Publications by authors named "Albert Saiz"

179 Publications

Clinical, Neuroimmunologic, and CSF Investigations in First Episode Psychosis.

Neurology 2021 May 12. Epub 2021 May 12.

Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Hospital Clínic, Universitat de Barcelona, Barcelona, Spain;

Objectives: To report the neuropsychiatric features and frequency of N-methyl-d-aspartate receptor (NMDAR) and other neuronal IgG antibodies in patients with first episode psychosis (FEP), and assess the performance of reported warning signs and criteria for autoimmune psychosis (AP).

Methods: Prospective observational study of patients with FEP assessed for neuropsychiatric symptoms, serum and CSF neuronal antibodies (brain immunohistochemistry, cell-based assays, live neurons), and warning signs and criteria of AP. Previous autoimmune FEP series were reviewed.

Findings: 105 patients were included; median age 30 years (range 14-75), 44 (42%) female. None had neuronal antibodies. Two/105 (2%) had CSF pleocytosis, 4/100 (4%) brain MRI abnormalities, and 3/73 (4%) EEG alterations. Thirty-four (32%) and 39 (37%) patients fulfilled two sets of warning signs of AP, and 21 (20%) fulfilled criteria of possible or probable AP, yet none developed AP. The cause of FEP was psychiatric in 101 (96%) and non-psychiatric in 4 (4%). During this study, 3 patients with psychosis caused by anti-NMDAR encephalitis were transferred to our center; 2 did not meet criteria for possible AP. Of 1159 reported FEP patients, only 7 (1%) had CSF studies; 36 (3%) had serum NMDAR-antibodies (without definite diagnosis of AP), and 4 had CSF NMDAR-antibodies (3 classic anti-NMDAR encephalitis and 1 with isolated psychiatric features).

Conclusions: NMDAR-antibodies were not found in patients with FEP unless they had anti-NMDAR encephalitis. Warning signs and criteria for AP have limited utility when neurological symptoms are absent or paraclinical tests are normal. A diagnostic algorithm for autoimmune FEP is provided.
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http://dx.doi.org/10.1212/WNL.0000000000012191DOI Listing
May 2021

In Vivo Molecular Changes in the Retina of Patients With Multiple Sclerosis.

Invest Ophthalmol Vis Sci 2021 May;62(6):11

Center of Neuroimmunology, Institut d'Investigacions Biomediques August Pi Sunyer, Barcelona, Spain.

Purpose: Raman spectroscopy allows molecular changes to be quantified in vivo from the tissues like the retina. Here we aimed to assess the metabolic changes in the retina of patients with multiple sclerosis (MS).

Methods: We built a Raman spectroscopy prototype by connecting a scanning laser ophthalmoscope to a spectrophotometer. We defined the spectra of 10 molecules participating on energy supply, axon biology, or synaptic damage, which have been shown to be altered in the brain of patients with MS: cytochrome C, flavin adenine dinucleotide (FAD), nicotinamide adenine dinucleotide (NADH), N-acetyl-aspartate (NAA), excitotoxicity, glutamate, amyloid β (Aβ), τ and α-synuclein (SNCA), phosphatidyl-ethanolamine, and phosphatidyl-choline. We studied these molecules in a prospective cohort of patients with MS, either in the chronic phase or during relapses of acute optic neuritis (AON).

Results: Significant changes to all these molecules were associated with age in healthy individuals. There was a significant decrease in NADH and a trend toward a decrease in NAA in patients with MS, as well as an increase in Aβ compared with healthy controls. Moreover, NADH and FAD increased over time in a longitudinal analysis of patients with MS, whereas Aβ diminished. In patients with acute retinal inflammation due to AON, there was a significant increase in FAD and a decrease in SNCA in the affected retina. Moreover, glutamate levels increased in the affected eyes after a 6-month follow-up.

Conclusions: Alterations of molecules related to axonal degeneration are observed during neuroinflammation and show dynamic changes over time, suggesting progressive neurodegeneration.
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http://dx.doi.org/10.1167/iovs.62.6.11DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8114005PMC
May 2021

Encephalitis with Autoantibodies against the Glutamate Kainate Receptors GluK2.

Ann Neurol 2021 May 5. Epub 2021 May 5.

Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Hospital Clínic, Universitat de Barcelona, Barcelona, Spain.

Objective: The objective of this study was to report the identification of antibodies against the glutamate kainate receptor subunit 2 (GluK2-abs) in patients with autoimmune encephalitis, and describe the clinical-immunological features and antibody effects.

Methods: Two sera from 8 patients with similar rat brain immunostaining were used to precipitate the antigen from neuronal cultures. A cell-based assay (CBA) with GluK2-expressing HEK293 cells was used to assess 596 patients with different neurological disorders, and 23 healthy controls. GluK2-ab effects were determined by confocal microscopy in cultured neurons and electrophysiology in GluK2-expressing HEK293 cells.

Results: Patients' antibodies precipitated GluK2. GluK2 antibody-specificity was confirmed by CBA, immunoprecipitation, GluK2-immunoabsorption, and GluK2 knockout brain immunohistochemistry. In 2 of 8 samples, antibodies reacted with additional GluK2 epitopes present in GluK1 or GluK3; in both, the reactivity was abrogated after GluK2 immuno-absorption. Six of 8 patients developed acute encephalitis and clinical or magnetic resonance imaging (MRI) features of predominant cerebellar involvement (4 presenting as cerebellitis, which in 2 patients caused obstructive hydrocephalus), and 2 patients had other syndromes (1 with cerebellar symptoms). One of the samples showed mild reactivity with non-kainate receptors (alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptors [AMPAR] and N-methyl-D-aspartate receptors [NMDAR]) leading to identify 6 additional cases with GluK2-abs among patients with anti-AMPAR (5/71) or anti-NMDAR encephalitis (1/73). GluK2-abs internalized GluK2 in HEK293 cells and neurons; these antibody-effects were reversible in neurons. A significant reduction of GluK2-mediated currents was observed in cells treated with patients' GluK2 serum following the time frame of antibody-mediated GluK2 internalization.

Interpretation: GluK2-abs associate with an encephalitis with prominent clinicoradiological cerebellar involvement. The antibody effects are predominantly mediated by internalization of GluK2. ANN NEUROL 2021.
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http://dx.doi.org/10.1002/ana.26098DOI Listing
May 2021

Natalizumab, Fingolimod and Dimethyl Fumarate Use and Pregnancy-Related Relapse and Disability in Women With Multiple Sclerosis.

Neurology 2021 Apr 20. Epub 2021 Apr 20.

Liverpool Hospital, Australia.

Objective: To investigate pregnancy-related disease activity in a contemporary multiple sclerosis (MS) cohort.

Methods: Using data from the MSBase Registry, we included pregnancies conceived after 31 Dec 2010 from women with relapsing-remitting MS or clinically isolated syndrome. Predictors of intrapartum relapse, and postpartum relapse and disability progression were determined by clustered logistic regression or Cox regression analyses.

Results: We included 1998 pregnancies from 1619 women with MS. Preconception annualized relapse rate (ARR) was 0.29 (95% CI 0.27-0.32), fell to 0.19 (0.14-0.24) in third trimester, and increased to 0.59 (0.51-0.67) in early postpartum. Among women who used fingolimod or natalizumab, ARR before pregnancy was 0.37 (0.28-0.49) and 0.29 (0.22-0.37), respectively, and increased during pregnancy. Intrapartum ARR decreased with preconception dimethyl fumarate use. ARR spiked after delivery across all DMT groups. Natalizumab continuation into pregnancy reduced the odds of relapse during pregnancy (OR 0.76 per month [0.60-0.95], p=0.017). DMT re-initiation with natalizumab protected against postpartum relapse (HR 0.11 [0.04-0.32], p<0.0001). Breastfeeding women were less likely to relapse (HR 0.61 [0.41-0.91], p=0.016). 5.6% of pregnancies were followed by confirmed disability progression, predicted by higher relapse activity in pregnancy and postpartum.

Conclusion: Intrapartum and postpartum relapse probabilities increased among women with MS after natalizumab or fingolimod cessation. In women considered to be at high relapse risk, use of natalizumab before pregnancy and continued up to 34 weeks gestation, with early re-initiation after delivery is an effective option to minimize relapse risks. Strategies of DMT use have to be balanced against potential fetal/neonatal complications.
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http://dx.doi.org/10.1212/WNL.0000000000012084DOI Listing
April 2021

Cortical fractal dimension predicts disability worsening in Multiple Sclerosis patients.

Neuroimage Clin 2021 Mar 29;30:102653. Epub 2021 Mar 29.

