MOG) antibodies (Ab). We explored the factors associated with fatigue within and across the two diseases, and compared fatigue levels between them.

Methods: We performed a cross-sectional study of 90 AQP4-Ab and 44 MOG-Ab patients. Fatigue was assessed using the Modified Fatigue Impact Scale (MFIS). Clinical, demographic, and psychometric (anxiety, depression, pain) data were used as independent variables. Multivariable linear regression was used to identify significant independent variables associated with fatigue within and across the two diseases.

Results: Within AQP4-Ab patients, age (P = 0.002), disease duration (P = 0.004), number of clinical attacks (P = 0.001), disability (P = 0.007), pain interference (P < 0.001), anxiety (P = 0.026), and depression (P < 0.001) were significant independent variables. Interestingly, disease duration had a negative association with fatigue (P = 0.004). Within MOG-Ab patients, pain interference score (P < 0.001) and anxiety (P = 0.001) were significant independent variables. Although fatigue was worse in AQP4-Ab patients compared to MOG-Ab patients (P = 0.008) in all patients as well as in those who ever had transverse myelitis (P = 0.023), this was driven by the differences in age, disability and pain interference rather than antibody subtype itself.

Interpretation: Multiple factors, but not the antibody specificity, appear to contribute to fatigue in antibody positive CNS inflammatory diseases. A multifaceted treatment approach is needed to better manage the physical, cognitive, and psychosocial aspects of fatigue in these patients.
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http://dx.doi.org/10.1002/acn3.51008DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7086003PMC
March 2020

Prodromal headache in MOG-antibody positive optic neuritis.

Mult Scler Relat Disord 2020 May 25;40:101965. Epub 2020 Jan 25.

Nuffield Department of Clinical Neurosciences, Level 6, West Wing, John Radcliffe Hospital, Oxford, OX3 9DU, UK.

Background: Myelin oligodendrocyte glycoprotein antibody (MOG-Ab) disease is an inflammatory autoimmune condition of the central nervous system, defined by antibodies (Abs) against MOG. Of the various clinical phenotypes optic neuritis (ON) is the commonest. We have observed that some patients with MOG-Ab ON present with a severe associated headache.

Objective: To highlight the importance of headache in MOG-Ab related optic neuritis.

Methods: Clinical and MRI data from MOG-Ab patients with ON (n = 129) were obtained from observational cohort studies and clinical notes at the NeuroCure Clinical Research Center, Charité Berlin and at the Diagnostic and Advisory Service for Neuromyelitis Optica, John Radcliffe Hospital, Oxford.

Results: Sixty-four of 129 MOG-Ab patients (49.6%) reported ≥1 headache-related ON. Headache usually started a few days prior to visual loss and extended from the ocular region to the periorbital and fronto-temporal area, sometimes mimicking migraine. Of those, thirty-two patients (50%) reported severe headache. Two patients did not have headache. No headache history was recorded for 63 patients. MRIs performed acutely during headache-related MOG-Ab ON (n = 15) showed anterior ON with extensive swelling and edema of the optic nerve/s in all patients, either unilaterally (n = 5) or bilaterally (n = 10). Peri-optic cerebro-spinal fluid (CSF) was undetectable due to the inflammatory extension in 12 out of 15 patients.

Conclusion: Our findings indicate that acute MOG-Ab ON shows florid intra-orbital and peri‑optic inflammation, likely to involve meninges and nociceptive fibers around the optic nerve. This may explain the frequent and often severe headache that precedes the visual deficit, sometimes misdiagnosed as migraine.
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http://dx.doi.org/10.1016/j.msard.2020.101965DOI Listing
May 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

MOG-antibody-associated disease is different from MS and NMOSD and should be considered as a distinct disease entity - Yes.

Mult Scler 2020 03 17;26(3):272-274. Epub 2019 Dec 17.

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

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http://dx.doi.org/10.1177/1352458519868796DOI Listing
March 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

Comparison of Clinical Outcomes of Transverse Myelitis Among Adults With Myelin Oligodendrocyte Glycoprotein Antibody vs Aquaporin-4 Antibody Disease.

