Publications by authors named "Eugenia Martinez-Hernandez"

53 Publications

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

A multidisciplinary registry of patients with autoimmune and immune-mediated diseases with symptomatic COVID-19 from a single center.

J Autoimmun 2021 02 30;117:102580. Epub 2020 Nov 30.

Rheumatology Department, Hospital Clínic, Barcelona, Catalonia, Spain. Electronic address:

Background And Aim: There is increasing interest regarding SARS-CoV-2 infection in patients with autoimmune and immune-mediated inflammatory diseases (AI/IMID) with some discrepancies in different cohorts about their risk and outcomes. The aim was to describe a multidisciplinary cohort of patients with AI/IMID and symptomatic SARS-CoV-2 infection in a single tertiary center and analyze sociodemographic, clinical, and therapeutic factors associated with poor outcomes.

Methods: A retrospective observational study was conducted from the 1st of March until May 29th, 2020 in a University tertiary hospital in Barcelona, Spain. Patients with an underlying AI/IMID and symptomatic SARS-CoV-2 infection were identified in our local SARS-CoV-2 infection database. Controls (2:1) were selected from the same database and matched by age and gender. The primary outcome was severe SARS-CoV-2 infection, which was a composite endpoint including admission to the intensive care unit (ICU), need for mechanical ventilation (MV), and/or death. Several covariates including age, sex, and comorbidities among others were combined into a multivariate model having severe SARS-CoV-2 as the dependent variable. Also, a sensitivity analysis was performed evaluating AID and IMID separately.

Results: The prevalence of symptomatic SARS-CoV-2 infection in a cohort of AI/IMID patients was 1.3%. Eighty-five patients with AI/IMID and symptomatic SARS-CoV-2 were identified, requiring hospitalization in 58 (68%) cases. A total of 175 patients admitted for SARS-CoV-2 (58 with AI/IMID and 117 matched-controls) were analyzed. In logistic regression analysis, a significant inverse association between AI/IMID group and severe SARS-CoV-2 (OR 0.28; 95% CI 0.12-0.61; p = 0.001), need of MV (OR 0.20; IC 95% 0.05-0.71; p = 0.014), and ICU admission (OR 0.25; IC 95% 0.10-0.62; p = 0.003) was found.

Conclusions: Patients with AI/IMID who require admission for SARS-CoV-2 infection have a lower risk of developing severe disease, including the need to stay in the ICU and MV.
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http://dx.doi.org/10.1016/j.jaut.2020.102580DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7836738PMC
February 2021

Serum neurofilament light chain predicts long-term prognosis in Guillain-Barré syndrome patients.

J Neurol Neurosurg Psychiatry 2020 Nov 5. Epub 2020 Nov 5.

Neuromuscular Diseases Unit, Department of Neurology, Hospital de la Santa Creu i Sant Pau, Universitat Autònoma de Barcelona, Barcelona, Spain

Objective: To study baseline serum neurofilament light chain (sNfL) levels as a prognostic biomarker in Guillain-Barré syndrome (GBS).

Methods: We measured NfL in serum (98 samples) and cerebrospinal fluid (CSF) (24 samples) of patients with GBS prospectively included in the International GBS Outcome Study (IGOS) in Spain using single-molecule array (SiMoA) and compared them with 53 healthy controls (HCs). We performed multivariable regression to analyse the association between sNfL levels and functional outcome at 1 year.

Results: Patients with GBS had higher NfL levels than HC in serum (55.49 pg/mL vs 9.83 pg/mL, p<0.0001) and CSF (1308.5 pg/mL vs 440.24 pg/mL, p=0.034). Patients with preceding diarrhoea had higher sNfL than patients with respiratory symptoms or no preceding infection (134.90 pg/mL vs 47.86 pg/mL vs 38.02 pg/mL, p=0.016). sNfL levels correlated with Guillain-Barré Syndrome Disability Score and Inflammatory Rasch-built Overall Disability Scale (I-RODS) at every timepoint. Patients with pure motor variant and Miller Fisher syndrome showed higher sNfL levels than patients with sensorimotor GBS (162.18 pg/mL vs 95.50 pg/mL vs 38.02 pg/mL, p=0.025). Patients with acute motor axonal neuropathy cute motor axonal neuropathy had higher sNfL levels than other variants (190.55 pg/mL vs 46.79 pg/mL, p=0.013). sNfL returned to normal levels at 1 year. High baseline sNfL levels were associated with inability to run (OR=1.65, 95% CI 1.14 to 2.40, p=0.009) and lower I-RODS (β -2.60, 95% CI -4.66 to -0.54, p=0.014) at 1 year. Cut-off points predicting clinically relevant outcomes at 1 year with high specificity were calculated: inability to walk independently (>319 pg/mL), inability to run (>248 pg/mL) and ability to run (<34 pg/mL).

Conclusion: Baseline sNfL levels are increased in patients with GBS, are associated with disease severity and axonal variants and have an independent prognostic value in patients with GBS.
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http://dx.doi.org/10.1136/jnnp-2020-323899DOI Listing
November 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

Reduced serial dependence suggests deficits in synaptic potentiation in anti-NMDAR encephalitis and schizophrenia.

Nat Commun 2020 08 25;11(1):4250. Epub 2020 Aug 25.

Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Carrer Rosselló 149, 08036, Barcelona, Spain.

A mechanistic understanding of core cognitive processes, such as working memory, is crucial to addressing psychiatric symptoms in brain disorders. We propose a combined psychophysical and biophysical account of two symptomatologically related diseases, both linked to hypofunctional NMDARs: schizophrenia and autoimmune anti-NMDAR encephalitis. We first quantified shared working memory alterations in a delayed-response task. In both patient groups, we report a markedly reduced influence of previous stimuli on working memory contents, despite preserved memory precision. We then simulated this finding with NMDAR-dependent synaptic alterations in a microcircuit model of prefrontal cortex. Changes in cortical excitation destabilized within-trial memory maintenance and could not account for disrupted serial dependence in working memory. Rather, a quantitative fit between data and simulations supports alterations of an NMDAR-dependent memory mechanism operating on longer timescales, such as short-term potentiation.
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http://dx.doi.org/10.1038/s41467-020-18033-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7447775PMC
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
July 2020

Increased CSF levels of IL-1β, IL-6, and ACE in SARS-CoV-2-associated encephalitis.

Neurol Neuroimmunol Neuroinflamm 2020 09 1;7(5). Epub 2020 Jul 1.