Institut d'Investigacions Biomèdiques August Pi Sunyer - Hospital Clinic, University of Barcelona, Spain; Stanford University, Stanford, CA, USA. Electronic address:

Background: Fractal geometry measures the morphology of the brain and detects CNS damage. We aimed to assess the longitudinal changes on brain's fractal geometry and its predictive value for disease worsening in patients with Multiple Sclerosis (MS).

Methods: We prospectively analyzed 146 consecutive patients with relapsing-remitting MS with up to 5 years of clinical and brain MRI (3 T) assessments. The fractal dimension and lacunarity were calculated for brain regions using box-counting methods. Longitudinal changes were analyzed in mixed-effect models and the risk of disability accumulation were assessed using Cox Proportional Hazard regression analysis.

Results: There was a significant decrease in the fractal dimension and increases of lacunarity in different brain regions over the 5-year follow-up. Lower cortical fractal dimension increased the risk of disability accumulation for the Expanded Disability Status Scale [HR 0.9734, CI 0.8420-0.9125; Harrell C 0.59; Wald p 0.038], 9-hole peg test [HR 0.9734, CI 0.8420-0.9125; Harrell C 0.59; Wald p 0.0083], 2.5% low contrast vision [HR 0.4311, CI 0.2035-0.9133; Harrell C 0.58; Wald p 0.0403], symbol digit modality test [HR 2.215, CI 1.043-4.705; Harrell C 0.65; Wald p 0.0384] and MS Functional Composite-4 [HR 0.55, CI 0.317-0.955; Harrell C 0.59; Wald p 0.0029].

Conclusions: Fractal geometry analysis of brain MRI identified patients at risk of increasing their disability in the next five years.
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http://dx.doi.org/10.1016/j.nicl.2021.102653DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8045041PMC
March 2021

Late Onset Macular Oedema in a Patient with Multiple Sclerosis Treated with Fingolimod.

Neuroophthalmology 2021 6;45(1):61-64. Epub 2020 Oct 6.

Ophthalmology Department, Hospital Clinic de Barcelona, Barcelona, Spain.

Macular oedema is a rare complication of fingolimod treatment. It usually presents within 3-4 months, but occasionally presents later. It can resolve without treatment despite continuation of fingolimod treatment. Herein we report a case of very late onset macular oedema in a 49-year-old woman with multiple sclerosis treated with fingolimod for 7 years. The patient presented with blurred vision in both eyes with visual acuities of 20/32 in her right eye and 20/25 in her left eye. She had macular oedema, that without discontinuing fingolimod treatment, resolved after 1 month.
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http://dx.doi.org/10.1080/01658107.2020.1821065DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7946040PMC
October 2020

Incidence and Impact of COVID-19 in MS: A Survey From a Barcelona MS Unit.

Neurol Neuroimmunol Neuroinflamm 2021 03 27;8(2). Epub 2021 Jan 27.

From the Neuroimmunology and Multiple Sclerosis Unit (M.S., S.L., E. Martínez-Hernández, M. Artola, A.H., C.M., I.P.-V., E. Martínez-Heras, M.G., E.S., L.L., D.E., Y.B., A.S.), Service of Neurology, Hospital Clinic, Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), and Universitat de Barcelona; Comparative Medicine and Bioimage Centre of Catalonia (CMCiB) (M.C., C.P.), Fundació Institut d'Investigació en Ciències de la Salut Germans Trias i Pujol; Department of Physics (M.C., C.P.), Universitat Politècnica de Catalunya; Preventive Medicine and Epidemiology Department (M. Aldea), Hospital Clinic of Barcelona, University of Barcelona; Neuroimmunology Program (F.G.), Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS); and Institut de Neurociències (A.S.), Universitat de Barcelona, Spain.

Objective: To investigate the incidence of coronavirus disease 2019 (COVID-19) in a single-center cohort of patients with MS and to explore the contribution of their comorbidities and therapies to the outcome.

Methods: A cross-sectional mixed-method study was conducted involving an email-based, self-administered questionnaire sent on May 21, 2020, to 586 patients with MS followed at the MS Unit of Hospital Clinic, University of Barcelona, along with telephone interview, and review of electronic medical records until June 18, 2020. The cumulative incidence of confirmed COVID-19 (positive PCR or antibody test) and all COVID-19 cases (confirmed and suspected) from the start of the pandemic was compared with the population estimates for Barcelona.

Results: A total of 407 patients (69.5%) completed the survey. Most of the responders (67%) were female. The responders had a median age of 48 years (range 19-86), relapsing-remitting disease (84%), at least 1 comorbidity (45%), and were on disease-modifying therapy (DMT; 74.7%). COVID-19 was confirmed in 5 patients (1.2%) and suspected in 46 (11.3%). The cumulative incidence of confirmed COVID-19 cases was similar to that of the general population but was almost 2-fold higher when all cases were considered ( < 0.001). Six patients (11.7%) were hospitalized, of which 5 had good recovery and 1 died. Hospitalized patients were more frequently male, had diabetes and had progressive forms of MS ( < 0.05). DMT was not associated with the risk of infection or the outcome.

Conclusions: In the studied MS cohort, the incidence of COVID-19 was higher than that of the general population; however, most patients did not require hospitalization and had a good outcome despite the frequent presence of comorbidities and treatment with DMT.
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http://dx.doi.org/10.1212/NXI.0000000000000954DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7862095PMC
March 2021

Absence of GluD2 Antibodies in Patients With Opsoclonus-Myoclonus Syndrome.

Neurology 2021 02 21;96(7):e1082-e1087. Epub 2020 Dec 21.

From the Neuroimmunology Program, Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS) (M.P.-P., M.G., T.A., A.S., F.G., J.D.), and Neurology Service (M.G., T.A., A.S., J.D.), Hospital Clínic, and Pediatric Neuroimmunology Unit, Department of Pediatric Neurology (T.A., C.L.), and Department of Haematology and Oncology (A.M.L.M.), Sant Joan de Déu Children Hospital, Universitat de Barcelona; Centro de Investigación Biomédica en Red Enfermedades Raras (CIBERER) (M.P.-P., M.G., T.A., J.D.), Valencia; Developmental Tumor Biology Laboratory (C.L.), Sant Joan de Déu Research Institute, Barcelona, Spain; Department of Neurology (J.D.), University of Pennsylvania, Philadelphia; and Institució Catalana de Recerca i Estudis Avançats (ICREA) (J.D.), Barcelona, Spain. M.P.P. is currently affiliated with the Université de Bordeaux, CNRS, Interdisciplinary Institute for Neuroscience, IINS, UMR 5297, France.

Objective: A recent study showed glutamate receptor delta 2 antibodies (GluD2-ab) in sera of patients with opsoclonus-myoclonus syndrome (OMS). Inconsistencies between cerebellar immunoreactivity and expression of GluD2 led us to hypothesize that these antibodies are not biomarkers of OMS.

Methods: Serum of 45 children with OMS (10 [22%] with neuroblastoma), 158 adults with OMS (53 [34%] with tumors), and 172 controls including 134 patients with several types of neurologic disorders, 18 with neuroblastoma without OMS, and 20 healthy participants were investigated. Antibodies were determined with 3 different techniques: (1) rat brain immunohistochemistry, (2) a live cell-based assay using a standard secondary antibody (2-step CBA), and (3) a similar CBA with a secondary and tertiary antibodies (3-step CBA). Two plasmids were used in the CBA studies. Three commercial GluD2-ab and 2 human sera with GluD2-ab served as controls for expression of GluD2.

Results: The 3 commercial GluD2-ab showed predominant reactivity with the molecular and Purkinje cell layers (where GluD2 is highly enriched), and were also positive with the indicated CBAs. Substantially milder reactivity with brain tissue and CBA was obtained with the 2 control human sera containing GluD2-ab. None of the 203 patients with OMS and 172 controls showed immunoreactivities consistent with GluD2-abs. Compared with a standard 2-step CBA, the 3-step assay did not improve antibody detection and showed more frequent nonspecific reactivity that was not immunoabsorbed with GluD2.

Conclusion: We did not find GluD2-ab in a large cohort of patients with OMS. GluD2-ab should not be considered diagnostic biomarkers of OMS.
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http://dx.doi.org/10.1212/WNL.0000000000011410DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8055333PMC
February 2021

Oligoclonal IgM bands in the cerebrospinal fluid of patients with relapsing MS to inform long-term MS disability.

Mult Scler 2021 Jan 12:1352458520981910. Epub 2021 Jan 12.