JAMA Netw Open 2019 10 2;2(10):e1912732. Epub 2019 Oct 2.

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

Importance: Recognizing the differences between transverse myelitis (TM) associated with myelin oligodendrocyte glycoprotein (MOG) antibody (Ab) disease vs aquaporin-4 (AQP4)-Ab disease and prognosticating patients within each group may be an important factor for better clinical treatment for these respective patients.

Objectives: To compare the clinical and radiological findings of the first TM episode in patients with MOG-Ab disease vs patients with AQP4-Ab disease and to assess factors associated with worse outcomes and relapse risk.

Design, Setting, And Participants: This retrospective cross-sectional study used data collected from the Oxford Neuromyelitis Optica Service database, a national service that serves the south of England, including detailed clinical data, and high-quality imaging from within 4 weeks of the first TM episode from patients with MOG-Ab disease or AQP4-Ab disease and a confirmed history of TM from April 2018 to January 2019. Data analyses were conducted from February 2019 to April 2019.

Main Outcomes And Measures: Onset features of each condition measured using the Expanded Disability Status Scale (EDSS) score, time to an EDSS score of 6, time to relapse, and residual sphincter dysfunction at least 6 months after the first TM episode and at last follow-up.

Results: The total cohort included 115 adult patients, including 46 patients with MOG-Ab disease and 69 patients with AQP4-Ab disease. Patients with AQP4-Ab disease, compared with patients with MOG-Ab disease, tended to be older at onset of disease (mean [SD] age, 48.5 [14.9] years vs 33.7 [1.2] years) and female (57 [83%] women vs 24 [52%] women). Transverse myelitis occurred at onset of disease for 32 patients (70%) with MOG-Ab disease and 57 patients (78%) with AQP4-Ab disease. Onset severity did not differ between groups. An acute disseminated encephalomyelitis-like presentation occurred at the time of the TM in 4 patients (9%) with MOG-Ab disease but no patients with AQP4-Ab disease. Compared with patients with AQP4-Ab disease, patients with MOG-Ab disease were more likely to have short cord lesions (22 patients [48%] vs 10 patients [15%]; P < .001) and multiple cord lesions (18 patients [39%] vs 7 patients [10%]; P < .001). Approximately 50% of patients with MOG-Ab disease had only short cord lesions when the TM occurred as a relapse. Median (range) recovery EDSS score was lower in patients with MOG-Ab disease than patients with AQP4-Ab disease (1.8 [1.0-8.0] vs 3.0 [1.0-8.0]). Persistent bladder dysfunction associated with an increased prevalence of conus lesions occurred more frequently in patients with MOG-Ab disease than in patients with AQP4-Ab disease (27 patients [59%] vs 33 patients [48%]). Long-term catheter requirement was roughly equal between groups (9 patients [20%] vs 16 patients [23%]). Relapses after TM occurred in 17 patients with MOG-Ab disease (37%) and 36 patients with AQP4-Ab disease (52%). Concomitant brainstem lesions in patients with MOG-Ab disease were associated with a higher mean (SD) EDSS score at recovery (3.5 [2.3] vs 1.4 [0.9]; P < .001). In patients with AQP4-Ab disease, those younger than 50 years were more likely to relapse (27 of 36 patients aged <50 years [75%] vs 9 of 33 patients aged ≥50 years [27%]; P < .001) and those 50 years and older were more likely to reach an EDSS score of 6 (19 of 33 patients aged ≥50 years [58%] vs 11 of 36 patients aged <50 years [31%]; P = .03).

Conclusions And Relevance: This study found that in patients who experienced a TM episode, short and multiple lesions at onset were more common in those with MOG-Ab disease than among those with AQP4-Ab disease. The presence of a brainstem lesion at the time of a TM episode in patients with MOG-Ab disease was associated with a worse recovery. In patients with AQP4-Ab disease, those 50 years and older at disease onset had more disability, and those younger than 50 years at disease onset had more relapses.
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http://dx.doi.org/10.1001/jamanetworkopen.2019.12732DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6802235PMC
October 2019

Refractory myasthenia gravis: Characteristics of a portuguese cohort.