From the Infectious Diseases Service (M.B., Á.S., F. García), Hospital Clínic de Barcelona, Catalonia; Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS) (M.B., Y.C., X.F., M.M.-R., J.Y., Á.S., F. Graus, F. García), Barcelona, Catalonia; Department of Medicine (M.B., Y.C., Á.S., F. García), Universitat de Barcelona, Catalonia; Neurology Service (Y.C., L.L., D.E., A.D.-M., A.R., J.S.), Hospital Clínic de Barcelona, Catalonia; Institut de Neurociències (Y.C.), Maria de Maeztu excellence center, Universitat de Barcelona, Catalonia; Endocrinology and Nutricion Service (A.M.), Hospital Clínic de Barcelona, Catalonia; Immunology Service (A.V., N.E., J.Y.), Centre de Diagnòstic Biomèdic (CDB), Hospital Clínic de Barcelona, Functional Unit of Clinical Immunology, Hospital Sant Joan de Déu & Hospital Clínic, Barcelona, Catalonia; CDB (X.F., M.M.-R.), Hospital Clínic de Barcelona, Barcelona, Catalonia; and Department of Biomedicine (M.M.-R.), Universitat de Barcelona; CIBERehd; Catalonia, Spain.

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http://dx.doi.org/10.1212/NXI.0000000000000821DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7357418PMC
September 2020

Sleep disorders in anti-NMDAR encephalitis.

Neurology 2020 08 23;95(6):e671-e684. Epub 2020 Jun 23.

From Clinical and Experimental Neuroimmunology (H.A., A.M.-L., E.M.-H., T.A., M.R.-J., D.E., F.G., G.S., J.C.-F., A.C., J.D., J.S.), Institut d'Investigació Biomèdica August Pi i Sunyer; Departments of Neurology (A.M.-L., E.M.-H., D.E., N.M., J.D., J.S.) and Child and Adolescent Psychiatry and Psychology (T.A., G.S., J.C.-F.), Hospital Clinic, and Pediatric Neuroimmunology Unit (T.A.), Sant Joan de Déu Children's Hospital, University of Barcelona, Spain; Department of Neurology (J.D.), University of Pennsylvania, Philadelphia; and Institució Catalana de Recerca i Estudis Avançats (J.D.), Barcelona, Spain.

Objective: To describe the sleep disorders in anti-NMDA receptor encephalitis (anti-NMDARe).

Methods: Patients recovering from anti-NMDARe were invited to participate in a prospective observational single-center study including comprehensive clinical, video-polysomnography (V-PSG) sleep assessment, and neuropsychological evaluation. Age- and sex-matched healthy participants served as controls.

Results: Eighteen patients (89% female, median age 26 years, interquartile range [IQR] 21-29 years) and 21 controls (81% female, median age 23 years, IQR 18-26 years) were included. In the acute stage, 16 (89%) patients reported insomnia and 2 hypersomnia; nightmares occurred in 7. After the acute stage, 14 (78%) had hypersomnia. At study admission (median 183 days after disease onset, IQR 110-242 days), 8 patients still had hypersomnia, 1 had insomnia, and 9 had normal sleep duration. Patients had more daytime sleepiness than controls (higher Barcelona Sleepiness Index, = 0.02, and Epworth Sleepiness Score, = 0.04). On V-PSG, sleep efficiency was similar in both groups, but patients more frequently had multiple and longer confusional arousals in non-REM (NREM) sleep (videos provided). In addition, 13 (72%) patients had cognitive deficits; 12 (67%) had psychological, social, or occupational disability; and 33% had depression or mania. Compared with controls, patients had a higher body mass index (median 23.5 [IQR 22.3-30.2] vs 20.5 [19.1-21.1] kg/m; = 0.007). Between disease onset and last follow-up, 14 (78%) patients developed hyperphagia, and 6 (33%) developed hypersexuality (2 requiring hospitalization), all associated with sleep dysfunction.

Conclusions: Sleep disturbances are frequent in anti-NMDARe. They show a temporal pattern (predominantly insomnia at onset; hypersomnia during recovery), are associated with behavioral and cognitive changes, and can occur with confusional arousals during NREM sleep.
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http://dx.doi.org/10.1212/WNL.0000000000009987DOI Listing
August 2020

First imported case of tick-borne encephalitis in Spain - was it alimentary?

Travel Med Infect Dis 2020 Sep - Oct;37:101701. Epub 2020 Apr 25.

Infectious Diseases Department, Hospital Clínic de Barcelona, Barcelona, Spain.

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http://dx.doi.org/10.1016/j.tmaid.2020.101701DOI Listing
February 2021

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

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

Pregnancy outcomes in anti-NMDA receptor encephalitis: Case series.

Neurol Neuroimmunol Neuroinflamm 2020 05 16;7(3). Epub 2020 Jan 16.

From the Neuroimmunology Program (B.J., A.G.-S., J.P., E.M.-H., F.G., J.D.), Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Hospital Clínic, Universitat de Barcelona, Spain; Department of Neurology (A.K.), Martha-Maria Hospital, Halle, Germany; Department of Neurology (F.P.), Helios Hospital, Schleswig, Germany; Department of Neurology (T.I.), Kitasato University School of Medicine, Sagamihara, Japan; French Reference Center on Paraneoplastic Neurological Syndromes (B.J., J.H.), Hospices Civils de Lyon, SynatAc Team, Institut NeuroMyoGène, INSERM U1217/CNRS UMR 5310, Université de Lyon, Université Claude Bernard Lyon 1; France; Neuroimmunology Section (F.L.), Institute of Clinical Chemistry, University Hospital Schleswig-Holstein, Kiel/Lübeck, Germany; Department of Neurology (F.L.), Christian-Albrechts-University, Kiel, Germany; Institució Catalana de Recerca i Estudis Avançats (ICREA) (J.D.), Barcelona, Spain; and Department of Neurology (J.D.), University of Pennsylvania, PA.

Objective: To report the effects of anti-NMDA receptor (NMDAR) encephalitis in pregnant patients and their babies.

Methods: We studied a retrospective cohort of patients who developed anti-NMDAR encephalitis during pregnancy or became pregnant while recovering from the encephalitis. In addition, we reviewed the English literature between 2010 and 2019 related to this topic.

Results: We studied 11 patients; 6 developed anti-NMDAR encephalitis during pregnancy, and 5 became pregnant while recovering. There were no obstetrical complications, but 6 (55%) babies were premature. Ten newborns were healthy, and 1 (9%) developed transient respiratory distress. Nine infants had assessable follow-up (median 18 months; range, 7-96 months), and all showed normal development. We identified 21 cases in the English literature. Obstetrical complications occurred in 7 (33%) pregnancies. Two patients died of septic shock (1 baby successfully delivered), another 2 had miscarriages, and in 2, the pregnancy was terminated. Sixteen babies (76%) were delivered, 9 (56%) premature. At birth, 13/16 (81%) newborns were healthy, 2/16 (13%) had transient neurologic or respiratory symptoms, and 1 (6%) died of brain edema. Follow-up (median 12 months; range, 6-36 months) was reported for 8 children: 7 (88%) showed normal development and behavior, and 1 (13%) cortical dysplasia. Immunotherapy was used during pregnancy in 7 (64%) of our patients and 18 (86%) of the reported cases, including rituximab in 4 cases, without adverse effects.