Center of Neuroimmunology and Department of Neurology, Advanced Imaging in Neuroimmunological Diseases group (ImaginEM), Service of Neurology, Hospital Clinic of Barcelona, Institut d'Investigacions Biomèdiques August Pi Sunyer (IDIBAPS), University of Barcelona, Barcelona, Spain.

Background: Prognostic markers are needed to guide multiple sclerosis (MS) management in the context of large availability of disease-modifying drugs (DMDs).

Objective: To investigate the role of cerebrospinal fluid (CSF) markers to inform long-term MS outcomes.

Methods: Demographic features, IgM index, oligoclonal IgM bands (OCMB), lipid-specific OCMB, CSF neurofilament light chain protein levels, expanded disability status scale (EDSS), relapses and DMD use over the study period and peripapillary retinal nerve fiber layer (pRNFL) and ganglion cell plus inner plexiform layer (GCIPL) thicknesses in non-optic neuritis eyes (end of follow-up) were collected from relapsing MS (RMS) patients with CSF obtained ⩽2 years after MS onset prospectively followed at the Hospital Clinic of Barcelona. We assessed associations between CSF markers and MS outcomes using multivariable models.

Results: A total of 89 patients (71 females; median 32.9 years of age) followed over a median of 9.6 years were included. OCMB were associated with a 33% increase in the annualized relapse rate (ARR; = 0.06), higher odds for high-efficacy DMDs use (OR = 4.8; 95% CI = (1.5, 16.1)), thinner pRNFL (β = -4.4; 95% CI = (-8.6, -0.2)) and GCIPL (β = -2.9; 95% CI = (-5.9, +0.05)), and higher rates to EDSS ⩾ 3.0 (HR = 4.4; 95% CI = (1.6, 11.8)) and EDSS ⩾ 4.0 (HR = 5.4; 95% CI = (1.1, 27.1)). No overall associations were found for other CSF markers.

Conclusion: The presence of OCMB was associated with unfavorable long-term outcomes. OCMB should be determined in RMS to inform long-term prognosis.
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http://dx.doi.org/10.1177/1352458520981910DOI Listing
January 2021

New Algorithms Improving PML Risk Stratification in MS Patients Treated With Natalizumab.

Front Neurol 2020 17;11:579438. Epub 2020 Dec 17.

Department of Neurology, NeuroCure Clinical Research Center, Charité-Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität zu Berlin, Berlin Institute of Health, Berlin, Germany.

We assessed the role of age and disease activity as new factors contributing to establish the risk of progressive multifocal leucoencephalopathy in multiple sclerosis patients treated with natalizumab in 36 University Hospitals in Europe. We performed the study in 1,307 multiple sclerosis patients (70.8% anti-John Cunninghan virus positive antibodies) treated with natalizumab for a median time of 3.28 years. Epidemiological, clinical, and laboratory variables were collected. Lipid-specific IgM oligoclonal band status was available in 277 patients. Factors associated with progressive multifocal leucoencephalopathy onset were explored by uni- and multivariate logistic regression. Thirty-five patients developed progressive multifocal leucoencephalopathy. The multivariate analysis identified anti-John Cunninghan virus antibody indices and relapse rate as the best predictors for the onset of this serious opportunistic infection in the whole cohort. They allowed to stratify progressive multifocal leucoencephalopathy risk before natalizumab initiation in individual patients [area under the curve (AUC) = 0.85]. The risk ranged from <1/3,300 in patients with anti-John Cunninghan virus antibody indices <0.9 and relapse rate >0.5, to 1/50 in the opposite case. In patients with lipid-specific IgM oligoclonal bands assessment, age at natalizumab onset, anti-John Cunninghan virus antibody indices, and lipid-specific IgM oligoclonal band status predicted progressive multifocal leucoencephalopathy risk (AUC = 0.92). The absence of lipid-specific IgM oligoclonal bands was the best individual predictor (OR = 40.94). The individual risk ranged from <1/10,000 in patients younger than 45 years at natalizumab initiation, who showed anti John Cunningham virus antibody indices <0.9 and lipid-specific IgM oligoclonal bands to 1/33 in the opposite case. In a perspective of personalized medicine, disease activity, anti-lipid specific IgM oligoclonal bands, anti Jonh Cunninghan virus antibody levels, and age can help tailor natalizumab therapy in multiple sclerosis patients, as predictors of progressive multifocal leucoencephalopathy.
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http://dx.doi.org/10.3389/fneur.2020.579438DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7780851PMC
December 2020

Effect of Ocrelizumab in Blood Leukocytes of Patients With Primary Progressive MS.

Neurol Neuroimmunol Neuroinflamm 2021 03 6;8(2). Epub 2021 Jan 6.

From the Immunology Department (J.I.F.-V., P.E.W.-D., E.R.-M., E.R., N.V., L.M.V.), Ramon y Cajal University Hospital, Madrid, Spain; Neurologic Clinic and Policlinic (J.K., A.M.), Departments of Medicine, Biomedicine, and Clinical Research, University Hospital Basel, University of Basel, Switzerland; Neurology Department (E.M., S.S.d.l.M., J.M., L.C.-F.), Ramon y Cajal University Hospital, Madrid; Neurology Department (V.M.-L., P.S.), La Princesa University Hospital, Madrid; Multiple Sclerosis and Clinical Neuroimmunology Unit (J.M.-L., E.C.-G.), Virgen de la Arrixaca University Hospital, Murcia; Multiple Sclerosis Unit (G.I.), Vithas Nisa Sevilla Hospital; Neurology Department (F.G.-G.), Valencia Clinic University Hospital; Center of Neuroimmunology (A.S., Y.B.), Neurology Department, Clínic of Barcelona Hospital, Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), and Institut de Neurociències, Universitat de Barcelona; Neurology Department (Y.A.), Getafe University Hospital, Madrid; Neurology Department (L.B.), Arnau de Vilanova Hospital, Lleida; Neurology Department (C.Í.), Lozano Blesa Clinic University Hospital, Zaragoza; Neurology Department (I.G.-S.), Alvaro Cunqueiro Hospital, Vigo; Neurology Department (L.A.R.d.A.), Fuenlabrada University Hospital, Madrid, Spain.

Objective: To analyze the changes induced by ocrelizumab in blood immune cells of patients with primary progressive MS (PPMS).

Methods: In this multicenter prospective study including 53 patients with PPMS who initiated ocrelizumab treatment, we determined effector, memory, and regulatory cells by flow cytometry at baseline and after 6 months of therapy. Wilcoxon matched paired tests were used to assess differences between baseline and 6 months' results. Values were corrected using the Bonferroni test.

Results: Ocrelizumab reduced the numbers of naive and memory B cells ( < 0.0001) and those of B cells producing interleukin (IL)-6, IL-10, granulocyte-macrophage colony-stimulating factor (GM-CSF), and tumor necrosis factor-alpha (TNFα) ( < 0.0001 in all cases). By contrast, the proportions of plasmablasts and B cells producing GM-CSF and TNFα increased significantly, suggesting the need for treatment continuation. We also observed a decrease in CD20 T-cell numbers ( < 0.0001) and percentages ( < 0.0001), and a clear remodeling of the T-cell compartment characterized by relative increases of the naive/effector ratios in CD4 ( = 0.002) and CD8 ( = 0.002) T cells and relative decreases of CD4 ( = 0.03) and CD8 ( = 0.004) T cells producing interferon-gamma. Total monocyte numbers increased ( = 0.002), but no changes were observed in those producing inflammatory cytokines. The immunologic variations were associated with a reduction of serum neurofilament light chain (sNfL) levels ( = 0.008). The reduction was observed in patients with Gd-enhanced lesions at baseline and in Gd- patients with baseline sNfL >10 pg/mL.

Conclusions: In PPMS, effector B-cell depletion changed T-cell response toward a low inflammatory profile, resulting in decreased sNfL levels.
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http://dx.doi.org/10.1212/NXI.0000000000000940DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7862094PMC
March 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

Impact of Cognitive Reserve and Structural Connectivity on Cognitive Performance in Multiple Sclerosis.

Front Neurol 2020 30;11:581700. Epub 2020 Oct 30.

Laboratory of Advanced Imaging in Neuroimmunological Diseases, Center of Neuroimmunology, Institut d'Investigacions Biomediques August Pi i Sunyer (IDIBAPS), Hospital Clinic Barcelona, Universitat de Barcelona, Barcelona, Spain.

