Publications by authors named "Nuria Solà-Valls"

44 Publications

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

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

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

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

Protective effects of 4-aminopyridine in experimental optic neuritis and multiple sclerosis.

Brain 2020 04;143(4):1127-1142

NeuroCure Clinical Research Center and Experimental and Clinical Research Center, Charité - Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health and Max Delbrueck Center for Molecular Medicine, Berlin, Germany.

Chronic disability in multiple sclerosis is linked to neuroaxonal degeneration. 4-aminopyridine (4-AP) is used and licensed as a symptomatic treatment to ameliorate ambulatory disability in multiple sclerosis. The presumed mode of action is via blockade of axonal voltage gated potassium channels, thereby enhancing conduction in demyelinated axons. In this study, we provide evidence that in addition to those symptomatic effects, 4-AP can prevent neuroaxonal loss in the CNS. Using in vivo optical coherence tomography imaging, visual function testing and histologic assessment, we observed a reduction in retinal neurodegeneration with 4-AP in models of experimental optic neuritis and optic nerve crush. These effects were not related to an anti-inflammatory mode of action or a direct impact on retinal ganglion cells. Rather, histology and in vitro experiments indicated 4-AP stabilization of myelin and oligodendrocyte precursor cells associated with increased nuclear translocation of the nuclear factor of activated T cells. In experimental optic neuritis, 4-AP potentiated the effects of immunomodulatory treatment with fingolimod. As extended release 4-AP is already licensed for symptomatic multiple sclerosis treatment, we performed a retrospective, multicentre optical coherence tomography study to longitudinally compare retinal neurodegeneration between 52 patients on continuous 4-AP therapy and 51 matched controls. In line with the experimental data, during concurrent 4-AP therapy, degeneration of the macular retinal nerve fibre layer was reduced over 2 years. These results indicate disease-modifying effects of 4-AP beyond symptomatic therapy and provide support for the design of a prospective clinical study using visual function and retinal structure as outcome parameters.
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http://dx.doi.org/10.1093/brain/awaa062DOI Listing
April 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

Telemedicine assessment of long-term cognitive and functional status in anti-leucine-rich, glioma-inactivated 1 encephalitis.

Neurol Neuroimmunol Neuroinflamm 2020 03 17;7(2). Epub 2019 Dec 17.

From the Neuroimmunology Program (N.S.-V., H.A., E.S., A.S., J.D., F.G.), Institut d'Investigació Biomèdica August Pi i Sunyer (IDIBAPS), Hospital Clinic; Neuroimmunology Unit (N.S.-V., D.E., Y.B., A.S.), Service of Neurology, Hospital Clinic, University of Barcelona; Alzheimer's Disease and Other Cognitive Disorders Unit (A.L., R.S.-V.), Service of Neurology, Hospital Clínic; Institut d'Investigacions Biomediques August Pi i Sunyer (IDIBAPS), University of 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 assess the feasibility of a structured telephone interview examining the long-term cognitive and functional status in anti-leucine-rich, glioma-inactivated 1 (LGI1) encephalitis.

Methods: Telephone interviews were conducted with 37 patients after a median follow-up of 87 months from disease onset and 23 healthy controls matched for age and sex. Cognitive status was assessed with the telephone Mini-Mental State Examination (t-MMSE) and 3 tests exploring verbal memory, fluency, and executive function. Functional status was evaluated with the Functional Activities Questionnaire and the modified Rankin Scale (mRS). Patients were classified as normal, with mild cognitive impairment (MCI), or with dementia based on cognitive and functional status. Assessment of the cognitive reserve was performed with a structured questionnaire. Logistic regression analysis was applied to identify predictors of cognitive impairment.

Results: Telephone interviews were successful in 36/37 (97%) patients. Cognitive impairment was detected in 27 (75%) including 17 with MCI and 10 with dementia. Eight (29%) patients would have been misclassified using only the t-MMSE. Twenty-six (72%) patients were functionally independent according to the mRS, but only 9 (35%) were cognitively normal. Independent predictors for long-term cognitive impairment were a low cognitive reserve (OR = 1.36, 95% CI: 1.05-1.76; = 0.02) and bilateral hippocampal hyperintensity at initial MRI (OR = 27.03, 95% CI: 1.87-390; = 0.02).

Conclusions: Telemedicine is a feasible tool to assess the cognitive and functional outcome in patients with anti-LGI1 encephalitis. Cognitive impairment is often missed if only functional scales are used. Premorbid cognitive reserve and MRI with bilateral hippocampal hyperintensity were predictors for long-term cognitive impairment.
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http://dx.doi.org/10.1212/NXI.0000000000000652DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6943366PMC
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

Evaluation of treatment response in adults with relapsing MOG-Ab-associated disease.