Conclusions: Patients who develop anti-NMDAR encephalitis during pregnancy or become pregnant during recovery often have obstetrical complications, but most of the newborns are healthy and appear to have normal development.
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http://dx.doi.org/10.1212/NXI.0000000000000668DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7051205PMC
May 2020

Paraneoplastic cerebellar ataxia and antibodies to metabotropic glutamate receptor 2.

Neurol Neuroimmunol Neuroinflamm 2020 03 11;7(2). Epub 2019 Dec 11.

From the Immunology Department (R.R.-G.), Centre Diagnòstic Biomèdic, Hospital Clínic; Neuroimmunology Program (E.M.-H., B.J., M.P.-P., T.A., L. Sabater, J.D., F.G.), Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS); Service of Neurology (E.M.-H.), Hospital Clinic; Service of Neurology (E.P.-B., L. Salais), Hospital General de Castellón, Spain; Service of Pediatrics (V.F.), Hospital General de Albacete, Spain; Onco-Hematology Unit (M.d.P.), Service of Pediatrics, Hospital General de Albacete; Institució Catalana de Recerca i Estudis Avançats (ICREA) (J.D.), Barcelona, Spain; and Department of Neurology (J.D.), University of Pennsylvania, Philadelphia, PA.

Objective: To report the presence of a new neuronal surface antibody against the metabotropic glutamate receptor 2 antibody (mGluR2-Ab) in 2 patients with paraneoplastic cerebellar ataxia.

Methods: mGluR2-Abs were initially characterized by immunohistochemistry on the rat brain and confirmed by immunofluorescence on HEK293 cells transfected with mGluR2. Additional studies included analysis of potential cross-reactivity with other mGluRs, expression of mGluR2 in patients' tumors, and the effects of mGluR2-Abs on cultures of rat hippocampal neurons.

Results: Patient 1 was a 78-year-old woman with progressive cerebellar ataxia with an initial relapsing-remitting course who developed a small-cell tumor of unknown origin. Patient 2 was a 3-year-old girl who presented a steroid-responsive acute cerebellitis preceding the diagnosis of an alveolar rhabdomyosarcoma. Patients' serum and CSF showed a characteristic immunostaining of the hippocampus and cerebellum in rat brain sections and immunolabeled the cell surface of live rat hippocampal neurons. HEK293 cells transfected with mGluR1, 2, 3, and 5 confirmed that patients' antibodies only recognized mGluR2. mGluR2-Abs were not detected in 160 controls, 120 with paraneoplastic, autoimmune, or degenerative ataxias, and 40 with autoimmune encephalitis and antibodies against mGluR5 or unknown antigens. Expression of mGluR2 in tumors was confirmed by immunohistochemistry using a commercial mGluR2-Ab. Incubation of live rat hippocampal neurons with CSF of patient 2 did not modify the density of surface mGluR2 clusters.

Conclusions: mGluR2-Abs are a novel biomarker of paraneoplastic cerebellar ataxia. The potential pathogenic effect of the antibodies is not mediated by downregulation or internalization of neuronal surface mGluR2.
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http://dx.doi.org/10.1212/NXI.0000000000000658DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6943365PMC
March 2020

Rebound of multiple sclerosis activity after fingolimod withdrawal due to planning pregnancy: Analysis of predisposing factors.

Mult Scler Relat Disord 2020 Feb 30;38:101483. Epub 2019 Oct 30.

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

Background: Rebound of multiple sclerosis (MS) activity has been described after the withdrawal of high-efficacy drugs, but its impact during pregnancy is less known. We describe a series of cases of rebound syndrome after the cessation of fingolimod due to pregnancy planning.

Methods: The clinical and radiological data of 7 MS patients who discontinued fingolimod therapy between May 2012 and March 2018 to plan a pregnancy was analysed.

Results: Three (42.8%) of the 7 patients experienced a rebound effect, all of whom became pregnant. During pregnancy, the 3 patients had a mean (SD) of 5.3 (1.3) relapses, and 13 of the 15 relapses were treated with intravenous steroids and/or immunoglobulin. These patients experienced a median increase of 3 points in the Expanded Disability Status Scale (range, 2-4), as well as a median increase of 27 new gadolinium-enhancing lesions (range, 9-40) and 38 new T2 lesions in a post-partum MRI (range, 21-70). The 3 pregnancies resulted in the delivery of healthy babies. A strong correlation was found between the lymphocyte count at fingolimod onset and the annual relapse rate in the period without therapy (r= -0.84, p = 0.005). The time to first relapse was shorter in patients who had <300/μl lymphocytes at fingolimod onset (median time 46 vs 426 days, p = 0.010).

Conclusion: Rebound activity after fingolimod suspension represents a severe long-lasting inflammatory syndrome that may affect up to 40% of female MS patient who discontinue therapy due to pregnancy planning. Lymphopenia (<300/μl) in the first 3 months of fingolimod onset may predispose patients to suffer earlier and higher disease activity upon cessation.
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http://dx.doi.org/10.1016/j.msard.2019.101483DOI Listing
February 2020

Using Acute Optic Neuritis Trials to Assess Neuroprotective and Remyelinating Therapies in Multiple Sclerosis.

JAMA Neurol 2020 02;77(2):234-244

Center of Neuroimmunology, Service of Neurology, Hospital Clinic of Barcelona, Institut d'Investigacions Biomèdiques August Pi Sunyer, University of Barcelona, Barcelona, Spain.

Importance: Neuroprotective and remyelinating therapies are required for multiple sclerosis (MS), and acute optic neuritis (AON) is a potential condition to evaluate such treatments.

Objective: To comprehensively assess key biological and methodological aspects of AON trials for testing neuroprotection and remyelination in MS.

Design, Setting, And Participants: The AON-VisualPath prospective cohort study was conducted from February 2011 to November 2018 at the Hospital Clinic of University of Barcelona, Barcelona, Spain. Consecutive patients with AON were prospectively enrolled in the cohort and followed up for 18 months. Data analyses occurred from November 2018 to February 2019.

Exposures: Participants were followed up for 18 months using optical coherence tomography, visual acuity tests, and in a subset of 25 participants, multifocal visual evoked potentials.

Main Outcomes And Measures: Dynamic models of retinal changes and nerve conduction and their associations with visual end points; and eligibility criteria, stratification, and sample-size estimation for future trials.