Cognitive reserve (CR) could attenuate the impact of the brain burden on the cognition in people with multiple sclerosis (PwMS). To explore the relationship between CR and structural brain connectivity and investigate their role on cognition in PwMS cognitively impaired (PwMS-CI) and cognitively preserved (PwMS-CP). In this study, 181 PwMS (71% female; 42.9 ± 10.0 years) were evaluated using the Cognitive Reserve Questionnaire (CRQ), Brief Repeatable Battery of Neuropsychological tests, and MRI. Brain lesion and gray matter volumes were quantified, as was the structural network connectivity. Patients were classified as PwMS-CI ( scores = -1.5 SD in at least two tests) or PwMS-CP. Linear and multiple regression analyses were run to evaluate the association of CRQ and structural connectivity with cognition in each group. Hedges's effect size was used to compute the strength of associations. We found a very low association between CRQ scores and connectivity metrics in PwMS-CP, while in PwMS-CI, this relation was low to moderate. The multiple regression model, adjusted for age, gender, mood, lesion volume, and graph metrics (local and global efficiency, and transitivity), indicated that the CRQ (β = 0.26, 95% CI: 0.17-0.35) was associated with cognition (adj = 0.34) in PwMS-CP (55%). In PwMS-CI, CRQ (β = 0.18, 95% CI: 0.07-0.29), age, and network global efficiency were independently associated with cognition (adj = 0.55). The age- and gender-adjusted association between CRQ score and global efficiency on having an impaired cognitive status was -0.338 (OR: 0.71, = 0.036) and -0.531 (OR: 0.59, = 0.002), respectively. CR seems to have a marginally significant effect on brain structural connectivity, observed in patients with more severe clinical impairment. It protects PwMS from cognitive decline regardless of their cognitive status, yet once cognitive impairment has set in, brain damage and aging are also influencing cognitive performance.
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http://dx.doi.org/10.3389/fneur.2020.581700DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7662554PMC
October 2020

Seizure-related 6 homolog like 2 autoimmunity: Neurologic syndrome and antibody effects.

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

From the Neuroimmunology Program (J.L., M.G., M.P.-P., E.M.-H., J.P., A.S., J.D., L.S., F.G.), Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS); Service of Neurology (M.G., E.M.-H., A.S., J.D.), Hospital Clinic, Barcelona; Centro de Investigación Biomédica en Red (M.G., J.D., L.S.), Enfermedades Raras (CIBERER); Immunology Department (R.R.-G.), Centre Diagnòstic Biomèdic, Hospital Clinic, Barcelona; Neurology Department (L.G.-F.), Hospital General San Jorge, Huesca, Spain; Leiden University Medical Center (J.V.), Leiden, The Netherlands; Icahn School of Medicine (R.S.-P.), Mount Sinai Beth Israel, New York; Massachussetts General Hospital (L.R.-G.), Department of Neurology, Boston; UCSF Department of Neurology Memory and Aging Center (M.D.G.), San Francisco, CA; Department of Neurology (J.D.), University of Pennsylvania, Philadelphia; Institució Catalana de Recerca i Estudis Avançats (ICREA) (J.D.), Barcelona, Spain; and Dr. Petit-Pedrol is now with Interdisciplinary Institute for Neuroscience, UMR 5297, Université de Bordeaux, Bordeaux, France.

Objective: To describe the clinical syndrome of 4 new patients with seizure-related 6 homolog like 2 antibodies (SEZ6L2-abs), study the antibody characteristics, and evaluate their effects on neuronal cultures.

Methods: SEZ6L2-abs were initially identified in serum and CSF of a patient with cerebellar ataxia by immunohistochemistry on rat brain sections and immunoprecipitation from rat cerebellar neurons. We used a cell-based assay (CBA) of HEK293 cells transfected with to test the serum of 95 patients with unclassified neuropil antibodies, 331 with different neurologic disorders, and 10 healthy subjects. Additional studies included characterization of immunoglobulin G (IgG) subclasses and the effects of SEZ6L2-abs on cultures of rat hippocampal neurons.

Results: In addition to the index patient, SEZ6L2-abs were identified by CBA in 3/95 patients with unclassified neuropil antibodies but in none of the 341 controls. The median age of the 4 patients was 62 years (range: 54-69 years), and 2 were female. Patients presented with subacute gait ataxia, dysarthria, and mild extrapyramidal symptoms. Initial brain MRI was normal, and CSF pleocytosis was found in only 1 patient. None improved with immunotherapy. SEZ6L2-abs recognized conformational epitopes. IgG4 SEZ6L2-abs were found in all 4 patients, and it was the predominant subclass in 2. SEZ6L2-abs did not alter the number of total or synaptic SEZ6L2 or the AMPA glutamate receptor 1 (GluA1) clusters on the surface of hippocampal neurons.

Conclusions: SEZ6L2-abs associate with a subacute cerebellar syndrome with frequent extrapyramidal symptoms. The potential pathogenic effect of the antibodies is not mediated by internalization of the antigen.
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http://dx.doi.org/10.1212/NXI.0000000000000916DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7641326PMC
January 2021

Characterization of multiple sclerosis lesions with distinct clinical correlates through quantitative diffusion MRI.

Neuroimage Clin 2020 9;28:102411. Epub 2020 Sep 9.

Center of Neuroimmunology, Laboratory of Advanced Imaging in Neuroimmunological Diseases, Hospital Clinic Barcelona, Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS) and Universitat de Barcelona, Barcelona, Spain. Electronic address:

Diffusion magnetic resonance imaging can reveal quantitative information about the tissue changes in multiple sclerosis. The recently developed multi-compartment spherical mean technique can map different microscopic properties based only on local diffusion signals, and it may provide specific information on the underlying microstructural modifications that arise in multiple sclerosis. Given that the lesions in multiple sclerosis may reflect different degrees of damage, we hypothesized that quantitative diffusion maps may help characterize the severity of lesions "in vivo" and correlate these to an individual's clinical profile. We evaluated this in a cohort of 59 multiple sclerosis patients (62% female, mean age 44.7 years), for whom demographic and disease information was obtained, and who underwent a comprehensive physical and cognitive evaluation. The magnetic resonance imaging protocol included conventional sequences to define focal lesions, and multi-shell diffusion imaging was used with b-values of 1000, 2000 and 3000 s/mm in 180 encoding directions. Quantitative diffusion properties on a macro- and micro-scale were used to discriminate distinct types of lesions through a k-means clustering algorithm, and the number and volume of those lesion types were correlated with parameters of the disease. The combination of diffusion tensor imaging metrics (fractional anisotropy and radial diffusivity) and multi-compartment spherical mean technique values (microscopic fractional anisotropy and intra-neurite volume fraction) differentiated two type of lesions, with a prediction strength of 0.931. The B-type lesions had larger diffusion changes compared to the A-type lesions, irrespective of their location (P < 0.001). The number of A and B type lesions was similar, although in juxtacortical areas B-type lesions predominated (60%, P < 0.001). Also, the percentage of B-type lesion volume was higher (64%, P < 0.001), indicating that these lesions were larger. The number and volume of B-type lesions was related to the severity of disease evolution, clinical disability and cognitive decline (P = 0.004, Bonferroni correction). Specifically, more and larger B-type lesions were correlated with a worse Multiple Sclerosis Severity Score, cerebellar function and cognitive performance. Thus, by combining several microscopic and macroscopic diffusion properties, the severity of damage within focal lesions can be characterized, further contributing to our understanding of the mechanisms that drive disease evolution. Accordingly, the classification of lesion types has the potential to permit more specific and better-targeted treatment of patients with multiple sclerosis.
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http://dx.doi.org/10.1016/j.nicl.2020.102411DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7502564PMC
September 2020

Seizures and epilepsy of autoimmune origin: A long-term prospective study.

Seizure 2020 Oct 25;81:157-165. Epub 2020 Jul 25.

Epilepsy Unit, Department of Neurology, Hospital Clinic i Provincial, Barcelona, Spain.

Objective: To follow prospectively a group of patients with seizures or epilepsy and suggestive clinical features of autoimmune aetiology and find out how many are finally diagnosed with acute symptomatic seizures (ASS) secondary to autoimmune encephalitis or autoimmune-related epilepsy, and how many develop epilepsy.

Methods: Consecutive patients meeting the inclusion criteria from 2010 to 2018 were identified. Patients were classified as confirmed, probable autoimmune, non-autoimmune, or unknown.