Muscle Nerve 2019 08 15;60(2):188-191. Epub 2019 May 15.

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

Introduction: Some myasthenia gravis (MG) patients are refractory to conventional treatments.

Methods: To describe the clinical features of refractory MG (RMG) and explore the association with human leukocyte antigen HLA-DRB1 alleles, a cohort study of 114 consecutive MG patients was performed. Patients were classified as RMG based on predefined criteria.

Results: Twenty-two patients were found to have RMG (19.3%). There were no differences between non-RMG and RMG patients with respect to sex, age of onset, abnormal 3-Hz repetitive nerve stimulation, anti-acetylcholine receptor antibody positivity, thymectomy, thymoma or thymic hyperplasia, and polyautoimmunity. HLA-DRB1*03 was more frequent in the non-RMG vs. control population (P = 3 × 10 ). The HLA-DRB1*13 allele was less frequent in non-RMG patients compared with controls (P = 0.002), and less frequent in the non-RMG group compared with the RMG group (P = 0.003).

Discussion: HLA-DRB1*03 was more common in non-RMG, and the HLA-DRB1*13 allele appeared to have a protective role, as reported previously in other autoimmune disorders. Muscle Nerve 60: 188-191, 2019.
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http://dx.doi.org/10.1002/mus.26507DOI Listing
August 2019

Outcome prediction models in AQP4-IgG positive neuromyelitis optica spectrum disorders.

Brain 2019 05;142(5):1310-1323

Department of Neurology, Mayo Clinic College of Medicine, 200 First Street S.W., Rochester, Minnesota, USA.

Pathogenic antibodies targeting the aquaporin-4 water channel on astrocytes are associated with relapsing inflammatory neuromyelitis optica spectrum disorders. The clinical phenotype is characterized by recurrent episodes of optic neuritis, longitudinally extensive transverse myelitis, area postrema attacks and less common brainstem and cerebral events. Patients often develop major residual disability from these attacks, so early diagnosis and initiation of attackpreventing medications is important. Accurate prediction of relapse would assist physicians in counselling patients, planning treatment and designing clinical trials. We used a large multicentre dataset of 441 patients from the UK, USA, Japan and Martinique who collectively experienced 1976 attacks, and applied sophisticated mathematical modelling to predict likelihood of relapse and disability at different time points. We found that Japanese patients had a lower risk of subsequent attacks except for brainstem and cerebral events, with an overall relative relapse risk of 0.681 (P = 0.001) compared to Caucasians and African patients, who had a higher likelihood of cerebral attacks, with a relative relapse risk of 3.309 (P = 0.009) compared to Caucasians. Female patients had a higher chance of relapse than male patients (P = 0.009), and patients with younger age of onset were more likely to have optic neuritis relapses (P < 0.001). Immunosuppressant drugs reduced and multiple sclerosis disease-modifying agents increased the likelihood of relapse (P < 0.001). Patients with optic neuritis at onset were more likely to develop blindness (P < 0.001), and those with older age of onset were more likely to develop ambulatory disability. Only 25% of long-term disability was related to initial onset attack, indicating the importance of early attack prevention. With respect to selection of patients for clinical trial design, there would be no gain in power by selecting recent onset patients and only a small gain by selecting patients with recent high disease activity. We provide risk estimates of relapse and disability for patients diagnosed and treated with immunosuppressive treatments over the subsequent 2, 3, 5 and 10 years according to type of attack at onset or the first 2-year course, ethnicity, sex and onset age. This study supports significant effects of onset age, onset phenotype and ethnicity on neuromyelitis optica spectrum disorders outcomes. Our results suggest that powering clinical treatment trials based upon relapse activity in the preceding 2 years may offer little benefit in the way of attack risk yet severely hamper clinical trial success.
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http://dx.doi.org/10.1093/brain/awz054DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6487334PMC
May 2019

Signs heralding appearance of thymomas after extended thymectomy for myasthenia gravis.