Results: A total of 60 patients (50 women [83%]; median age, 34 years) with AON were included. The patients studied displayed early and intense inner retinal thinning, with a thinning rate of approximately 2.38 μm per week in the ganglion cell plus inner plexiform layer (GCIPL) during the first 4 weeks. Eyes with AON displayed a 6-month change in latency of about 20 milliseconds, while the expected change in the eyes of healthy participants by random variability was 0.13 (95% CI, -0.80 to 1.06) milliseconds. The strongest associations with visual end points were for the 6-month intereye difference in 2.5% low-contrast letter acuity, which was correlated with the peripapillary retinal nerve fiber layer thinning (adjusted R2, 0.57), GCIPL thinning (adjusted R2, 0.50), and changes in mfVEP latency (adjusted R2, 0.26). A 5-letter increment in high-contrast visual acuity at presentation (but not sex or age) was associated with 6-month retinal thinning (1.41 [95% CI, 0.60-2.23] μm less peripapillary retinal nerve fiber layer thinning thinning; P = .001; adjusted R2, 0.20; 0.86 [95% CI, 0.35-1.37] μm less GCIPL thinning; P = .001; adjusted R2, 0.19) but not any change in multifocal visual evoked potential latency. To demonstrate 50% efficacy in GCIPL thinning or change in multifocal visual evoked potential latency, a 6-month, 2-arm, parallel-group trial would need 37 or 50 participants per group to test a neuroprotective or remyelinating drug, respectively (power, 80%; α, .05).

Conclusions And Relevance: Acute optic neuritis is a suitable condition to test neuroprotective and remyelinating therapies after acute inflammation, providing sensitive markers to assess the effects on both processes and prospective visual recovery within a manageable timeframe and with a relatively small sample size.
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http://dx.doi.org/10.1001/jamaneurol.2019.3283DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6777247PMC
February 2020

Late-onset neuromyelitis optica spectrum disorder: The importance of autoantibody serostatus.

Neurol Neuroimmunol Neuroinflamm 2019 11 30;6(6). Epub 2019 Aug 30.

From the Center of Neuroimmunology (M.S., G.D.-G., Y.B., N.S.-V., E.H.M.-L., T.A., C.M., I.P.-V., E.M.-H., H.A., D.E., S.L., J.D., F.G., A.S.), Service of Neurology, Laboratory of Advanced Imaging in Neuroimmunological Diseases, Hospital Clínic of Barcelona, Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), and Universitat de Barcelona, Barcelona, Spain; Division of Neurology (G.D.-G.), National Institute of Neurology and Neurosurgery, Mexico City; Pediatric Neuroimmunology Unit (T.A.), Neurology Service, Sant Joan de Deu Children's Hospital, University of Barcelona, Spain; Servicio de Inmunología (R.R.-G.), Centro de Diagnóstico Biomédico, Hospital Clinic of Barcelona, Spain; Department of Neurology (J.D.), University of Pennsylvania, Philadelphia, PA; and Catalan Institution for research and Advanced Studies (ICREA) (J.D.), Barcelona, Spain.

Objective: To describe the clinical features of late-onset (≥50 years) neuromyelitis optica spectrum disorder (LO-NMOSD), to compare the outcome with that of early-onset (EO-NMOSD), and to identify predictors of disability.

Methods: A retrospective, multicenter study of 238 patients with NMOSD identified by the 2015 criteria. Clinical and immunologic features of patients with LO-NMOSD were compared with those with EO-NMOSD. All patients were evaluated for aquaporin-4 (AQP4-IgG) and myelin oligodendrocyte glycoprotein (MOG-IgG) antibodies.

Results: Sixty-nine (29%) patients had LO-NMOSD. Demographic features, initial disease presentation, annualized relapse rate, and frequency of AQP4-IgG and MOG-IgG did not differ between patients with LO-NMOSD and EO-NMOSD. Among patients with AQP4-IgG or double seronegativity, those with LO-NMOSD had a higher risk to require a cane to walk (hazard ratio [HR], 2.10, 95% CI 1.3-3.54, = 0.003 for AQP4-IgG, and HR, 13.0, 95% CI 2.8-59.7, = 0.001, for double seronegative). No differences in outcome were observed between patients with MOG-IgG and LO-NMOSD or EO-NMOSD. Older age at onset (for every 10-year increase, HR 1.63, 95% CI 1.35-1.92 0.001) in NMOSD, and higher disability after the first attack (HR 1.68, 95% CI 1.32-2.14, < 0.001), and double seronegativity (HR 3.74, 95% CI 1.03-13.6, = 0.045) in LO-NMOSD were the main independent predictors of worse outcome.

Conclusions: Patients with LO-NMOSD have similar clinical presentation but worse outcome than EO-NMOSD when they are double seronegative or AQP4-IgG positive. Serostatus and residual disability after first attack are the main predictors of LO-NMOSD outcome.
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http://dx.doi.org/10.1212/NXI.0000000000000607DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6745725PMC
November 2019

Caveats and Pitfalls of SOX1 Autoantibody Testing With a Commercial Line Blot Assay in Paraneoplastic Neurological Investigations.

Front Immunol 2019 12;10:769. Epub 2019 Apr 12.

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

SOX1 autoantibodies are considered markers of small cell lung cancer (SCLC) and paraneoplastic neurological syndromes (PNS) and are usually determined by commercial line blot in many clinical services. Recent studies suggested that SOX1 autoantibodies also occur in patients with neuropathies unrelated to SCLC, questioning the value of SOX1 autoantibodies as paraneoplastic biomarkers. Here, we compared the specificity and sensitivity of a commercial line blot (Euroimmun, Lübeck, Germany) with those of an in house cell-based assay (CBA) with HEK293 cells transfected with SOX1. Overall, 210 patients were included in the study, 139 patients with polyneuropathies without SCLC, and 71 with disorders associated with SOX1 autoantibodies detected with the in-house CBA. Forty one of these 71 cases had been referred to our laboratory for onconeuronal antibody assessment and 30/71 were patients with known PNS and SCLC. None of the patients with polyneuropathies had SOX1 autoantibodies by either line blot or CBA (specificity of the immunoblot: 100%; 95%C.I.: 97.8-100). Among the 71 patients with CBA SOX1 autoantibodies, only 53 were positive by line blot (sensitivity: 74.6%; 95%C.I.: 62.9-84.2). Lung cancer was detected in 37/41 (90%; 34 with SCLC) patients referred for onconeuronal antibody assessment and 34 of them also had a PNS. Our study confirms the association of SOX1 autoantibodies with SCLC and PNS. The line blot test misses 25% of the cases; therefore, to minimize the frequency of false negative results we recommend the use of a confirmatory test, such as CBA, in patients suspected to have a SCLC-related PNS.
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http://dx.doi.org/10.3389/fimmu.2019.00769DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6473043PMC
August 2020

Frequency and relevance of IgM, and IgA antibodies against MOG in MOG-IgG-associated disease.

Mult Scler Relat Disord 2019 Feb 3;28:230-234. Epub 2019 Jan 3.

Neuroimmunology Program, Institut d' Investigació Biomèdica August Pi i Sunyer (IDIBAPS), Barcelona, Spain; Unitat de Neuroimmunologia-Esclerosi múltiple, Servei de Neurología, Hospital Clinic, and Universitat de Barcelona, Barcelona, Spain. Electronic address:

Objective: To determine the frequency and relevance of IgM, and IgA antibodies against myelin oligodendrocyte glycoprotein (MOG) in MOG-IgG-associated disease.