Results: One-hundred and nine patients were included, 64 (48.7 %) women, mean age 55.2 years (SD 17.9). ASS were reported by 61 patients (56 %), while 48 presented epilepsy (44 %). During follow-up 18 patients died (16.5 %). Final diagnosis was autoimmune-relatedepilepsy (confirmed + probable) in 22 cases and ASS secondary to autoimmune encephalitis (confirmed or probable) in 27, non-autoimmune aetiologies or other diagnosis in 49 (44 %), and unknown aetiology in 11 (10.2 %). Neuronal antibodies (ab) were found in 27 patients (24.7 %). T-lymphocyte infiltration in temporal lobes was observed in 2/8 patients (20 %). Neuronal ab were more frequent in the autoimmune groups: 17 patients (29.8 %) vs 1(2.3 %), p:0.001, and they suffered more autoimmune diseases: 37 (75.5 %) vs 12 (24.48 %), p:0.0001, and 34 (69 %) vs 22 (44.9 %) p:0.027, respectively. All patients with GAD ab 17/17 (100 %) evolved to chronic disease. Four patients (29 %) with ASS secondary to autoimmune encephalitis developed epilepsy.

Significance: ASS secondary to autoimmune encephalitis or autoimmune-related epilepsy will be diagnosed in nearly half of patients who have been suspected of it. The only diagnostic clue is neuronal ab. Patients who have suffered ASS secondary to autoimmune encephalitis may develop epilepsy over time.
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http://dx.doi.org/10.1016/j.seizure.2020.07.019DOI Listing
October 2020

Retinal and brain damage during multiple sclerosis course: inflammatory activity is a key factor in the first 5 years.

Sci Rep 2020 08 7;10(1):13333. Epub 2020 Aug 7.

Service of Neurology, Department of Neurology, Center of Neuroimmunology, Hospital Clinic of Barcelona, Institut d'Investigacions Biomèdiques August Pi Sunyer (IDIBAPS), University of Barcelona, Villarroel 170, 08036, Barcelona, Spain.

Understanding of the role of focal inflammation, a treatable feature, on neuro-axonal injury, is paramount to optimize neuroprotective strategy in MS. To quantify the impact of focal inflammatory activity on the rate of neuro-axonal injury over the MS course. We quantified the annualized rates of change in peripapillary retinal nerve fiber layer, ganglion cell plus inner plexiform layer (GCIPL), whole-brain, gray matter and thalamic volumes in patients with and without focal inflammatory activity in 161 patients followed over 5 years. We used mixed models including focal inflammatory activity (the presence of at least one relapse or a new/enlarging T2-FLAIR or gadolinium- enhancing lesion), and its interaction with time adjusted by age, sex, use of disease-modifying therapies and steroids, and prior optic neuritis. The increased rate of neuro-axonal injury during the first five years after onset was more prominent among active patients, as reflected by the changes in GCIPL thickness (p = 0.02), whole brain (p = 0.002) and thalamic volumes (p < 0.001). Thereafter, rates of retinal and brain changes stabilized and were similar in active and stable patients. Focal inflammatory activity is associated with neurodegeneration early in MS which reinforces the use of an early intensive anti-inflammatory therapy to prevent neurodegeneration in MS.
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http://dx.doi.org/10.1038/s41598-020-70255-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7414206PMC
August 2020

The Diagnostic Value of Onconeural Antibodies Depends on How They Are Tested.

Front Immunol 2020 14;11:1482. Epub 2020 Jul 14.

Neuroimmunology Program, Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Spain.

Detection of onconeural antibodies is important because establishes a definitive diagnosis of paraneoplastic neurological syndrome (PNS). The recommended method for diagnosis of onconeural antibodies is by immunohistochemistry on rodent brain sections and confirmation of results by immunoblot. However, in many diagnostic laboratories samples are only tested with commercial line blots. In this study we inquired whether this change in diagnostic methodology (line blot alone vs. combined immunohistochemistry and line blot) would affect the results. Among 439 samples examined by immunohistochemistry and a commercial line blot (Euroimmun, Lübeck, Germany) 96 (22%) were positive by line blot, and their clinical information was reviewed. Onconeural antibodies were detected by both assays in 46/96 (48%) patients (concordant group) whereas 50 (52%) were only positive by line blot (discordant group). In the concordant group 42/46 (91%) patients had a definite diagnosis of PNS whereas in the discordant group only 4/50 (8%) had PNS ( < 0.00001). None of the 14 patients with ZIC4 antibodies and 1/13 (8%) with Yo antibodies demonstrated only by line blot had PNS. These findings show a robust diagnostic value of combined diagnostic techniques, and both should be used to demonstrate onconeural antibodies, If antibody testing is performed only with line blot assay, positive bands should be confirmed by rodent brain immunohistochemistry. For ZIC4 or Yo antibody testing, line blot positivity with negative immunohistochemistry has no diagnostic significance, and for the rest of onconeural antibodies the predictive diagnostic value is low.
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http://dx.doi.org/10.3389/fimmu.2020.01482DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7372120PMC
April 2021

Effects of IgLON5 Antibodies on Neuronal Cytoskeleton: A Link between Autoimmunity and Neurodegeneration.

Ann Neurol 2020 11 27;88(5):1023-1027. Epub 2020 Aug 27.

Neuroimmunology Program, Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Universitat de Barcelona, Barcelona, Spain.

Anti-IgLON5 disease is a neurological disorder characterized by autoantibodies against IgLON5 and pathological evidence of neuronal-specific tau accumulation. Here, we report that patients' IgLON5 IgG, but not other cell-surface antibodies, disrupt the cytoskeletal organization in cultured rat hippocampal neurons, resulting in dystrophic neurites and axonal swelling. Adsorption of IgLON5 IgG with HEK293 cells expressing IgLON5 abrogated the indicated cytoskeletal changes. These findings, along with an increase of levels of neurofilaments in patients' cerebrospinal fluid, suggest that IgLON5 IgG, unlike other cell-surface antibodies, disrupts neuronal cytoskeleton maintenance, providing a link between autoimmunity and neurodegeneration. ANN NEUROL 2020;88:1023-1027.
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http://dx.doi.org/10.1002/ana.25857DOI Listing
November 2020

Treatment and outcome of aquaporin-4 antibody-positive NMOSD: A multinational pediatric study.

Neurol Neuroimmunol Neuroinflamm 2020 09 30;7(5). Epub 2020 Jul 30.

From the Department of Neurology (R.B.P., S.L.A.-P., J.A.d.P.) and Department of Radiology (INRAD) (C.d.M.R.), Hospital das Clínicas, Faculty of Medicine, University of São Paulo (HCFMUSP), Brazil; Queen Square MS Centre (Y.H., O.C.), UCL Institute of Neurology, Faculty of Brain Sciences, University College London; Department of Paediatric Neurology (Y.H., C.H.), Great Ormond Street Hospital for Children, London, United Kingdom; Assistance Publue-Hôpitaux de Paris (E.Y., K.D.), University Hospitals Paris South, Bicêtre Hospital, Le Kremlin Bicêtre, France; Neuroimmunology Program (T.A.) and Neurology Service (A.S.), Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Hospital Clínic, and Pediatric Neuroimmunology Unit (T.A.), Sant Joan de Deu (SJD) Children's Hospital, Universitat de Barcelona, Spain; Department of Neurology (A.B., R.N.), Erasmus University Medical Center, Rotterdam, the Netherlands; Division of Paediatric Neurology (C.L., M.B.), Department of Pediatrics I, Medical University of Innsbruck, Austria; Medical Center of Physical Therapy and Pain Medicine INNOVO (Y.M.), Lviv, Ukraine; Division of Pediatric Neurology (M.B.), Department of Pediatrics and Adolescent Medicine, and Department of Neurology (B.K.), Medical University of Vienna, Austria; Pediatric Neurology (E.W.), Birmingham Women and Children's Hospital, United Kingdom; Department of Neuroscience (L.P.), Pediatric Multiple Sclerosis Center, Bambino Gesù Children Hospital, IRCCS, Rome, Italy; Department of Neurology (M.C.) and Regional Multiple Sclerosis Centre (M.C.), University Hospital San Luigi Gonzaga, Orbassano, Italy; Department of Pediatric Neurology (K.R.), Vestische Kinder und Jugendklinik, Witten/Herdecke University, Datteln, Germany; Children's Neurosciences (M.L.), Evelina London Children's Hospital at Guy's and St Thomas' NHS Foundation Trust, King's Health Partners Academic Health Science Centre; Faculty of Life Sciences and Medicine (M.L.), King's College Hospital, London, United Kingdom; Neurology Department (R.M.), Hôpital Neurologique Pierre Wertheimer, Hospices Civils de Lyon; French Reference Network of Rare Inflammatory Brain and Spinal Diseases (R.M., K.D.), Le Kremlin Bicêtre, France; School of Medicine (D.K.S.), Brain Institute of Rio Grande do Sul (Brains), Pontifical Catholic University of Rio Grande Do Sul (PUCRS), Porto Alegre, Brazil; and Inserm UMR 1184 (K.D.), Immunology of Viral Infections and Autoimmune Diseases, CEA, IDMIT, Le Kremlin Bicêtre, France.