Neurol Clin Pract 2019 Feb;9(1):48-52

Departments of Neurology (ES, AMS) and Pathology (CL), Clinical Immunology (A. Marinho) Hospital Santo Antonio/ Centro Hospitalar Universitario do Porto; Instituto de Ciencias Biomedicas de Abel Salazar (ES, AMS, GG), University of Porto, Portugal; Institute of Pathology (PS), University Medical Center Göttingen, University of Göttingen, Germany; Neurosciences Group (NW, MIL), Nuffield Department of Clinical Neurology, Institute of Molecular Medicine, John Radcliffe Hospital, University of Oxford, UK; and Institute of Pathology (A. Marx), University Medical Centre Mannheim, University of Heidelberg, Mannheim, Germany.

Purpose Of Review: Thymomas appear very rarely after extended thymectomy for early-onset myasthenia gravis (EOMG). We describe 2 such cases that highlight potential early warning signs.

Recent Findings: In their 20s, one woman and one man developed EOMG (AChR antibody-positive), requiring extended transsternal removal of hyperplastic thymi at ages 35 and 27, respectively. Their myasthenia gravis was readily controlled for the next 10 and 7 years before deteriorating in both, with appearance of late clinical features and anticytokine autoantibodies suggesting underlying thymomas, namely respiratory infections, genital herpes, chronic candidiasis, and alopecia in the woman and erythroderma and lichen planus in the man, followed by , , and cytomegalovirus infections plus chronic hepatitis during intensifying immunosuppressive therapy. Type B thymomas were then detected. Despite surgery or radiotherapy, and intensive drug therapy, the patients died 7 and 1 years later.

Summary: Certain infections/dermatologic manifestations that associate with long-standing thymomas may herald their late appearance, despite previous thymectomy.
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http://dx.doi.org/10.1212/CPJ.0000000000000551DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6382375PMC
February 2019

Brain and cord imaging features in neuromyelitis optica spectrum disorders.

Ann Neurol 2019 03 28;85(3):371-384. Epub 2019 Jan 28.

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

Objectives: To validate imaging features able to discriminate neuromyelitis optica spectrum disorders from multiple sclerosis with conventional magnetic resonance imaging (MRI).

Methods: In this cross-sectional study, brain and spinal cord scans were evaluated from 116 neuromyelitis optica spectrum disorder patients (98 seropositive and 18 seronegative) in chronic disease phase and 65 age-, sex-, and disease duration-matched multiple sclerosis patients. To identify independent predictors of neuromyelitis optica diagnosis, after assessing the prevalence of typical/atypical findings, the original cohort was 2:1 randomized in a training sample (where a multivariate logistic regression analysis was run) and a validation sample (where the performance of the selected variables was tested and validated).

Results: Typical brain lesions occurred in 50.9% of neuromyelitis optica patients (18.1% brainstem periventricular/periaqueductal, 32.7% periependymal along lateral ventricles, 3.4% large hemispheric, 6.0% diencephalic, 4.3% corticospinal tract), 72.2% had spinal cord lesions (46.3% long transverse myelitis, 36.1% short transverse myelitis), 37.1% satisfied 2010 McDonald criteria, and none had cortical lesions. Fulfillment of at least 2 of 5 of absence of juxtacortical/cortical lesions, absence of periventricular lesions, absence of Dawson fingers, presence of long transverse myelitis, and presence of periependymal lesions along lateral ventricles discriminated neuromyelitis optica patients in both training (sensitivity = 0.92, 95% confidence interval [CI] = 0.84-0.97; specificity = 0.91, 95% CI = 0.78-0.97) and validation samples (sensitivity = 0.82, 95% CI = 0.66-0.92; specificity = 0.91, 95% CI = 0.71-0.99). MRI findings and criteria performance were similar irrespective of serostatus.