J Neuroinflammation 2019 Jul 2;16(1):134. Epub 2019 Jul 2.

Service de Neurologie, Sclérose en Plaques, Pathologies de la Myéline et Neuro-Inflammation, Hôpital Neurologique Pierre Wertheimer Hospices Civils de Lyon, Lyon, France.

Background: Myelin oligodendrocyte glycoprotein antibodies (MOG-Ab) are related to several acquired demyelinating syndromes in adults, but the therapeutic approach is currently unclear. We aimed to describe the response to different therapeutic strategies in adult patients with relapsing MOG-Ab-associated disease.

Methods: This is a retrospective study conducted in France and Spain including 125 relapsing MOG-Ab patients aged ≥ 18 years. First, we performed a survival analysis to investigate the relapse risk between treated and non-treated patients, performing a propensity score method based on the inverse probability of treatment weighting. Second, we assessed the annualised relapse rates (ARR), Expanded Disability Status Scale (EDSS) and visual acuity pre-treatment and on/end-treatment.

Results: Median age at onset was 34.1 years (range 18.0-67.1), the female to male ratio was 1.2:1, and 96% were Caucasian. At 5 years, 84% (95% confidence interval [CI], 77.1-89.8) patients relapsed. At the last follow-up, 66 (52.8%) received maintenance therapy. Patients initiating immunosuppressants (azathioprine, mycophenolate mophetil [MMF], rituximab) were at lower risk of new relapse in comparison to non-treated patients (HR, 0.41; 95CI%, 0.20-0.82; p = 0.011). Mean ARR (standard deviation) was reduced from 1.05(1.20) to 0.43(0.79) with azathioprine (n = 11; p = 0.041), from 1.20(1.11) to 0.23(0.60) with MMF (n = 11; p = 0.033), and from 1.08(0.98) to 0.43(0.89) with rituximab (n = 26; p = 0.012). Other immunosuppressants (methotrexate/mitoxantrone/cyclophosphamide; n = 5), or multiple sclerosis disease-modifying drugs (MS-DMD; n = 9), were not associated with significantly reduced ARR. Higher rates of freedom of EDSS progression were observed with azathioprine, MMF or rituximab.

Conclusion: In adults with relapsing MOG-Ab-associated disease, immunosuppressant therapy (azathioprine, MMF and rituximab) is associated with reduced risk of relapse and better disability outcomes. Such an effect was not found in the few patients treated with MS-DMD.
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http://dx.doi.org/10.1186/s12974-019-1525-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6607517PMC
July 2019

Immune tolerance in multiple sclerosis and neuromyelitis optica with peptide-loaded tolerogenic dendritic cells in a phase 1b trial.

Proc Natl Acad Sci U S A 2019 04 8;116(17):8463-8470. Epub 2019 Apr 8.

Center of Neuroimmunology, Institut d'Investigacions Biomediques August Pi Sunyer, 08036 Barcelona, Spain;

There are adaptive T-cell and antibody autoimmune responses to myelin-derived peptides in multiple sclerosis (MS) and to aquaporin-4 (AQP4) in neuromyelitis optica spectrum disorders (NMOSDs). Strategies aimed at antigen-specific tolerance to these autoantigens are thus indicated for these diseases. One approach involves induction of tolerance with engineered dendritic cells (tolDCs) loaded with specific antigens. We conducted an in-human phase 1b clinical trial testing increasing concentrations of autologous tolDCs loaded with peptides from various myelin proteins and from AQP4. We tested this approach in 12 patients, 8 with MS and 4 with NMOSD. The primary end point was the safety and tolerability, while secondary end points were clinical outcomes (relapses and disability), imaging (MRI and optical coherence tomography), and immunological responses. Therapy with tolDCs was well tolerated, without serious adverse events and with no therapy-related reactions. Patients remained stable clinically in terms of relapse, disability, and in various measurements using imaging. We observed a significant increase in the production of IL-10 levels in PBMCs stimulated with the peptides as well as an increase in the frequency of a regulatory T cell, known as Tr1, by week 12 of follow-up. In this phase 1b trial, we concluded that the i.v. administration of peptide-loaded dendritic cells is safe and feasible. Elicitation of specific IL-10 production by peptide-specific T cells in MS and NMOSD patients indicates that a key element in antigen specific tolerance is activated with this approach. The results warrant further clinical testing in larger trials.
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http://dx.doi.org/10.1073/pnas.1820039116DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6486735PMC
April 2019

Correction to: Usefulness of MOG-antibody titres at first episode to predict the future clinical course in adults.