Methods: Evaluation of IgM, and IgA MOG antibodies in serum of 120 patients with MOG-IgG (53 pediatric and 67 adults), and 114 patients with seronegative-MOG-IgG (35 children with first demyelinating syndrome, 20 adults with clinically isolated syndrome, and 59 adults with other diseases). Antibodies were examined by cell-based assays.

Results: IgM or IgA MOG antibodies were identified in 23/120 (19%) patients with MOG-IgG (13/53 [24.5%] pediatric, and 10/67 [15%] adult patients), and 2/114 (1.7%) patients with seronegative-MOG-IgG (2/35 [5.7%] pediatric patients). Of the 25 patients, 14 had IgA, 9 IgM, and 2 both antibodies. Fourteen of the 15 (93%) children with IgM (4), IgA (9), or both (2) had acute demyelinating encephalomyelitis (ADEM), and 7 of the 10 (70%) adults with IgM (5) or IgA (5) had optic neuritis at onset. At the last follow-up, the final diagnoses remained as ADEM in 14 (100%) children and optic neuritis in 6 (86%) adults. The outcome was not different between patients with or without additional classes of antibodies.

Conclusion: Coexisting IgM and IgA antibodies occurs in 19% of children and adult patients with MOG-IgG-associated disease. The presence of these antibodies does not seem to play a relevant clinical role in the disorder.
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http://dx.doi.org/10.1016/j.msard.2019.01.007DOI Listing
February 2019

Multi-centre validation of a flow cytometry method to identify optimal responders to interferon-beta in multiple sclerosis.

Clin Chim Acta 2019 Jan 5;488:135-142. Epub 2018 Nov 5.

Immunology Dpt. and Biostatistic Unit, Hospital Universitario Ramón y Cajal, IRYCIS, Ctra. de Colmenar Viejo km 9.100, 28034 Madrid, Spain; Red Española de Esclerosis Múltiple (REEM), Spain. Electronic address:

Background And Objectives: Percentages of blood CD19+CD5+ B cells and CD8+perforin+ T lymphocytes can predict response to Interferon (IFN)-beta treatment in relapsing-remitting multiple sclerosis (RRMS) patients. We aimed to standardize their detection in a multicenter study, prior to their implementation in clinical practice.

Methods: Fourteen hospitals participated in the study. A reference centre was established for comparison studies. Peripheral blood cells of 105 untreated RRMS patients were studied. Every sample was analyzed in duplicate in the participating centre and in the reference one by flow cytometry. When needed, participating centres corrected fluorescence compensations and negative cut-off position following reference centre suggestions. Concordance between results obtained by participating centres and by reference one was evaluated by intraclass correlation coefficients (ICC) and Spearman correlation test. Centre performance was measured by using z-scores values.

Results: After results review and corrective actions implementation, overall ICC was 0.86 (CI: 0.81-0.91) for CD19+CD5+ B cell and 0.89 (CI: 0.85-0.93) for CD8+ perforin+ T cell quantification; Spearman r was 0.92 (0.89-0.95; p <0.0001) and 0.92 (0.88-0.95; p <0.0001) respectively. All centres obtained z-scores≤0.5 for both biomarkers.

Conclusion: Homogenous percentages of CD19+CD5+ B cells and CD8 perforin+ T lymphocytes can be obtained if suitable compensation values and negative cut-off are pre-established.
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http://dx.doi.org/10.1016/j.cca.2018.11.008DOI Listing
January 2019

Frequency, symptoms, risk factors, and outcomes of autoimmune encephalitis after herpes simplex encephalitis: a prospective observational study and retrospective analysis.

Lancet Neurol 2018 09 23;17(9):760-772. Epub 2018 Jul 23.

Neuroimmunology Program, Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Hospital Clínic, University of Barcelona, Barcelona, Spain; Service of Neurology, Hospital Clínic, University of Barcelona, Barcelona, Spain; Department of Neurology, University of Pennsylvania, PA, USA; Catalan Institution for Research and Advanced Studies (ICREA), Barcelona, Spain. Electronic address:

Background: Herpes simplex encephalitis can trigger autoimmune encephalitis that leads to neurological worsening. We aimed to assess the frequency, symptoms, risk factors, and outcomes of this complication.

Methods: We did a prospective observational study and retrospective analysis. In the prospective observational part of this study, we included patients with herpes simplex encephalitis diagnosed by neurologists, paediatricians, or infectious disease specialists in 19 secondary and tertiary Spanish centres (Cohort A). Outpatient follow-up was at 2, 6, and 12 months from onset of herpes simplex encephalitis. We studied another group of patients retrospectively, when they developed autoimmune encephalitis after herpes simplex encephalitis (Cohort B). We compared demographics and clinical features of patients who developed autoimmune encephalitis with those who did not, and in patients who developed autoimmune encephalitis we compared these features by age group (patients ≤4 years compared with patients >4 years). We also used multivariable binary logistic regression models to assess risk factors for autoimmune encephalitis after herpes simplex encephalitis.

Findings: Between Jan 1, 2014, and Oct 31, 2017, 54 patients with herpes simplex encephalitis were recruited to Cohort A, and 51 were included in the analysis (median age 50 years [IQR 5-68]). At onset of herpes simplex encephalitis, none of the 51 patients had antibodies to neuronal antigens; during follow-up, 14 (27%) patients developed autoimmune encephalitis and all 14 (100%) had neuronal antibodies (nine [64%] had NMDA receptor [NMDAR] antibodies and five [36%] had other antibodies) at or before onset of symptoms. The other 37 patients did not develop autoimmune encephalitis, although 11 (30%) developed antibodies (n=3 to NMDAR, n=8 to unknown antigens; p<0·001). Antibody detection within 3 weeks of herpes simplex encephalitis was a risk factor for autoimmune encephalitis (odds ratio [OR] 11·5, 95% CI 2·7-48·8; p<0·001). Between Oct 7, 2011, and Oct 31, 2017, there were 48 patients in Cohort B with new-onset or worsening neurological symptoms not caused by herpes simplex virus reactivation (median age 8·8 years [IQR 1·1-44·2]; n=27 male); 44 (92%) patients had antibody-confirmed autoimmune encephalitis (34 had NMDAR antibodies and ten had other antibodies). In both cohorts (n=58 patients with antibody-confirmed autoimmune encephalitis), patients older than 4 years frequently presented with psychosis (18 [58%] of 31; younger children not assessable). Compared with patients older than 4 years, patients aged 4 years or younger (n=27) were more likely to have shorter intervals between onset of herpes simplex encephalitis and onset of autoimmune encephalitis (median 26 days [IQR 24-32] vs 43 days [25-54]; p=0·0073), choreoathetosis (27 [100%] of 27 vs 0 of 31; p<0·001), decreased level of consciousness (26 [96%] of 27 vs seven [23%] of 31; p<0·001), NMDAR antibodies (24 [89%] of 27 vs 19 [61%] of 31; p=0·033), and worse outcome at 1 year (median modified Rankin Scale 4 [IQR 4-4] vs 2 [2-3]; p<0·0010; seizures 12 [63%] of 19 vs three [13%] of 23; p=0·001).