Interpretation: Although up to 50% of neuromyelitis optica patients have no typical lesions and a relatively high percentage of them satisfy multiple sclerosis criteria, several easily applicable imaging features can help to distinguish neuromyelitis optica from multiple sclerosis. ANN NEUROL 2019;85:371-384.
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http://dx.doi.org/10.1002/ana.25411DOI Listing
March 2019

Racial differences in neuromyelitis optica spectrum disorder.

Neurology 2018 11 26;91(22):e2089-e2099. Epub 2018 Oct 26.

From the Department of Neurology (S.-H.K., H.-J.S., J.-W.H., H.J.K.) and Biometric Research Branch (M.H.), Research Institute and Hospital of National Cancer Center, Goyang, South Korea; Department of Neurology (M.A.M., M.L.), Johns Hopkins University School of Medicine, Baltimore, MD; NeuroCure Clinical Research Center (F.S., F.P.) and Department of Neurology (F.S., K.R., F.P.), Charité-Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health; Experimental and Clinical Research Center (F.S., F.P.), Max Delbrück Center for Molecular Medicine and Charité-Universitätsmedizin Berlin; Department of Neurology (M.R., O.A., H.-P.H.), Medical Faculty, Heinrich Heine University, Düsseldorf, Germany; Department of Neurology (N.A.), Slagelse Hospital and Institute of Regional Health Research & Molecular Medicine, University of Southern Denmark, Odense; Department of Neurology (J.L.T.-C.), Queen Elizabeth Hospital, Hong Kong, China; Department of Medicine (S.S., N.P.), Siriraj Hospital, Mahidol University, Bangkok, Thailand; and Nuffield Department of Clinical Neurosciences (M.I.L., J.P.), John Radcliffe Hospital, University of Oxford, UK.

Objective: We aimed to evaluate racial differences in the clinical features of neuromyelitis optica spectrum disorder.

Methods: This retrospective review included 603 patients (304 Asian, 207 Caucasian, and 92 Afro-American/Afro-European), who were seropositive for anti-aquaporin-4 antibody, from 6 centers in Denmark, Germany, South Korea, United Kingdom, United States, and Thailand.

Results: Median disease duration at last follow-up was 8 years (range 0.3-38.4 years). Asian and Afro-American/Afro-European patients had a younger onset age than Caucasian patients (mean 36, 33, and 44 years, respectively; < 0.001). During the disease course, Caucasian patients (23%) had a lower incidence of brain/brainstem involvement than Asian (42%) and Afro-American/Afro-European patients (38%) ( < 0.001). Severe attacks (visual acuity ≤0.1 in at least one eye or Expanded Disability Status Scale score ≥6.0 at nadir) at onset occurred more frequently in Afro-American/Afro-European (58%) than in Asian (46%) and Caucasian (38%) patients ( = 0.005). In the multivariable analysis, older age at onset, higher number of attacks before and after immunosuppressive treatment, but not race, were independent predictors of severe motor disabilities at last follow-up.

Conclusion: A review of a large international cohort revealed that race affected the clinical phenotype, age at onset, and severity of attacks, but the overall outcome was most dependent on early and effective immunosuppressive treatment.
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http://dx.doi.org/10.1212/WNL.0000000000006574DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6282238PMC
November 2018

Area postrema syndrome: Frequency, criteria, and severity in AQP4-IgG-positive NMOSD.

Neurology 2018 10 26;91(17):e1642-e1651. Epub 2018 Sep 26.

From the Departments of Neurology (E.S., D.D., M.M., E.F., A.G., B.W., S.J.P.), Laboratory Medicine and Pathology (M.M., E.F., A.G., S.J.P.), and Clinical Research Unit (C.H., J.S.), Mayo Clinic College of Medicine, Rochester, MN; Nuffield Department of Clinical Neurosciences (J.P., M.I.L., S.M.), Oxford; The Walton Centre (A.J., D.W., L.E.), NHS Foundation Trust, Liverpool, UK; Department of Neurology (I.N., K.F., T.T., T.M., Y.T.), Tohoku University Graduate School of Medicine, Sendai; Department of Multiple Sclerosis Therapeutics (K.F.), Fukushima Medical University School of Medicine and Multiple Sclerosis and Neuromyelitis Optica Center, Southern Tohoku Research Institute for NeuroScience, Koriyama, Japan; Department of Neurology (M.L., A.B.), Johns Hopkins University, Baltimore, MD; Departments of Neurology and Neurotherapeutics (B.M.G.), UT Southwestern Medical Center, Dallas, TX; Department of Neurology (T.T.), Yonezawa National Hospital; and Department of Neurology (I.N.), Tohoku Medical and Pharmaceutical University, Sendai, Japan.