J Neurol 2019 Apr;266(4):816

Service de neurologie, sclérose en plaques, pathologies de la myéline et neuro-inflammation and Centre de référence pour les maladies inflammatoires rares du cerveau et de la moelle (MIRCEM), Hôpital Neurologique Pierre Wertheimer Hospices Civils de Lyon, 59 boulevard Pinel, BRON cedex, 69677, Lyon, France.

The original version of this article unfortunately contained a mistake.
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http://dx.doi.org/10.1007/s00415-019-09215-1DOI Listing
April 2019

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

Usefulness of MOG-antibody titres at first episode to predict the future clinical course in adults.

J Neurol 2019 Apr 3;266(4):806-815. Epub 2019 Jan 3.

Service de neurologie, sclérose en plaques, pathologies de la myéline et neuro-inflammation and Centre de référence pour les maladies inflammatoires rares du cerveau et de la moelle (MIRCEM), Hôpital Neurologique Pierre Wertheimer Hospices Civils de Lyon, 59 boulevard Pinel, BRON cedex, 69677, Lyon, France.

Objective: To analyze whether myelin oligodendrocyte glycoprotein antibody (MOG-Ab) titres at onset of the disease were different according to the clinical phenotype at presentation, and to investigate whether the titres were associated with risk of further relapses or predicted clinical outcome in adult patients. Finally, we assessed an alternative method to the classical measurement of MOG-Ab levels by serial dilutions.

Methods: This is a retrospective study including 79 MOG-Ab-positive adult patients, whose samples were obtained at first episode. MOG-Ab were tested by cell-based assay. HEK293 cells were transfected (tHEK293) with human-MOG plasmid. Non-tHEK293 cells were used as negative controls. Assessment of antibody titres was performed by serial dilution, and delta mean fluorescence intensity ratio signal (MOG-ratio ΔMFI) by flow cytometry. MOG-ratio ΔMFI was calculated as follows: (MFI tHEK293cells- MFI non-tHEK293cells)/MFI non-tHEK293cells. MOG-ratio ΔMFI was calculated from the first serum dilution at 1:320. The association between MOG-Ab titres and risk of relapse was analyzed by Cox regression. The association between MOG-Ab titres and visual or motor disability at last follow-up was performed by binary logistic regression. Poor visual outcome was defined when patients displayed some degree of visual disability (visual acuity [VA] < 20/20) and poor motor outcome when patients displayed some degree of motor disability (Disability Status Scale [DSS] > 1). We also investigated correlations between MOG-Ab titres and MOG-ratio ΔMFI.

Results: MOG-Ab titres were higher in Caucasians than in those with other ethnicities, and in patients with a more severe VA (VA ≤ 20/100) or motor disability (DSS ≥ 3.0) at onset (p = 0.006, 0.034, and 0.058, respectively). MOG-Ab titres were not associated with risk of relapses or with the final clinical outcome. MOG-ratio ΔMFI correlated with MOG-Ab titres in the whole cohort (ρ = 0.90; p < 0.001), and when stratified by initial clinical phenotype.

Conclusion: High MOG-Ab titres at onset are associated with a more severe presentation, but do not predict the future disease course. MOG-ratio ΔMFI is an alternative and straightforward method to determine MOG-Ab levels.
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http://dx.doi.org/10.1007/s00415-018-9160-9DOI Listing
April 2019

Spanish validation of the telephone assessed Expanded Disability Status Scale and Patient Determined Disease Steps in people with multiple sclerosis.

Mult Scler Relat Disord 2019 Jan 19;27:333-339. Epub 2018 Nov 19.

Center of Neuroimmunology, Service of Neurology, Hospital Clinic Barcelona and Neuroimmunology Program, Institut d'Investigació Biomèdica August Pi i Sunyer (IDIBAPS), University of Barcelona. Villarroel 170, 08036, Barcelona, Spain.

Background: The Expanded Disability Status Scale (EDSS) and Patient Determined Disease Steps (PDDS) are two of the most widely disability scales used in multiple sclerosis (MS). When physical visits are unavailable, remote evaluation through telephone interview may be helpful. We aimed to translate both scales into Spanish, and to 1) validate the telephone EDSS and PDDS, and 2) explore the association pattern between both telephone questionnaires.

Methods: 103 patients underwent a neurological examination to generate the EDSS and completed the PDDS questionnaire. Telephone questionnaires (EDSS, PDDS) were performed within 15 days. Feasibility and psychometric properties of both telephone questionnaires included internal consistency, acceptability, inter-rater agreement and validity. Test-retest reliability was evaluated in 36 patients.