Interpretation: The results of our prospective study show that autoimmune encephalitis occurred in 27% of patients with herpes simplex encephalitis. It was associated with development of neuronal antibodies and usually presented within 2 months after treatment of herpes simplex encephalitis; the symptoms were age-dependent, and the neurological outcome was worse in young children. Prompt diagnosis is important because patients, primarily those older than 4 years, can respond to immunotherapy.

Funding: Mutua Madrileña Foundation, Fondation de l'Université de Lausanne et Centre Hospitalier Universitaire Vaudois, Instituto Carlos III, CIBERER, National Institutes of Health, Generalitat de Catalunya, Fundació CELLEX.
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http://dx.doi.org/10.1016/S1474-4422(18)30244-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6128696PMC
September 2018

Antibodies against cell adhesion molecules and neural structures in paraneoplastic neuropathies.

Ann Clin Transl Neurol 2018 May 26;5(5):559-569. Epub 2018 Mar 26.

Neuromuscular Diseases Unit Neurology Department Hospital de la Santa Creu i Sant Pau Universitat Autònoma de Barcelona Barcelona Spain.

Objective: Paraneoplastic neurological syndromes (PNS) are rare neurological disorders in which ectopic expression of neural antigens by a tumor results in an autoimmune attack against the nervous system. Onconeural antibodies not only guide PNS diagnosis but may also help detecting underlying malignancies. Our project aims to uncover new potential antibodies in paraneoplastic neuropathies (PN).

Methods: Thirty-four patients fulfilling diagnostic criteria of possible ( = 9; 26.5%) and definite ( = 25; 73.5%) PN without onconeural antibodies and 28 healthy controls were included in our study. Sera were tested for known antibodies against neural cell adhesion molecules and screened for novel IgG and IgM reactivities against nerve components: dorsal root ganglia (DRG) neurons, motor neurons, and Schwann cells. Patients showing autoantibodies against any of these cell types were used for immunoprecipitation (IP) studies.

Results: Overall, 9 (26.5%) patients showed significant reactivity against DRG neurons, motor neurons, or Schwann cells, whereas 5 (17.9%) healthy controls only showed moderate reactivity. Compared with control sera, serum samples from patients with paraneoplastic sensory-motor neuropathies had a higher frequency of IgM antibodies against Schwann cells (0% vs. 40%; = 0.0028). No novel antigens were identified from our IP experiments. Antibodies against the neural adhesion molecules CNTN1, NF155, NF140, NF186, NCAM1, L1CAM, and the CNTN1/CASPR1 complex were not detected in patients with PN. One (2.9%) patient with CIDP and thymoma had CASPR2 antibodies.

Interpretation: Almost 30% of patients with PN harbor antibodies targeting neural structures, suggesting that novel neoplasm-associated antigens remain to be discovered.
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http://dx.doi.org/10.1002/acn3.554DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5945957PMC
May 2018

Encephalitis with mGluR5 antibodies: Symptoms and antibody effects.

Neurology 2018 05 27;90(22):e1964-e1972. Epub 2018 Apr 27.

From the Institut d'Investigacions Biomèdiques August Pi i Sunyer (M.S., L.S., J.P., E.M.-H., T.A., M.R.R., F.G., J.D.) and Hospital Clínic, University of Barcelona, Spain; Department of Clinical Neuroscience (M.S.), University of Lausanne, Switzerland; Centro de Investigación Biomédica en Red de Enfermedades Raras (L.S., J.P., E.M.-H., T.A., M.R.R., F.G., J.D.), Valencia; ICFO-Institut de Ciències Fotòniques (J.P.); Pediatric Neuroimmunology Unit (T.A.), Sant Joan de Déu Children's Hospital, University of Barcelona, Spain; Charité Universitätsmedizin Berlin (H.P.), Experimentelle Neurologie und Klinik und Poliklinik für Neurologie; German Center for Neurodegenerative Diseases (H.P.), Berlin, Germany; Department of Neurology (T.I.), Kitasato University School of Medicine, Sagamihara, Japan; Hospital Nacional Edgardo Rebagliati Martins (R.L.C.O.), Lima, Peru; Department of Neurology (J.-C.A.), University Hospital, Saint-Etienne, France; Pamela Youde Nethersole Eastern Hospital (R.L.), Hong Kong; Beatson West of Scotland Cancer Centre (N.H.), Glasgow, UK; Department of Neurology (N.T.), St. Vincent's University Hospital, Dublin, Ireland; Service of Neurology (E.M.O.), Hospital del Mar, IMIM, Barcelona, Spain; Department of Neurology (M.R.R., J.D.), University of Pennsylvania, Philadelphia; and Catalan Institution for Research and Advanced Studies (J.D.), Barcelona, Spain.

Objective: To report the clinical features of 11 patients with metabotropic glutamate receptor 5 (mGluR5) antibody-associated encephalitis, immunoglobulin G (IgG) subclass, and effects of the antibodies on neuronal mGluR5 clusters.

Methods: Clinical information was retrospectively obtained from referring physicians. Antibodies to mGluR5 and IgG subclasses were determined with brain immunohistochemistry and cell-based assays. The effects of the antibodies were examined on rat hippocampal neurons with reported techniques.

Results: From January 2005 to May 2017, 11 patients (median age 29 years, range 6-75 years, 5 female) were identified. The main clinical features were psychiatric (10), cognitive (10), movement disorders (7), sleep dysfunction (7), and seizures (6). Median modified Rankin Scale score at the peak of the disease was 4; 4 patients required intensive care. Five patients had Hodgkin lymphoma, and 1 had small cell lung cancer. CSF showed pleocytosis (median white blood cell count 22 mm) in all patients; brain MRI was abnormal in 5, involving limbic (1) or extralimbic (4) regions. Treatments included immunotherapy and/or oncologic therapy; at the last follow-up (median 48 months), 6 patients had complete and 5 had partial recovery. Neurologic relapse occurred in 2 patients. Antibodies were IgG1 alone (4 of 9) or in combination with IgG2 (1 of 9), IgG3 (3 of 9), or both (1). Patients' IgG caused a significant and specific decrease of cell-surface synaptic and extrasynaptic mGluR5 without altering the levels of postsynaptic density protein 95.

Conclusions: Anti-mGluR5 encephalitis associates with a complex neuropsychiatric syndrome, not restricted to limbic encephalitis, and can occur without tumor. Patients respond to treatment, but relapses can occur. The antibodies have pathogenic effects altering the levels of cell-surface mGluR5.
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http://dx.doi.org/10.1212/WNL.0000000000005614DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5980520PMC
May 2018

Clinical and pathogenic significance of IgG, IgA, and IgM antibodies against the NMDA receptor.

Neurology 2018 04 16;90(16):e1386-e1394. Epub 2018 Mar 16.