Objective: To describe the clinical phenotypes, treatment response, and outcome of children with antibodies against aquaporin-4 (AQP4-Ab) neuromyelitis optica spectrum disorder (NMOSD).

Methods: Retrospective, multicenter, and multinational study of patients with AQP4-Ab NMOSD aged <18 years at disease onset from a center in Brazil and 13 European centers. Data on demographics, clinical findings, and laboratory results were analyzed; calculation of annualized relapse rates (ARRs) pre- and on-treatment with disease-modifying therapies (DMTs) and of ORs for predictors of poor outcome was performed.

Results: A total of 67 children were identified. At last follow-up (median 4 years, interquartile range 2-10 years), 37/67(57.8%) were found to have permanent disability. A more severe disease course was seen in the non-White ethnicity with both a shorter time to first relapse ( = 0.049) and a worse Expanded Disability Status Scale score at last follow-up ( = 0.008). The median ARR on treatment was 0.18 on azathioprine (n = 39, range 0-4), 0 on mycophenolate mofetil (n = 18, range 0-3), and 0 on rituximab (n = 29, range 0-2). No patient treated with rituximab as first-line therapy relapsed. Optic neuritis at onset was associated with a poor visual outcome below 20/200 (OR 8.669, 95% CI 1.764-42.616, = 0.008), and a younger age at onset was associated with cognitive impairment (OR 0.786, 95% CI 0.644-0.959, = 0.018).

Conclusions: AQP4-Ab NMOSD in children is an aggressive disease with permanent disabilities observed in over half the cohort. All DMTs were associated with a reduction of ARR. First-line rituximab prevented further clinical relapses. International consensus on treatment protocols for children is required to reduce heterogeneity of treatment regimens used worldwide.

Classification Of Evidence: This study provides Class IV evidence that for children with AQP4-Ab NMOSD, all DMTs, particularly first-line rituximab, reduced the ARR and prevented further clinical relapses.
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http://dx.doi.org/10.1212/NXI.0000000000000837DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7413715PMC
September 2020

Does education really not matter for health?

Soc Sci Med 2020 08 10;258:113094. Epub 2020 Jun 10.

Department of Urban Studies and Planning, Massachusetts Institute of Technology, 77 Massachusetts Avenue, Cambridge, MA, 02139, USA. Electronic address:

In a recent paper, Albarrán et al. (2020) use a well-known quasi-randomization strategy to study the impact of education on health outcomes. Concretely, they use the fact that changes in compulsory education laws--usually extending the age of release from the school system--result in exogenous differences in educational attainment between people who may only be separated by a few months of age. They deploy an Instrumental Variable (IV) strategy to compare the outcomes of people forced to stay longer in school to those of individuals who were allowed to drop out earlier. Their empirical strategy does not find a statistically significant effect of education on health outcomes. The paper is timely, well written, and well executed, and deserves careful attention. However, we hope readers consider four caveats--some already raised by the authors--before concluding from the results that education does not matter for health. To help readers interpret this solid research piece, we call attention to: 1) previous research on the links between education and health; 2) the selection of countries in the paper in the presence of heterogenous treatment effects; 3) biases generated by misclassification and measurement errors; and 4) the interpretation of local average treatment effects (LATE) arising from the policy interventions used as instrumental variables.
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http://dx.doi.org/10.1016/j.socscimed.2020.113094DOI Listing
August 2020

GAD antibodies in neurological disorders - insights and challenges.

Nat Rev Neurol 2020 Jul 26;16(7):353-365. Epub 2020 May 26.

Neuroimmunology Program, Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Hospital Clínic, University of Barcelona, Barcelona, Spain.

Antibodies to glutamic acid decarboxylase (GAD) have been associated with several neurological syndromes, including stiff-person syndrome, cerebellar ataxia and epilepsy. These antibodies were first described in 1988, but several controversies about GAD autoimmunity still remain. No criteria exist to establish when a neurological syndrome is pathogenically linked to GAD antibodies, often leading to the assumption that any syndrome in which these antibodies are present is immune mediated, sometimes resulting in misdiagnosis and unnecessary treatment. In this Review, we provide recommendations for assessing the association between a neurological syndrome and the presence of GAD antibodies, and we critically review the evidence on the pathogenicity of GAD antibodies. Given that stiff-person syndrome is usually autoimmune, the presence of GAD antibodies in the cerebrospinal fluid is sufficient to confirm a pathogenic link with GAD autoimmunity. However, for cerebellar ataxia, epilepsy and other syndromes with different aetiologies, we propose that confirmation of a pathogenic link with GAD autoimmunity requires demonstration of intrathecal GAD antibody synthesis. Nevertheless, the evidence that GAD antibodies are directly pathogenic is not yet convincing. Studies in animal models are needed to demonstrate whether neurological syndromes are directly caused by specific disruption of GAD function by GAD antibodies.
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http://dx.doi.org/10.1038/s41582-020-0359-xDOI Listing
July 2020

CSF levels of glutamine synthetase and GFAP to explore astrocytic damage in seronegative NMOSD.

J Neurol Neurosurg Psychiatry 2020 06 26;91(6):605-611. Epub 2020 Mar 26.

Institute of Neurology, Neuroimmunology and CSF Laboratory, University College London, London, UK.

Objective: To explore levels of astrocytopathy in neuromyelitis optica spectrum disorder (NMOSD) by measuring levels of the astrocytic enzyme glutamine synthetase (GS) and glial fibrillary acidic protein (GFAP), an established astrocytic biomarker known to be associated with disease activity in multiple sclerosis.

Methods: Cerebrospinal fluid concentrations of GS and GFAP were measured by ELISA in patients with NMOSD (n=39, 28 aquaporin-4 (AQP4)-Ab-seropositive, 3 double-Ab-seronegative, 4 myelin oligodendrocyte glycoprotein (MOG)-Ab-seropositive and 4 AQP4-Ab-seronegative with unknown MOG-Ab-serostatus), multiple sclerosis (MS) (n=69), optic neuritis (n=5) and non-neurological controls (n=37).

Results: GFAP and GS concentrations differed significantly across groups (both p<0.001), showing a similar pattern of elevation in patients with AQP4-Ab-seropositive NMOSD. GS and GFAP were significantly correlated, particularly in patients with AQP4-Ab-seropositive NMOSD (r=0.70, p<0.001). Interestingly, GFAP levels in some patients with double-Ab-seronegative NMOSD were markedly increased.

Conclusions: Our data indicate astrocytic injury occurs in some patients with double-Ab-seronegative NMOSD, which hints at the possible existence of yet undiscovered astrocytic autoimmune targets. We hypothesise that elevated GS and GFAP levels could identify those double-Ab-seronegative patients suitable to undergo in-depth autoimmune screening for astrocytic antibodies.
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http://dx.doi.org/10.1136/jnnp-2019-322286DOI Listing
June 2020

Targeted resequencing reveals rare variants enrichment in multiple sclerosis susceptibility genes.

Hum Mutat 2020 07 1;41(7):1308-1320. Epub 2020 Apr 1.

Servei de Neurologia-Neuroimmunologia, Center d'Esclerosi Múltiple de Catalunya (Cemcat), Institut de Recerca Vall d'Hebron (VHIR), Hospital Universitari Vall d'Hebron, Universitat Autònoma de Barcelona, Barcelona, Spain.

Although genome-wide association studies have identified a number of common variants associated with multiple sclerosis (MS) susceptibility, little is known about the relevance of rare variants. Here, we aimed to explore the role of rare variants in 14 MS risk genes (FCRL1, RGS1, TIMMDC1, HHEX, CXCR5, LTBR, TSFM, GALC, TRAF3, STAT3, TNFSF14, IFI30, CD40, and CYP24A1) by targeted resequencing in an Iberian population of 524 MS cases and 546 healthy controls. Four rare variants-enriched regions within CYP24A1, FCRL1, RGS1, and TRAF3 were identified as significantly associated with MS. Functional studies revealed significantly decreased regulator of G protein signaling 1 (RGS1) gene expression levels in peripheral blood mononuclear cells from MS patients with RGS1 rare variants compared to noncarriers, whereas no significant differences in gene expression were observed for CYP24A1, FCRL1, and TRAF3 between rare variants carriers and noncarriers. Immunophenotyping showed significant decrease in RGS1 expression in peripheral blood B lymphocytes from MS patients with RGS1 rare variants relative to noncarriers. Lastly, peripheral blood mononuclear cell from MS patients carrying RGS1 rare variants showed significantly lower induction of RGS1 gene expression by interferon-β compared to MS patients lacking RGS1 variants. The presence of rare variants in RGS1 reinforce the ideas of high genetic heterogeneity and a role of rare variants in MS pathogenesis.
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http://dx.doi.org/10.1002/humu.24016DOI Listing
July 2020

Clinical significance of anti-NMDAR concurrent with glial or neuronal surface antibodies.