Results: Both scales showed excellent internal consistency and test-retest reliability. The agreement between conventional and telephone assessments in ambulatory impaired patients (EDSS > 4.0) was good for EDSS (kappa = 0.72) and excellent for PDDS (kappa = 0.93); fully ambulatory patients (EDSS ≤ 4.0) showed lower values (kappa = 0.24, and 0.54, respectively). Full agreement was higher for telephone PDDS than telephone EDSS (78% vs 44%). Overestimation of disability was more frequent in fully ambulatory patients. Strong correlation was found between telephone questionnaires (rho = 0.88; p < 0.001). The pattern of association was not isomorphic, but a PDDS cut-off of 3 identified with high accuracy patients with ambulatory impairment.

Discussion: Telephone EDSS and PDDS questionnaires for Spanish patients are valid tools to assess disability status in MS and offer complementary information. Patients with ambulatory impairment are those who benefit the most from a remote assessment.
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http://dx.doi.org/10.1016/j.msard.2018.11.018DOI Listing
January 2019

Magnetic resonance markers of tissue damage related to connectivity disruption in multiple sclerosis.

Neuroimage Clin 2018 12;20:161-168. Epub 2018 Jul 12.

Center of Neuroimmunology, Laboratory of Advanced Imaging in Neuroimmunological Diseases, Barcelona, Spain. Electronic address:

Patients with multiple sclerosis (MS) display reduced structural connectivity among brain regions, but the pathogenic mechanisms underlying network disruption are still unknown. We aimed to investigate the association between the loss of diffusion-based structural connectivity, measured with graph theory metrics, and magnetic resonance (MR) markers of microstructural damage. Moreover, we evaluated the cognitive consequences of connectivity changes. We analysed the frontoparietal network in 102 MS participants and 25 healthy volunteers (HV). MR measures included radial diffusivity (RD), as marker of demyelination, and ratios of myo-inositol, -acetylaspartate and glutamate+glutamine with creatine in white (WM) and grey matter as markers of astrogliosis, neuroaxonal integrity and glutamatergic neurotoxicity. Patients showed decreased global and local efficiency, and increased assortativity (p < 0.01) of the network, as well as increased RD and myo-inositol, and decreased -acetylaspartate in WM compared with HV (p < 0.05). In patients, the age-adjusted OR of presenting abnormal global and local efficiency was increased for each increment of 0.01 points in RD and myo-inositol, while it was decreased for each increment of 0.01 points in -acetylaspartate (the increase of -acetylaspartate reduced the risk of having abnormal connectivity), all in WM. In a multiple logistic regression analysis, the OR of presenting abnormal global efficiency was 0.95 (95% confidence interval, CI: 0.91-0.99, p = 0.011) for each 0.01 increase in -acetylaspartate, and the OR of presenting abnormal local efficiency was 1.39 (95% CI: 1.14-1.71, p = 0.001) for each 0.01 increase in RD. Patients with abnormal efficiency had worse performance in attention, working memory and processing speed (p < 0.05). In conclusion, patients with MS exhibit decreased structural network efficiency driven by diffuse microstructural impairment of the WM, probably related to demyelination, astroglial and neuroaxonal damage. The accumulation of neuroaxonal pathological burden seems to magnify the risk of global network collapse, while demyelination may contribute to the regional disorganization. These network modifications have negative consequences on cognition.
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http://dx.doi.org/10.1016/j.nicl.2018.07.012DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6072676PMC
January 2019

Combined walking outcome measures identify clinically meaningful response to prolonged-release fampridine.

Ther Adv Neurol Disord 2018 10;11:1756286418780007. Epub 2018 Jun 10.

Service of Neurology, Hospital Clinic, University of Barcelona, Spain Neuroimmunology Program, Institut d'Investigació Biomèdica August Pi i Sunyer (IDIBAPS), Barcelona, Spain.

Background: Gait impairment is common in multiple sclerosis (MS) and negatively impacts patients' health-related quality of life (HRQoL). Prolonged-release fampridine (PR-fam) improves walking speed, but it is unclear which walking measures are the most suitable for identifying treatment response. Our aim was to assess the effect of PR-fam and the outcome measures that best identify short- and long-term clinically meaningful response.

Methods: We conducted a prospective study in 32 MS patients treated with PR-fam for a year. The assessments at 2 weeks, 3, 6 and 12 months included: timed 25-foot walk (T25FW), 6-minute walk test (6MWT), MS Walking Scale-12 (MSWS-12), a five-level version of the EuroQoL-5 dimensions, and accelerometry. PR-fam response was defined as an improvement in T25FW ⩾20%.