Objective: To define the frequency, duration, and severity of intractable nausea, vomiting, or hiccups in aquaporin-4-immunoglobulin G (AQP4-IgG)-positive neuromyelitis optica spectrum disorder (NMOSD) and propose diagnostic criteria and a severity scale for area postrema syndrome (APS).

Methods: An International NMOSD database was interrogated for frequency of APS. Patients with AQP4-IgG-positive NMOSD completed an APS symptom questionnaire. Nausea and vomiting severity was derived from the Pregnancy-Unique Quantification of Emesis and Nausea (PUQE) score. The diagnostic criteria, severity scale, and immunotherapy response was applied to a prospective validation cohort of patients from multiple centers.

Results: Analysis of an international database for AQP4-IgG-seropositive NMOSD (n = 430) revealed a high prevalence of isolated APS attacks (onset 7.1%-10.3%; subsequent 9.4%-14.5%) across continents. For 100 patients with 157 episodes of APS, nausea (n = 127, 81%) lasted for a median of 14 days (range 2-365), vomiting (113, 72%) with a median of 5 episodes/d (2-40) lasted 1-20 minutes, and hiccups (102, 65%) lasted a median of 14 days (2-365). Symptoms consistently and completely resolved following immunotherapy. Data were used to propose APS diagnostic criteria and repurpose PUQE score (hiccups severity grade based on symptom duration). The clinical utility was demonstrated in a prospective validation cohort.

Conclusion: Isolated APS attacks are frequently encountered both at onset and during the NMOSD course. The diagnostic criteria proposed here will assist clinicians in recognizing APS. Diagnosis of an APS attack earlier than 48 hours is possible if a dorsal medulla lesion is detected. Accurate diagnosis and evaluation of APS attack severity will assist in outcome measurement in NMOSD clinical trials.
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http://dx.doi.org/10.1212/WNL.0000000000006392DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6205685PMC
October 2018

Retinal ganglion cell loss in neuromyelitis optica: a longitudinal study.

J Neurol Neurosurg Psychiatry 2018 12 19;89(12):1259-1265. Epub 2018 Jun 19.

NeuroCure Clinical Research Center, Charité-Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, Berlin, Germany.

Objectives: Neuromyelitis optica spectrum disorders (NMOSD) are inflammatory conditions of the central nervous system and an important differential diagnosis of multiple sclerosis (MS). Unlike MS, the course is usually relapsing, and it is unclear, if progressive neurodegeneration contributes to disability. Therefore, we aimed to investigate if progressive retinal neuroaxonal damage occurs in aquaporin4-antibody-seropositive NMOSD.

Methods: Out of 157 patients with NMOSD screened, 94 eyes of 51 patients without optic neuritis (ON) during follow-up (F/U) and 56 eyes of 28 age-matched and sex-matched healthy controls (HC) were included (median F/U 2.3 years). The NMOSD cohort included 60 eyes without (Eye) and 34 eyes with a history of ON prior to enrolment (Eye). Peripapillary retinal nerve fibre layer thickness (pRNFL), fovea thickness (FT), volumes of the combined ganglion cell and inner plexiform layer (GCIP) and the inner nuclear layer (INL) and total macular volume (TMV) were acquired by optical coherence tomography (OCT).