Neurology 2020 06 11;94(22):e2302-e2310. Epub 2020 Mar 11.

From the Neuroimmunology Program (E.M.-H., M.G., A.G.-S., E.M., H.A., T.A., A.S., F.G., J.D.), Institut d'Investigacions Biomediques August Pi i Sunyer; Neurology Department (E.M.-H., M.G., H.A., M.S., T.A., A.S., J.D.), Hospital Clinic, and Pediatric Neuroimmunology Unit (T.A.), Sant Joan de Deu Children's Hospital, University of Barcelona; Centro de Investigaciones Biomedicas en Red de Enfermedades Raras (E.M.-H., M.G., T.A., J.D.), Madrid, Spain; Hospital Cayetano Heredia (A.P.R.), San Martin de Porres, Perú; Hadassah-Hebrew University Medical Center (T.B.-H.), Jerusalem, Israel; Department of Neurology (T.I.), Kitasato University School of Medicine, Sagamihara, Japan; Department of Neurology (J.D.), University of Pennsylvania, Philadelphia; and Catalan Institution for Research and Advanced Studies (J.D.), Barcelona, Spain.

Objective: To determine the frequency and significance of concurrent glial (glial-Ab) or neuronal-surface (NS-Ab) antibodies in patients with anti-NMDA receptor (NMDAR) encephalitis.

Methods: Patients were identified during initial routine screening of a cohort (C1) of 646 patients consecutively diagnosed with anti-NMDAR encephalitis and another cohort (C2) of 200 patients systematically rescreened. Antibodies were determined with rat brain immunostaining and cell-based assays.

Results: Concurrent antibodies were identified in 42 patients (4% from C1 and 7.5% from C2): 30 (71%) with glial-Ab and 12 (29%) with NS-Ab. Glial-Ab included myelin oligodendrocyte glycoprotein (MOG) (57%), glial fibrillary acidic protein (GFAP) (33%), and aquaporin 4 (AQP4) (10%). NS-Ab included AMPA receptor (AMPAR) (50%), GABAa receptor (GABAaR) (42%), and GABAb receptor (8%). In 39 (95%) of 41 patients, concurrent antibodies were detected in CSF, and in 17 (41%), concurrent antibodies were undetectable in serum. On routine clinical-immunologic studies, the presence of MOG-Ab and AQP4-Ab was suggested by previous episodes of encephalitis or demyelinating disorders (8, 27%), current clinical-radiologic features (e.g., optic neuritis, white matter changes), or standard rat brain immunohistochemistry (e.g., AQP4 reactivity). GFAP-Ab did not associate with distinct clinical-radiologic features. NS-Ab were suggested by MRI findings (e.g., medial temporal lobe changes [AMPAR-Ab], or multifocal cortico-subcortical abnormalities [GABAaR-Ab]), uncommon comorbid conditions (e.g., recent herpesvirus encephalitis), atypical tumors (e.g., breast cancer, neuroblastoma), or rat brain immunostaining. Patients with NS-Ab were less likely to have substantial recovery than those with glial-Ab (5 of 10 [50%] vs 17 of 19 [89%], = 0.03).

Conclusions: Between 4% and 7.5% of patients with anti-NMDAR encephalitis have concurrent glial-Ab or NS-Ab. Some of these antibodies (MOG-Ab, AQP4-Ab, NS-Ab) confer additional clinical-radiologic features and may influence prognosis.
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http://dx.doi.org/10.1212/WNL.0000000000009239DOI Listing
June 2020

A New Risk Variant for Multiple Sclerosis at 11q23.3 Is Associated with Expansion of Circulating Regulatory T Cells.

J Clin Med 2020 Feb 26;9(3). Epub 2020 Feb 26.

Servei de Neurologia-Neuroimmunologia, Centre d'Esclerosi Múltiple de Catalunya (Cemcat). Institut de Recerca Vall d'Hebron (VHIR). Hospital Universitari Vall d'Hebron. Universitat Autònoma de Barcelona, 08035 Barcelona, Spain.

Genome-wide association studies and meta-analysis have contributed to the identification of more than 200 associated with multiple sclerosis (MS). However, a proportion of MS heritability remains unknown. We aimed to uncover new genetic variants associated with MS and determine their functional effects. For this, we resequenced the exons and regulatory sequences of 14 MS risk genes in a cohort of MS patients and healthy individuals ( = 1,070) and attempted to validate a selection of signals through genotyping in an independent cohort ( = 5,138). We identified three new MS-associated variants at C-X-C motif chemokine receptor 5 (, Ts translation elongation factor, mitochondrial ( and cytochrome P450 family 24 subfamily A member 1 (. Rs10892307 resulted in a new signal at the region that explains one of the associations with MS within the . This polymorphism and three others in high linkage disequilibrium mapped within regulatory regions. Of them, rs11602393 showed allele-dependent enhancer activity in the forward orientation as determined by luciferase reporter assays. Immunophenotyping using peripheral blood mononuclear cells from MS patients associated the minor allele of rs10892307 with increased percentage of regulatory T cells expressing CXCR5. This work reports a new signal for the MS risk and points to rs11602393 as the causal variant. The expansion of CXCR5+ circulating regulatory T cells induced by this variant could cause its MS association.
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http://dx.doi.org/10.3390/jcm9030625DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7141122PMC
February 2020

Associations of paediatric demyelinating and encephalitic syndromes with myelin oligodendrocyte glycoprotein antibodies: a multicentre observational study.

Lancet Neurol 2020 03 10;19(3):234-246. Epub 2020 Feb 10.

Neuroimmunology Program, Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Hospital Clínic, Universitat de Barcelona, Barcelona, Spain; Department of Neurology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA; Catalan Institute for Research and Advanced Studies, Barcelona, Spain. Electronic address:

Background: Investigations of myelin oligodendrocyte glycoprotein (MOG) antibodies are usually focused on demyelinating syndromes, but the entire spectrum of MOG antibody-associated syndromes in children is unknown. In this study, we aimed to determine the frequency and distribution of paediatric demyelinating and encephalitic syndromes with MOG antibodies, their response to treatment, and the phenotypes associated with poor prognosis.

Methods: In this prospective observational study, children with demyelinating syndromes and with encephalitis other than acute disseminated encephalomyelitis (ADEM) recruited from 40 secondary and tertiary centres in Spain were investigated for MOG antibodies. All MOG antibody-positive cases were included in our study, which assessed syndromes, treatment and response to treatment (ie, number of relapses), outcomes (measured with the modified Rankin scale [mRS]), and phenotypes associated with poor prognosis. We used Fisher's exact and Wilcoxon rank sum tests to analyse clinical features, and survival Cox regression to analyse time to antibody negativity.

Findings: Between June 1, 2013, and Dec 31, 2018, 239 children with demyelinating syndromes (cohort A) and 296 with encephalitis other than ADEM (cohort B) were recruited. 116 patients had MOG antibodies, including 94 (39%) from cohort A and 22 (7%) from cohort B; 57 (49%) were female, with a median age of 6·2 years (IQR 3·7-10·0). Presenting syndromes in these 116 patients included ADEM (46 [68%]), encephalitis other than ADEM (22 [19%]), optic neuritis (20 [17%]), myelitis (13 [11%]), neuromyelitis optica spectrum disorders (six [5%]), and other disorders (nine [8%]). Among the patients with autoimmune encephalitis in cohort B (n=64), MOG antibodies were more common than all neuronal antibodies combined (22 [34%] vs 21 [33%]). After a median follow-up of 42 months (IQR 22-67), 33 (28%) of the 116 patients had relapses, including 17 (17%) of 100 diagnosed at first episode. Steroids, intravenous immunoglobulin, or plasma exchange were used in 100 (86%) patients at diagnosis, and 32 (97%) of 33 at relapses. Rituximab was mainly used at relapses (11 [33%]). 99 (85%) of 116 patients had substantial recovery (mRS <2) and 17 (15%) moderate to severe deficits (mRS >2; one died). Phenotypes of poor prognosis included ADEM-like relapses progressing to leukodystrophy-like features, and extensive cortical encephalitis evolving to atrophy. Time to antibody negativity was longer in patients with relapses (HR 0·18, 95% CI 0·05-0·59).