Results: Twenty-five (78%) patients were considered responders after 2 weeks of PR-fam and improved significantly in all measures. Responders to T25FW and MSWS-12 ( = 19) showed a significant improvement in HRQoL and accelerometer data compared with responders only to T25FW ( = 6). At 1 year, 15/20 (75%) patients remained responders, but only those with permanent response to T25FW and MSWS-12 ( = 8; 53%) showed a significant improvement in 6MWT and HRQoL.

Conclusion: The combination of T25FW and MSWS-12 identify better those patients with a clinically significant benefit of PR-fam.
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http://dx.doi.org/10.1177/1756286418780007DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6024337PMC
June 2018

Assessing Biological and Methodological Aspects of Brain Volume Loss in Multiple Sclerosis.

JAMA Neurol 2018 10;75(10):1246-1255

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

Importance: Before using brain volume loss (BVL) as a marker of therapeutic response in multiple sclerosis (MS), certain biological and methodological issues must be clarified.

Objectives: To assess the dynamics of BVL as MS progresses and to evaluate the repeatability and exchangeability of BVL estimates with Jacobian Integration (JI) and Functional Magnetic Resonance Imaging of the Brain (FMRIB) Software Library (FSL) (specifically, the Structural Image Evaluation, Using Normalisation, of Atrophy-Cross-Sectional [SIENA-X] tool or FMRIB's Integrated Registration and Segmentation Tool [FIRST]).

Design, Setting, And Participants: A cohort of patients who had either clinically isolated syndrome or MS was enrolled from February 2011 through October 2015. All underwent a series of annual magnetic resonance imaging (MRI) scans. Images from 2 cohorts of healthy volunteers were used to evaluate short-term repeatability of the MRI measurements (n = 34) and annual BVL (n = 20). Data analysis occurred from January to May 2017.

Main Outcomes And Measures: The goodness of fit of different models to the dynamics of BVL throughout the MS disease course was assessed. The short-term test-retest error was used as a measure of JI and FSL repeatability. The correlations (R2) of the changes quantified in the brain using JI and FSL, together with the accuracy of the annual BVL cutoffs to discriminate patients with MS from healthy volunteers, were used to measure compatibility of imaging methods.

Results: A total of 140 patients with clinically isolated syndrome or MS were enrolled, including 95 women (67.9%); the group had a median (interquartile range) age of 40.7 (33.6-48.1) years. Patients underwent 4 MRI scans with a median (interquartile range) interscan period of 364 (351-379) days. The 34 healthy volunteers (of whom 18 [53%] were women; median [IQR] age, 33.5 [26.2-42.5] years) and 20 healthy volunteers (of whom 10 [50%] were women; median [IQR] age, 33.0 [28.7-39.2] years) underwent 2 MRI scans within a median (IQR) of 24.5 (0.0-74.5) days and 384.5 (366.3-407.8) days for the short-term and long-term MRI follow-up, respectively. The BVL rates were higher in the first 5 years after MS onset (R2 = 0.65 for whole-brain volume change and R2 = 0.52 for gray matter volume change) with a direct association with steroids (β = 0.280; P = .02) and an inverse association with age at MS onset, particularly in the first 5 years (β = 0.015; P = .047). The reproducibility of FSL (SIENA) and JI was similar for whole-brain volume loss, while JI gave more precise, less biased estimates for specific brain regions than FSL (SIENA-X and FIRST). The correlation between whole-brain volume loss using JI and FSL was high (R2 = 0.92), but the same correlations were poor for specific brain regions. The area under curve of the whole-brain volume change to discriminate between patients with MS and healthy volunteers was similar, although the thresholds and accuracy index were distinct for JI and FSL.

Conclusions And Relevance: The proposed BVL threshold of less than 0.4% per year as a marker of therapeutic efficiency should be reconsidered because of the different dynamics of BVL as MS progresses and because of the limited reproducibility and variability of estimates using different imaging methods.
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http://dx.doi.org/10.1001/jamaneurol.2018.1596DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6233851PMC
October 2018

Predictors of vision impairment in Multiple Sclerosis.

PLoS One 2018 17;13(4):e0195856. Epub 2018 Apr 17.

Department of Neurology and Institut d'Investigacions Biomèdiques August Pi Sunyer (IDIBAPS), University of Barcelona, Barcelona, Spain.