From the Clinical and Experimental Neuroimmunology Program, August Pi i Sunyer Biomedical Research Institute, Hospital Clínic (M.H., E.M.-H., H.A., T.A., M.S., M.P.-P., A.S., M.R.R., F.G., J.D.), and Department of Neurology, Sant Joan de Deu Childrens Hospital (T.A., J.D.), University of Barcelona, Spain; Division of Neurology (M.H.), Department of Medicine, Nihon University School of Medicine, Japan; University of Lausanne (M.S.), Switzerland; Department of Neurology (M.R.R., J.D.), University of Pennsylvania, Philadelphia; and Catalan Institution for Research and Advanced Studies (J.D.), Barcelona, Spain.

Objective: To determine the frequency and clinical relevance of immunoglobulin (Ig)G, IgA, and IgM -methyl-d-aspartate receptor (NMDAR) antibodies in several diseases, and whether the IgG antibodies occur in disorders other than anti-NMDAR encephalitis.

Methods: Evaluation of IgG, IgA, and IgM NMDAR antibodies in serum of 300 patients with anti-NMDAR encephalitis, stroke, dementia, schizophrenia, or seronegative autoimmune encephalitis. Antibodies and their effect on cultured neurons were examined with cell-based assays and brain and live neuronal immunostaining. Retrospective analysis of the clinical diagnoses of a cohort of 1,147 patients with IgG NMDAR antibodies identified since 2005.

Results: Among the 300 patients studied, IgG NMDAR antibodies were only identified in those with anti-NMDAR encephalitis and all reacted with brain and live neurons. By cell-based assay, IgA or IgM antibodies were detected in 22 of 300 patients (7%) with different diseases, but only 10 (3%) reacted with brain and 7 (2%) with live neurons. In cultured neurons, IgG but not IgA or IgM antibodies caused a decrease of synaptic and extrasynaptic NMDAR. Among the cohort of 1,147 patients with IgG NMDAR antibodies, 1,015 (88.5%) had anti-NMDAR encephalitis, 45 (3.9%) a limited form of the disease, 41 (3.6%) autoimmune post-herpes simplex encephalitis, 37 (3.2%) overlapping syndromes (anti-NMDAR encephalitis and demyelinating disease), and 9 (0.8%) atypical encephalitic syndromes; none had schizophrenia.

Conclusions: IgG NMDAR antibodies are highly specific for anti-NMDAR encephalitis and cause a decrease of the levels of NMDAR. In contrast, IgA or IgM antibodies occur infrequently and nonspecifically in other diseases and do not alter the receptor levels.
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http://dx.doi.org/10.1212/WNL.0000000000005329DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5902781PMC
April 2018

Antibody-associated CNS syndromes without signs of inflammation in the elderly.

Neurology 2017 Oct 6;89(14):1471-1475. Epub 2017 Sep 6.

From the Service of Neurology (D.E., M.G., C.G., J.D., F.G.), Hospital Clinic, University of Barcelona; Neuroimmunology Program (H.A., C.G., E.M.-H., J.D., F.G.), Institut d'Investigació Biomèdica August Pi i Sunyer; Institució Catalana de Recerca i Estudis Avançats (J.D.), Barcelona, Spain; and Department of Neurology (J.D.), University of Pennsylvania, Philadelphia.

Objective: To report the CNS syndromes of patients ≥60 years of age with antibodies against neuronal surface antigens but no evidence of brain MRI and CSF inflammatory changes.

Methods: This was a retrospective clinical analysis of patients with antibodies against neuronal surface antigens who fulfilled 3 criteria: age ≥60 years, no inflammatory abnormalities in brain MRI, and no CSF pleocytosis. Antibodies were determined with reported techniques.

Results: Among 155 patients ≥60 years of age with neurologic syndromes related to antibodies against neuronal surface antigens, 35 (22.6%) fulfilled the indicated criteria. The median age of these 35 patients was 68 years (range 60-88 years). Clinical manifestations included faciobrachial dystonic seizures (FBDS) in 11 of 35 (31.4%) patients, all with LGI1 antibodies; a combination of gait instability, brainstem dysfunction, and sleep disorder associated with IgLON5 antibodies in 10 (28.6%); acute confusion, memory loss, and behavioral changes suggesting autoimmune encephalitis (AE) in 9 (25.7%; 2 patients with AMPAR, 2 with NMDAR, 2 with GABAbR, 2 with LGI1, and 1 with CASPR2 antibodies); and rapidly progressive cognitive deterioration in 5 (14.3%; 3 patients with IgLON5 antibodies, 1 with chorea; 1 with DPPX antibody-associated cerebellar ataxia and arm rigidity; and 1 with CASPR2 antibodies).

Conclusions: In patients ≥60 years of age, the correct identification of characteristic CNS syndromes (FBDS, anti-IgLON5 syndrome, AE) should prompt antibody testing even without evidence of inflammation in MRI and CSF studies. Up to 15% of the patients developed rapidly progressive cognitive deterioration, which further complicated the differential diagnosis with a neurodegenerative disorder.
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http://dx.doi.org/10.1212/WNL.0000000000004541DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5631166PMC
October 2017

Postmalaria neurologic syndrome associated with neurexin-3α antibodies.

Neurol Neuroimmunol Neuroinflamm 2017 Sep 21;4(5):e392. Epub 2017 Aug 21.

Department of Neurology (A.C., P.A.), Department of Infectious Diseases (A.S.-P., J.A., N.N., A.S.), Centro Hospitalar São João, Porto, Portugal; Department of Neuroscience and Mental Health (A.C., P.A.), Faculty of Medicine of University of Porto, Portugal; Nephrology and Infectious Diseases R&D Group (A.S.-P., J.A., N.N., A.S.), Health Investigation and Innovation Institute (I3S), University of Porto, Portugal; and Neuroimmunology Program (E.M.-H.), Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Spain.

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http://dx.doi.org/10.1212/NXI.0000000000000392DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5565625PMC
September 2017

Motor polyradiculopathy during pembrolizumab treatment of metastatic melanoma.

Muscle Nerve 2017 Dec 16;56(6):E162-E167. Epub 2017 May 16.

Department of Neurology, Hospital Clínic, University of Barcelona, Barcelona, Spain.

Introduction: Pembrolizumab, a monoclonal antibody directed against the immune checkpoint programmed cell death-1 receptor (PD-1), has improved survival in patients with advanced melanoma. Neuromuscular immune-mediated side effects have been rarely reported.

Methods: We describe a 44-year-old man with metastatic melanoma who presented with progressive muscle weakness after 23 doses of pembrolizumab.

Results: The patient developed asymmetric, proximal muscle weakness and atrophy in all four limbs. Cerebrospinal fluid examination showed albuminocytologic dissociation. MRI revealed contrast enhancement of the lumbosacral roots. Electrodiagnostic studies demonstrated widespread fibrillation potentials in all four limbs, suggesting a generalized motor polyradiculopathy. Despite pembrolizumab discontinuation and treatment with steroids and intravenous immunoglobulin, limb weakness worsened. Electrodiagnostic studies were repeated, and showed marked and diffuse axonal motor damage. Seven weeks after clinical onset the patient was treated with plasma exchanges. He showed no further deterioration.