Results: At baseline, GCIP, FT and TMV were reduced in Eye (GCIP p<2e; FT p=3.7e; TMV p=3.7e) and in Eye (GCIP p=0.002; FT p=0.040; TMV p=6.1e) compared with HC. Longitudinally, we observed GCIP thinning in Eye (p=0.044) but not in Eye. Seven patients had attacks during F/U; they presented pRNFL thickening compared with patients without attacks (p=0.003).

Conclusion: This study clearly shows GCIP loss independent of ON attacks in aquaporin4-antibody-seropositive NMOSD. Potential explanations for progressive GCIP thinning include primary retinopathy, drug-induced neurodegeneration and retrograde neuroaxonal degeneration from lesions or optic neuropathy. pRNFL thickening in the patients presenting with attacks during F/U might be indicative of pRNFL susceptibility to inflammation.
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http://dx.doi.org/10.1136/jnnp-2018-318382DOI Listing
December 2018

High and low pressure headaches: a spinal cause.

Pract Neurol 2018 Oct 18;18(5):413-414. Epub 2018 May 18.

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

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http://dx.doi.org/10.1136/practneurol-2017-001769DOI Listing
October 2018

Thymus imaging in myasthenia gravis: The relevance in clinical practice.

Muscle Nerve 2018 Feb 9. Epub 2018 Feb 9.

Nuffield Department of Clinical Neurosciences, John Radcliffe Hospital, Oxford University Hospitals, Headley Way Headington, Oxford, OX3 9DU, United Kingdom.

Introduction: The ability to distinguish between normal thymus, thymic hyperplasia, and thymoma should aid clinical management and decision making in patients with myasthenia gravis (MG). We sought to determine the accuracy of routine imaging in predicting thymic pathology.

Methods: We retrospectively analyzed records of patients with MG from the Oxford Myasthenia Centre registry who had undergone thymectomy. Each patient received 1 radiological diagnosis and 1 histological diagnosis.

Results: We included 106 patients. Radiological and histological diagnoses agreed in 73 (68.9%) patients. Sensitivity and specificity, respectively, were calculated for each radiological diagnosis as follows: thymoma 90% and 95.5%, hyperplasia 17.6% and 98.6%, and normal 96.9% and 60.8%.

Discussion: Routine chest computed tomography and MRI can effectively identify thymoma. However, they are not reliable tools to differentiate between thymic hyperplasia and normal thymus in patients with MG. Muscle Nerve, 2018.
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http://dx.doi.org/10.1002/mus.26096DOI Listing
February 2018

MuSK myasthenia gravis and pregnancy.

Neuromuscul Disord 2018 02 28;28(2):150-153. Epub 2017 Nov 28.

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

Muscle specific kinase (MuSK) myasthenia gravis (MG, MuSK-MG) is a rare subgroup of MG affecting mainly women during childbearing years. We investigated the influence of pregnancy in the course of MuSK-MG and pregnancy outcomes in females with MuSK-MG. A multicentre cohort of 17 women with MuSK-MG was studied retrospectively; 13 of them with ≥1 pregnancy. MuSK-MG onset age was 35,4 years; 23,0% had other autoimmune disorder; 46,2% were treatment refractory. Thirteen women experienced 27 pregnancies, either after MG onset (group I) (n = 4; maternal age at conception = 29.8 years) or before MG onset (group II) (n = 23; maternal age at conception = 26.2 years). In group I pregnancy occurred in average 9.8 years after the MG onset; it occurred in average 17.0 years before MG in group II. In group I, all were on steroids at time of conception, one on azathioprine and another receiving IVIG regularly. There were mild exacerbations that responded to treatment adjustments. There were no relapses in the 12 months following the delivery. There was no pre-eclampsia, birth defects or stillbirths in either group; 3 miscarriages in group II. One case of neonatal MG was recorded. In this small series, pregnancy did not seem to precipitate MuSK-MG or to have a major influence in the MuSK-MG course, and there was no apparent negative impact in pregnancy outcomes in those where pregnancy followed the MG onset. The weight was lower in the newborn of the group I mothers, although none had low birth weight.
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http://dx.doi.org/10.1016/j.nmd.2017.11.014DOI Listing
February 2018