Visual impairment significantly alters the quality of life of people with Multiple Sclerosis (MS). The objective of this study was to identify predictors (independent variables) of visual outcomes, and to define their relationship with neurological disability and retinal atrophy when assessed by optical coherence tomography (OCT). We performed a cross-sectional analysis of 119 consecutive patients with MS, assessing vision using high contrast visual acuity (LogMar), 2.5% and 1.25% low contrast visual acuity (Sloan charts), and color vision (Hardy-Rand-Rittler plates). Quality of vision is a patient reported outcome based on an individual's unique perception of his or her vision and was assessed with the Visual Functioning Questionnaire-25 (VFQ-25) with the 10 neuro-ophthalmologic items. MS disability was assessed using the expanded disability status scale (EDSS), the MS functional composite (MSFC) and the brief repetitive battery-neuropsychology (BRB-N). Retinal atrophy was assessed using spectral domain OCT, measuring the thickness of the peripapillar retinal nerve fiber layer (pRNFL) and the volume of the ganglion cell plus inner plexiform layer (GCIPL). The vision of patients with MS was impaired, particularly in eyes with prior optic neuritis. Retinal atrophy (pRNFL and GCIPL) was closely associated with impaired low contrast vision and color vision, whereas the volume of the GCIPL showed a trend (p = 0.092) to be associated with quality of vision. Multiple regression analysis revealed that EDSS was an explanatory variable for high contrast vision after stepwise analysis, GCIPL volume for low contrast vision, and GCIPL volume and EDSS for color vision. The explanatory variables for quality of vision were high contrast vision and color vision. In summary, quality of vision in MS depends on the impairment of high contrast visual acuity and color vision due to the disease.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0195856PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5903642PMC
July 2018

Liver injury and glatiramer acetate, an uncommon association: case report and literature review.

Ther Adv Neurol Disord 2017 Nov 26;10(11):367-372. Epub 2017 Jul 26.

Neuroimmunology Program, Service of Neurology, Hospital Clinic, Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS) and Universitat de Barcelona, Barcelona, Spain.

We report the case of a 65-year-old woman who presented with a 1-month history of progressive paraparesia associated with a thoracic lesion with irregular ring-like gadolinium enhancement. Biopsy of the lesion confirmed the demyelinating origin and brain magnetic resonance imaging showed additional lesions demonstrative of dissemination in space. Immunomodulatory therapy with glatiramer acetate (GA) was started after having a second relapse 2 months later. Shortly after initiation, the patient developed acute hepatitis. Liver function tests returned to normal values 5 months after discontinuation and the patient was diagnosed with drug-induced liver injury (DILI) associated with GA. A literature review identified 11 previous cases of GA-related liver injury associated with two specific mechanisms: DILI (seven cases) and autoimmune hepatitis (four cases). Despite the fact that GA hepatic toxicity is uncommon and laboratory monitoring is not required during GA therapy, it should be considered at least in some special conditions such as comorbidities and previous history of DILI associated with other drugs.
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http://dx.doi.org/10.1177/1756285617722352DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5642009PMC
November 2017

Clinical profile of patients with paraneoplastic neuromyelitis optica spectrum disorder and aquaporin-4 antibodies.

Mult Scler 2018 11 18;24(13):1753-1759. Epub 2017 Sep 18.

Service of Neurology, Hospital Clinic, University of Barcelona, Barcelona, Spain Neuroimmunology Program, Institut d'Investigació Biomèdica August Pi i Sunyer (IDIBAPS), Barcelona, Spain.

Background: In a minority of patients with neuromyelitis optica spectrum disorder (NMOSD) and aquaporin-4 antibodies (AQP4-IgG), the disease has a paraneoplastic origin. It is unknown whether these patients have distinctive clinical features.

Objective: To report the clinical features of a series of patients with paraneoplastic NMOSD and AQP4-IgG and to review previously reported cases.

Methods: Retrospective analysis of clinical records of 156 patients with NMOSD and AQP4-IgG and review of previously reported patients with paraneoplastic NMOSD and AQP4-IgG. Paraneoplastic patients were defined as those with cancer identified within 2 years of the diagnosis of NMOSD.

Results: Five (3.2%) of 156 patients had paraneoplastic NMOSD, and 12 previously reported patients were identified. The most common tumors were adenocarcinoma of the lung (five patients) and breast (five). Compared with the 151 non-paraneoplastic NMOSD patients, the 17 (5 current cases and 12 previously reported) were older at symptom onset (median age = 55 (range: 17-87) vs 40 (range: 10-77) years; p = 0.006), more frequently male (29.4% vs 6.6%; p = 0.009), and presented with severe nausea and vomiting (41.2% vs 6.6%; p < 0.001). The frequency of longitudinal extensive transverse myelitis (LETM) as heralding symptom was similar in both groups, but patients with paraneoplastic NMOSD were older than those with non-paraneoplastic NMOSD (median age: 63 (range: 48-73) vs 43 (range: 14-74) years; p = 0.001).

