Ann Neurol. 2021 Dec 30. doi: 10.1002/ana.26290. Online ahead of print.
Authors: Vinzenz Fleischer, Dumitru Ciolac, Gabriel Gonzalez-Escamilla, Matthias Grothe, Sebastian Strauss, Lara S Molina Galindo, Angela Radetz, Anke Salmen, Carsten Lukas, Luisa Klotz, Sven G Meuth, Antonios Bayas,
Friedemann Paul, Hans-Peter Hartung, Christoph Heesen, Martin Stangel, Brigitte Wildemann, Florian Then Bergh,
Björn Tackenberg, Tania Kümpfel, Uwe K Zettl, Matthias Knop, Hayrettin Tumani, Heinz Wiendl, Ralf Gold , Stefan Bittner, Frauke Zipp, Sergiu Groppa, Muthuraman Muthuraman, German Competence Network Multiple Sclerosis (KKNMS)
Objective: Fatigue is a frequent and severe symptom in multiple sclerosis (MS), but its pathophysiological origin remains incompletely understood. We aimed to examine the predictive value of subcortical gray matter volumes for fatigue severity at disease onset and after four years by applying structural equation mod- eling (SEM).
Methods: This multi-center cohort study included 601 treatment-naive MS patients after the ﬁrst demyelinat- ing event. All patients underwent a standardized 3T MRI protocol. A subgroup of 230 patients with available clinical follow-up data after four years was also analyzed. Associations of subcortical volumes (included into SEM) with MS-related fatigue were studied regarding their predictive value. In addition, subcortical regions that have a central role in the brain network (hubs) were determined through structural covariance network (SCN) analysis.
Results: Predictive causal modeling identiﬁed volumes of the caudate (s [standardized path coefﬁ- cient]=0.763, p=0.003 [left]; s=0.755, p=0.006 [right]), putamen (s=0.614, p=0.002 [left]; s=0.606, p=0.003 [right]) and pallidum (s=0.606, p=0.012 [left]; s=0.606, p=0.012 [right]) as prognostic factors for fatigue severity in the cross-sectional cohort. Moreover, the volume of the pons was additionally predictive for fatigue severity in the longitudinal cohort (s=0.605, p=0.013). In the SCN analysis, network hubs in patients with fatigue worsening were detected in the putamen (p=0.008 [left]; p=0.007 [right]) and pons (p=0.0001).
Interpretation: We unveiled predictive associations of speciﬁc subcortical gray matter volumes with fatigue in an early and initially untreated MS cohort. The colocalization of these subcortical structures with network hubs suggests an early role of these brain regions in terms of fatigue evolution.
• PMID: 34967456
Clin Neurol Neurosurg. 2021 Dec 21;213:107099. doi: 10.1016/j.clineuro.2021.107099. Online ahead of print.
Authors: Justin Jain, Maksim Son, Derek B Debicki, Mandar Jog, Courtney S Casserly, Jorge G Burneo, Adrian Budhram
Epilepsia partialis continua (EPC) is a rare phenomenon in multiple sclerosis (MS). We describe a patient with relapsing-remitting MS and three episodes of EPC, with refractoriness to anti-seizure drugs but corticoste- roid-responsiveness. No lesions likely attributable to her episodes of EPC were seen on 1.5 Tesla MRI, which we hypothesize was due to the small volume of presumed cortical/juxtacortical lesions involving the primary motor cortex. The association with relapsing-remitting disease, corticosteroid responsiveness, and dissemi- nation of episodes of EPC in both space and time in our patient suggest that EPC may represent a distinct relapse phenotype in MS.
• PMID: 34959105
CNS Drugs. 2021 Dec 23;1-15. doi: 10.1007/s40263-021-00887-w. Online ahead of print.