Interpretation: The spectrum of paediatric MOG antibody-associated syndromes is wider than previously reported and includes demyelinating syndromes and encephalitis. Recognition of these disorders has important clinical and prognostic implications.

Funding: Mutua Madrileña Foundation; ISCIII-Subdirección General de Evaluación y Fomento de la Investigación Sanitaria; Fondo Europeo de Desarrollo Regional; Pediatrics Spanish Society; Departament de Salut, Generalitat de Catalunya; Marato TV3 Foundation; Red Española de Esclerosis Múltiple; La Caixa Foundation; and Fundació CELLEX.
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http://dx.doi.org/10.1016/S1474-4422(19)30488-0DOI Listing
March 2020

Clinical significance of Kelch-like protein 11 antibodies.

Neurol Neuroimmunol Neuroinflamm 2020 05 17;7(3). Epub 2020 Jan 17.

From the Neuroimmunology Program (E.M., J.L., A.M.-L., T.A., M.A., A.S., F.G., J.D., L.S.), Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Hospital Clínic, Universitat de Barcelona; Pediatric Neuroimmunology Unit (T.A.), Neurology Service, Sant Joan de Deu (SJD) Children's Hospital. Barcelona; Service of Child and Adolescent Psychiatry (T.A.), Hospital Clínic, University of Barcelona; Unitat de Neuroimmunologia-Esclerosi Múltiple (A.S., J.D.), Servei de Neurología, Hospital Clinic, Barcelona, Spain; Department of Neurology (J.D.), University of Pennsylvania, PA; and Institució Catalana de Recerca i Estudis Avançats (ICREA) (J.D.), Barcelona, Spain.

Objective: To report the clinical and oncologic associations of antibodies against Kelch-like protein 11 (KLHL11-ab), recently suggested as biomarkers of a paraneoplastic brainstem cerebellar syndrome associated with testicular seminoma, and to determine the value of immunohistochemistry as a screening technique.

Methods: Studies included 432 sera or CSF from 329 patients with paraneoplastic (157) or autoimmune neurologic syndromes (172); 63 with neurologic symptoms and benign teratomas; 28 with small-cell lung cancer, and 12 healthy subjects. KLHL11-abs were examined using a cell-based assay (CBA) with HEK293 cells transfected with a human KLHL11 clone. The CBA specificity was confirmed by immunoprecipitation. All positive samples were examined by immunohistochemistry on rat brain sections.

Results: KLHL11-abs were detected in 32 patients by CBA, and patients' antibodies immunoprecipitated KLHL11. Using rat brain immunohistochemistry, only 7 samples (22%) were positive. Patients' median age was 28 years (range 9-76 years), and 16 (50%) were women. Tumors were identified in 23/32 (72%) patients, including 14 teratomas and 7 seminomas or mixed germ cell tumors. Thirteen (41%) patients had cerebellar ataxia (7) or encephalitis with brainstem cerebellar symptoms (6), 7 (22%) anti-NMDA receptor (NMDAR) encephalitis (5 with ovarian teratoma), 5 (16%) opsoclonus-myoclonus, 3 (9%) limbic encephalitis, and 4 (12%) diverse neurologic symptoms (3 with benign teratomas). Concurrent autoantibodies occurred in 14 (44%) patients (7 anti-NMDAR, 6 Ma2, and 1 Hu).

Conclusions: KLHL11-abs associate with a spectrum of syndromes and tumors wider than those previously reported; 44% of patients have concurrent neuronal antibodies, some of them (anti-NMDAR) pathogenically relevant. Brain immunostaining is not useful for routine screening of KLHL11-abs.
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http://dx.doi.org/10.1212/NXI.0000000000000666DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7051195PMC
May 2020

Modified connectivity of vulnerable brain nodes in multiple sclerosis, their impact on cognition and their discriminative value.

Sci Rep 2019 12 27;9(1):20172. Epub 2019 Dec 27.

Center of Neuroimmunology, Laboratory of Advanced Imaging in Neuroimmunological Diseases, Hospital Clinic Barcelona, Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS) and Universitat de Barcelona, Barcelona, Spain.

Brain structural network modifications in multiple sclerosis (MS) seem to be clinically relevant. The discriminative ability of those changes to identify MS patients or their cognitive status remains unknown. Therefore, this study aimed to investigate connectivity changes in MS patients related to their cognitive status, and to define an automatic classification method to classify subjects as patients and healthy volunteers (HV) or as cognitively preserved (CP) and impaired (CI) patients. We analysed structural brain connectivity in 45 HV and 188 MS patients (104 CP and 84 CI). A support vector machine with k-fold cross-validation was built using the graph metrics features that best differentiate the groups (p < 0.05). Local efficiency (LE) and node strength (NS) network properties showed the largest differences: 100% and 69.7% of nodes had reduced LE and NS in CP patients compared to HV. Moreover, 55.3% and 57.9% of nodes had decreased LE and NS in CI compared to CP patients, in associative multimodal areas. The classification method achieved an accuracy of 74.8-77.2% to differentiate patients from HV, and 59.9-60.8% to discriminate CI from CP patients. Structural network integrity is widely reduced and worsens as cognitive function declines. Central network properties of vulnerable nodes can be useful to classify MS patients.
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http://dx.doi.org/10.1038/s41598-019-56806-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6934774PMC
December 2019

Hashimoto encephalopathy in the 21st century.

Neurology 2020 01 27;94(2):e217-e224. Epub 2019 Dec 27.

From the Neuroimmunology Program (S.M., L.S., H.A., T.A., A.S., J.D., F.G.), Institut d'Investigació Biomèdica August Pi i Sunyer, Barcelona, Spain; Department of Medical, Surgical and Experimental Medicine (S.M., S.S.), University of Sassari, Italy; Service of Neurology (D.E., A.S.), Hospital Clinic, and Pediatric Neuroimmunology Unit (T.A.), Neurology Department, Sant Joan de Déu Children's Hospital, University of Barcelona, Spain; Neurology Division (M.S.), Hospital das Clínicas, São Paulo University, Brazil; Department of Neurology (T.I.), Kitasato University School of Medicine, Sagamihara; Division of Neurology (M.H.), Department of Medicine, Nihon University School of Medicine, Tokyo, Japan; Department of Neurology (J.D.), University of Pennsylvania, Philadelphia; and Institució Catalana de Recerca i Estudis Avançats (J.D.), Barcelona, Spain.

Objective: To report the presenting syndromes and to determine whether pretreatment criteria of Hashimoto encephalopathy (HE) predict response to steroids.

Methods: We assessed symptoms and steroid responsiveness in 24 patients with pretreatment criteria of HE, including (1) subacute onset of cognitive impairment, psychiatric symptoms, or seizures; (2) euthyroid status or mild hypothyroidism; (3) serum thyroid peroxidase antibodies (TPOAb) >200 IU/mL; (4) absent neuronal antibodies in serum/CSF; and (5) no other etiologies. Additional studies included determination of TPOAb (>200 IU/mL) in 74 patients with criteria of possible autoimmune encephalitis (AE) without neuronal antibodies and 205 patients with different neuroimmunologic diseases, psychosis, or new-onset refractory status epilepticus (NORSE). Serum antibodies to the amino (ΝΗ2)-terminal of α-enolase (NH2-α-enolaseAb) were examined in the indicated 24 patients and 13 controls.

Results: The 24 patients (14 women) with suspected HE had a median age of 48 years (range 8-79 years). Four syndromes were identified: psychiatric (7, 29%), encephalopathy (7, 29%), NORSE-like (6, 25%), and limbic encephalitis (4, 17%). Only 6 of 19 (31.6%) patients completely responded to steroids. The frequency of TPOAb in the 74 patients with possible AE (6 of 74, 8.1%) was similar to that of the 205 controls (17 of 205, 8.2%; = 0.84). NH2-α-enolaseAb were identified in 1 of 24 suspected HE cases and 1 of 13 controls.

Conclusion: Current pretreatment criteria of HE do not predict steroid responsiveness. The detection of TPOAb across all control groups reveals their poor disease-specificity. NH2-α-enolaseAb did not help in the diagnosis of HE. These findings imply a redefinition of HE that requires a systematic exclusion of antibody-mediated encephalitis.
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http://dx.doi.org/10.1212/WNL.0000000000008785DOI Listing
January 2020