Discussion: We report a severe motor polyradiculopathy associated with an anti-PD-1 agent that expands the spectrum of neuromuscular complications of this class of drugs. Muscle Nerve 56: E162-E167, 2017.
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http://dx.doi.org/10.1002/mus.25672DOI Listing
December 2017

DPPX antibody-associated encephalitis: Main syndrome and antibody effects.

Neurology 2017 Apr 3;88(14):1340-1348. Epub 2017 Mar 3.

From the Clinical and Experimental Neuroimmunology Program (M.H., H.A., M.P.-P., L.S., E.M.-H., M.R.R., F.G., J.D.), August Pi Sunyer Biomedical Research Institute, Hospital Clínic, University of Barcelona, Spain; Division of Neurology (M.H.), Department of Medicine, Nihon University School of Medicine, Tokyo, Japan; Biomedical Research Networking Centre for Rare Diseases (H.A., J.D., M.P.-P., L.S., E.M.-H., M.R.R.), Valencia, Spain; Departments of Neurology (M.J.T.) and Immunology (M.W.J.S.), Erasmus Medical Center, Rotterdam, the Netherlands; Department of Neurology (M.R.R., J.D.), University of Pennsylvania, Philadelphia; and Catalan Institution for Research and Advanced Studies (J.D.), Barcelona, Spain.

Objective: To report the main syndrome of dipeptidyl-peptidase-like protein 6 (DPPX) antibody-associated encephalitis, immunoglobulin G (IgG) subclass, and the antibody effects on DPPX/Kv4.2 potassium channels.

Methods: A retrospective analysis of new patients and cases reported since 2013 was performed. IgG subclass and effects of antibodies on cultured neurons were determined with described techniques.

Results: Nine new patients were identified (median age 57 years, range 36-69 years). All developed severe prodromal weight loss or diarrhea followed by cognitive dysfunction (9), memory deficits (5), CNS hyperexcitability (8; hyperekplexia, myoclonus, tremor, or seizures), or brainstem or cerebellar dysfunction (7). The peak of the disease was reached 8 months (range 1-54 months) after onset. All patients had both IgG4 and IgG1 DPPX antibodies. In cultured neurons, the antibodies caused a decrease of DPPX clusters and Kv4.2 protein that was reversible on removal of the antibodies. Considering the current series and previously reported cases (total 39), 67% developed the triad: weight loss (median 20 kg; range 8-53 kg)/gastrointestinal symptoms, cognitive-mental dysfunction, and CNS hyperexcitability. Outcome was available from 35 patients (8 not treated with immunotherapy): 60% had substantial or moderate improvement, 23% had no improvement (most of them not treated), and 17% died. Relapses occurred in 8 of 35 patients (23%) and were responsive to immunotherapy.

Conclusions: DPPX antibodies are predominantly IgG1 and IgG4 and associate with cognitive-mental deficits and symptoms of CNS hyperexcitability that are usually preceded by diarrhea, other gastrointestinal symptoms, and weight loss. The disorder is responsive to immunotherapy, and this is supported by the reversibility of the antibody effects in cultured neurons.
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http://dx.doi.org/10.1212/WNL.0000000000003796DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5379928PMC
April 2017

Cerebellar ataxia and autoantibodies restricted to glutamic acid decarboxylase 67 (GAD67).

J Neuroimmunol 2016 11 5;300:15-17. Epub 2016 Oct 5.

Service of Neurology, Hospital Clínic, Universitat de Barcelona, Barcelona, Spain; Centro de Investigación Biomédica en Red en Enfermedades Raras (CIBERER), Spain. Electronic address:

Cerebellar ataxia is one of the most frequent syndromes associated with autoantibodies against glutamic acid decarboxylase (GAD-ab). Antibodies recognize the isoform GAD65, which is the standard biomarker, but additional immunoreactivity against GAD67 is found in high proportion of patients with GAD-ab-associated neurological disorders. We describe the case of a 59-year-old woman who presented with pancerebellar syndrome of subacute onset (9weeks to nadir). In the etiological study, high titers of GAD-ab were found, but these only recognized the GAD67 isoform and not the GAD65. Screening of GAD67-ab should be considered in late-onset cerebellar ataxia when GAD65-ab are absent.
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http://dx.doi.org/10.1016/j.jneuroim.2016.09.019DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5831398PMC
November 2016

Anti-LGI1-associated cognitive impairment: Presentation and long-term outcome.

Neurology 2016 Aug 27;87(8):759-65. Epub 2016 Jul 27.

From the Neuroimmunology Program (H.A., T.A., M.P.-P., L.S., E.M.-H., M.H., A.S., J.D., F.G.), August Pi Sunyer Biomedical Research Institute (IDIBAPS), Hospital Clínic, University of Barcelona, Spain; Department of Neurology (E.L., J.D.), University of Pennsylvania, Philadelphia; and Catalan Institution for Research and Advanced Studies (ICREA) (J.D.), Barcelona, Spain.

Objective: We investigated a series of patients with LGI1 antibody (Ab)-related cognitive deterioration to determine the clinical presentation, long-term outcome, and LGI1 Ab evolution.

Methods: We retrospectively analyzed the clinical information of 76 patients with LGI1 Ab-related cognitive deterioration. Presenting syndromes were classified as limbic encephalitis (LE), non-LE, or encephalopathy (normal MRI and no CSF pleocytosis). Frequency of relapses and clinical outcome were assessed in 48 patients with prolonged follow-up (median 39 months, range 18-200).

Results: Sixty-three patients (83%) developed LE, 3 (4%) non-LE, and 10 (13%) encephalopathy. All patients received steroids, IV immunoglobulins (Ig), or both. At 2 years, 17 (35%; 95% CI 21%-49%) fully recovered, 17 (35%) became functionally independent but not at baseline or were unable to return to work, 11 (23%) required assistance because of moderate or severe cognitive deficits, and 3 (6%) died. Predictors of bad outcome included no response to initial immunotherapy (odds ratio 23.0, 95% CI 2.4-215.6, p = 0.006) and clinical relapses (odds ratio 10.2, 95% CI 1.0-100.1, p = 0.047) that occurred in 13 patients (27%). In all patients, the LGI1 Abs were IgG4 and usually detectable in both serum and CSF (only CSF, 8%). Abs remained positive in serum of 4 of 16 patients with long-term follow-up; 3 of these 4 patients fully recovered and none showed class switch to IgG1.

Conclusions: Up to 13% of patients with LGI1 Abs develop cognitive impairment without criteria of encephalitis. After immunotherapy, only 35% of patients return to their baseline cognitive function. Serum LGI1 Abs may remain detectable after full clinical recovery.
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http://dx.doi.org/10.1212/WNL.0000000000003009DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4999321PMC
August 2016