Conclusion: Patients, predominantly male, with NMOSD and AQP4-IgG should be investigated for an underlying cancer if they present with nausea and vomiting, or LETM after 45 years of age.
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http://dx.doi.org/10.1177/1352458517731914DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5832634PMC
November 2018

Vanishing spinal cord after varicella-zoster virus myelitis.

Neurol Neuroimmunol Neuroinflamm 2017 Jul 5;4(4):e364. Epub 2017 Jun 5.

Neurology Service (M.S., J.A., N.S.-V., Y.B., S.L., F.G., A.S.) and Radiology Department (J.B.), Hospital Clinic de Barcelona; and Neurology Service (J.S.), Althaia, Manresa, Barcelona, Spain.

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http://dx.doi.org/10.1212/NXI.0000000000000364DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5459790PMC
July 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

Structural networks involved in attention and executive functions in multiple sclerosis.

Neuroimage Clin 2017 5;13:288-296. Epub 2016 Dec 5.

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

Attention and executive deficits are disabling symptoms in multiple sclerosis (MS) that have been related to disconnection mechanisms. We aimed to investigate changes in structural connectivity in MS and their association with attention and executive performance applying an improved framework that combines high order probabilistic tractography and anatomical exclusion criteria postprocessing. We compared graph theory metrics of structural networks and fractional anisotropy (FA) of white matter (WM) connections or edges between 72 MS subjects and 38 healthy volunteers (HV) and assessed their correlation with cognition. Patients displayed decreased network transitivity, global efficiency and increased path length compared with HV ( < 0.05, corrected). Also, nodal strength was decreased in 26 of 84 gray matter regions. The distribution of nodes with stronger connections or hubs of the network was similar among groups except for the right pallidum and left insula, which became hubs in patients. MS subjects presented reduced edge FA widespread in the network, while FA was increased in 24 connections ( < 0.05, corrected). Decreased integrity of frontoparietal networks, deep gray nuclei and insula correlated with worse attention and executive performance (r between 0.38 and 0.55,  < 0.05, corrected). Contrarily, higher strength in the right transverse temporal cortex and increased FA of several connections (mainly from cingulate, frontal and occipital cortices) were associated with worse functioning (r between - 0.40 and - 0.47,  < 0.05 corrected). In conclusion, structural brain connectivity is disturbed in MS due to widespread impairment of WM connections and gray matter structures. The increased edge connectivity suggests the presence of reorganization mechanisms at the structural level. Importantly, attention and executive performance relates to frontoparietal networks, deep gray nuclei and insula. These results support the relevance of network integrity to maintain optimal cognitive skills.
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http://dx.doi.org/10.1016/j.nicl.2016.11.026DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5192049PMC
November 2017

Impairment of decision-making in multiple sclerosis: A neuroeconomic approach.

Mult Scler 2017 Nov 7;23(13):1762-1771. Epub 2016 Dec 7.

Center of Neuroimmunology, Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Department of Neurology, Hospital Clinic of Barcelona, Barcelona, Spain/Department of Neurology, University of California-San Francisco (UCSF), San Francisco, CA, USA.

Objective: To assess the decision-making impairment in patients with multiple sclerosis (MS) and how they relate to other cognitive domains.

Methods: We performed a cross-sectional analysis in 84 patients with MS, and 21 matched healthy controls using four tasks taken from behavioral economics: (1) risk preferences, (2) choice consistency, (3) delay of gratification, and (4) rate of learning. All tasks were conducted using real-world reward outcomes (food or money) in different real-life conditions. Participants underwent cognitive examination using the Brief Repeatable Battery-Neuropsychology.

Results: Patients showed higher risk aversion (general propensity to choose the lottery was 0.51 vs 0.64, p = 0.009), a trend to choose more immediate rewards over larger but delayed rewards ( p = 0.108), and had longer reactions times ( p = 0.033). Choice consistency and learning rates were not different between groups. Progressive patients chose slower than relapsing patients. In relation to general cognitive impairments, we found correlations between impaired decision-making and impaired verbal memory ( r = 0.29, p = 0.009), visual memory ( r = -0.37, p = 0.001), and reduced processing speed ( r = -0.32, p = 0.001). Normalized gray matter volume correlated with deliberation time ( r = -0.32, p = 0.005).

Conclusion: Patients with MS suffer significant decision-making impairments, even at the early stages of the disease, and may affect patients' quality and social life.
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http://dx.doi.org/10.1177/1352458516682103DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6047072PMC
November 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

Usefulness of optical coherence tomography to distinguish optic neuritis associated with AQP4 or MOG in neuromyelitis optica spectrum disorders.

Ther Adv Neurol Disord 2016 Sep 15;9(5):436-40. Epub 2016 Aug 15.

Center of Neuroimmunology and Service of Neurology, August Pi Sunyer Institute of Biomedical Research, Hospital Clinic of Barcelona, University of Barcelona, Barcelona, Spain.

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http://dx.doi.org/10.1177/1756285616655264DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4994783PMC
September 2016

Clinical spectrum associated with MOG autoimmunity in adults: significance of sharing rodent MOG epitopes.

J Neurol 2016 Jul 4;263(7):1349-60. Epub 2016 May 4.

Service of Neurology, Department of Neurology, Hospital Clínic, University of Barcelona, Villarroel 170, 08036, Barcelona, Spain.

The aim of this study was to report the clinical spectrum associated with antibodies to myelin oligodendrocyte glycoprotein (MOG) in adult patients, and to assess whether phenotypic variants are dependent on recognition of rodent MOG epitopes. We retrospectively analyzed the features, course and outcome of 56 patients whose samples were investigated by brain tissue immunohistochemistry and cell-based assays using human and rodent MOG. The median age at symptom onset was 37 years (range 18-70); 35 patients (63 %) were female. After a median follow-up of 43 months (range 4-554), only 14 patients (25 %) developed a neuromyelitis optica spectrum disorder (NMOSD), 27 patients (47 %) retained the initial diagnosis of isolated optic neuritis, 7 (12 %) of longitudinally extensive transverse myelitis, and 2 (4 %) of acute disseminated encephalomyelitis; 6 patients (11 %) developed atypical demyelinating syndromes (4 had relapsing episodes of short myelitis lesions which in one occurred with optic neuritis; 1 had relapsing brainstem symptoms, and 1 relapsing demyelinating encephalomyelitis). The course was frequently associated with relapses (71 %) and good outcome. Twenty-seven patients (49 %) had antibodies that recognized rodent MOG epitopes, and 9 of them (16 %) showed a myelin staining pattern in rodent tissue. Only the myelin staining pattern was linked to NMOSD (p = 0.005). In conclusion, MOG autoimmunity in adult patients associates with a clinical spectrum wider than the one expected for patients with suspected NMOSD and overall good outcome. Antibodies to rodent MOG epitopes do not associate with any phenotypic variant.
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http://dx.doi.org/10.1007/s00415-016-8147-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5831396PMC
July 2016

Neuromyelitis optica spectrum disorders: Comparison according to the phenotype and serostatus.

Neurol Neuroimmunol Neuroinflamm 2016 Jun 14;3(3):e225. Epub 2016 Apr 14.

Authors' affiliations are listed at the end of the article.

Objective: To (1) determine the value of the recently proposed criteria of neuromyelitis optica (NMO) spectrum disorder (NMOSD) that unify patients with NMO and those with limited forms (NMO/LF) with aquaporin-4 immunoglobulin G (AQP4-IgG) antibodies; and (2) investigate the clinical significance of the serologic status in patients with NMO.

Methods: This was a retrospective, multicenter study of 181 patients fulfilling the 2006 NMO criteria (n = 127) or NMO/LF criteria with AQP4-IgG (n = 54). AQP4-IgG and myelin oligodendrocyte glycoprotein immunoglobulin G (MOG-IgG) antibodies were tested using cell-based assays.

Results: Patients were mainly white (86%) and female (ratio 6.5:1) with median age at onset 39 years (range 10-77). Compared to patients with NMO and AQP4-IgG (n = 94), those with NMO/LF presented more often with longitudinally extensive transverse myelitis (LETM) (p < 0.001), and had lower relapse rates (p = 0.015), but similar disability outcomes. Nonwhite ethnicity and optic neuritis presentation doubled the risk for developing NMO compared with white race (p = 0.008) or LETM presentation (p = 0.008). Nonwhite race (hazard ratio [HR] 4.3, 95% confidence interval [CI] 1.4-13.6) and older age at onset were associated with worse outcome (for every 10-year increase, HR 1.7, 95% CI 1.3-2.2). Patients with NMO and MOG-IgG (n = 9) had lower female:male ratio (0.8:1) and better disability outcome than AQP4-IgG-seropositive or double-seronegative patients (p < 0.001).

Conclusions: In patients with AQP4-IgG, the similar outcomes regardless of the clinical phenotype support the unified term NMOSD; nonwhite ethnicity and older age at onset are associated with worse outcome. Double-seronegative and AQP4-IgG-seropositive NMO have a similar clinical outcome. The better prognosis of patients with MOG-IgG and NMO suggests that phenotypic and serologic classification is useful.
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http://dx.doi.org/10.1212/NXI.0000000000000225DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4841645PMC
June 2016