Authors: Dejan Jakimovski, Samreen Awan, Svetlana P Eckert, Osman Farooq, Bianca Weinstock-Guttman
Pediatric-onset multiple sclerosis (POMS) is a rare neuroinﬂammatory and neurodegenerative disease that has a signiﬁcant impact on long-term physical and cognitive patient outcomes. A small percentage of multiple sclerosis (MS) diagnoses occur before the age of 18 years. Before treatment initiation, a careful differential diagnosis and exclusion of other similar acquired demyelinating syndromes such as anti-aquaporin-4-associated neuromyelitis optica spectrum disorder (AQP4-NMOSD) and myelin oligodendrocyte glycoprotein antibody spectrum disorder (MOGSD) is warranted. The recent 2017 changes to the McDonald criteria can successfully predict up to 71% of MS diagnoses and have good speciﬁcity of 95% and sensitivity of 71%. Additional measures such as the presence of T1-weighted hypointense lesions and/or contrast-enhancing lesions signiﬁcantly increase the accuracy of diagnosis. In adults, early use of disease-modifying therapies (DMTs) is instrumental to a better long-term prognosis, including lower rates of relapse and disability worsening, and numerous FDA-approved therapies for adult-onset MS are available. However, unlike their adult counterparts, the development, testing, and regulatory approval of POMS treatments have been signiﬁcantly slower and hindered by logistic and/or ethical considerations. Currently, only two MS DMTs (ﬁngolimod and teriﬂunomide) have been tested in large phase III trials and approved by regulatory agencies for use in POMS. First-line therapies not approved by the FDA for use in children (interferon-β and glatiramer acetate) are also commonly used and result in a signiﬁcant reduction in inﬂammatory activity when compared with non-treated POMS patients. An increasing number of POMS patients are now treated with moderate efﬁcacy therapies such as dimethyl fumarate and high-efﬁcacy therapies such as natalizumab, anti-CD20 monoclonal antibodies, anti-CD52 monoclonal antibodies, and/or autologous hematopoietic stem cell transplantation. These high-efﬁcacy DMTs generally provide additional reduction in inﬂammatory activity when compared with the ﬁrst-line medications (up to 62% of relapse-rate reduction). Therefore, a number of phase II and III trials are currently investigating their efﬁcacy and safety in POMS patients. In this review, we discuss potential changes in the regulatory approval process for POMS patients that are recommended for DMTs already approved for the adult MS population, including smaller sample size for pharmacokinetic/pharmacodynamic studies, MRI-centered primary outcomes, and/or inclusion of teenagers in the adult trials.
• PMID: 34940954
Eur J Neurol. 2021 Dec 22. doi: 10.1111/ene.15227. Online ahead of print.
Authors: Svenja Klinsing, Yavor Yalachkov, Christian Foerch
Background: The transition from relapsing-remitting (RRMS) to secondary progressive (SPMS) multiple sclerosis is not well deﬁned. Different deﬁnitions and tools to identify SPMS have been proposed. Meanwhile, early diagnosis of "active" SPMS is getting progressively more important as pharmaceutical treatment options are being developed. In this study, we compared different classiﬁcation methods regarding their accuracy to reliably identify "active SPMS".
Methods: Independent from previous diagnostic classiﬁcation, we descriptively analyzed the disease course (regarding relapses, progression and MR-activity) in 208 consecutive multiple sclerosis patients treated in our MS outpatient clinic in 2018. Patients were reclassiﬁed according to different SPMS criteria and tools. Diagnostic accuracy to identify patients with "active SPMS" was determined.
Results: Comparing the tools to each other, signiﬁcant variability in the number of patients identiﬁed as having SPMS as well as in the proportion of these patients having "active SPMS" was noted. Applying both diagnostic criteria "SPMS" and "active disease" reduced the sensitivity to identify patients with active progressive disease in all approaches.
Conclusion: We propose to lessen the emphasis on the label "SPMS" in favor of the more open term "active progressive disease" to simplify the process of identiﬁcation of patients who may beneﬁt from immune therapy.
• PMID: 34939266
Neurology. 2021 Dec 22;10.1212/WNL.0000000000013245. doi: 10.1212/WNL.0000000000013245. Online ahead of print.
Authors: Ali I Mirza, Feng Zhu, Natalie Knox, Jessica D Forbes, Gary Van Domselaar, Charles N Bernstein, Morag Graham, Ruth Ann Marrie, Janace Hart , E Ann Yeh, Douglas Arnold, Amit Bar-Or, Julia O'Mahony, Yinshan Zhao, William Hsiao, Brenda Banwell, Emmanuelle Waubant, Helen Tremlett
Background and objectives: Little is known of the functional potential of the gut microbiome in pediatric-onset multiple sclerosis (MS). We performed metagenomic analyses using stool samples from individuals with pediatric-onset MS and unaffected controls.
Methods: Persons ≤21 years old enrolled in the Canadian Pediatric Demyelinating Disease Network providing a stool sample were eligible. Twenty MS patients (McDonald criteria) with symptom onset <18 years were matched to 20 controls by sex, age (±3 years), stool consistency, and race. Microbial taxonomy and functional potentials were estimated from stool sample-derived metagenomic reads and compared by disease status (MS vs controls) and disease-modifying drug (DMD) exposure using alpha-diversity, relative abundance, and prevalence using Wilcoxon rank-sum, ALDEx2 and Fisher's exact tests, respectively.
Results: Individuals with MS were aged 13.6 years (mean) at symptom onset and 8 were DMD naïve. Mean ages at stool sample were 16.1 and 15.4 years for MS and control participants, respectively; 80% were girls. Alpha-diversity of enzymes and proteins did not differ by disease or DMD status (p>0.20), but metabolic pathways, gene annotations and microbial taxonomy did. Individuals with MS (vs controls) exhibited higher methanogenesis prevalence (odds ratio=10, p=0.044), and Methanobrevibacter abundance (log2 fold-change[LFC]=1.7, p=0.0014), but lower homolactic fermentation abundance (LFC=-0.48, p=0.039). Differences by DMD status included lower phosphate butyryltransferase for DMD-naïve vs exposed MS patients (LFC=-1.0, p=0.033).
Discussion: The gut microbiome's functional potential and taxonomy differed between individuals with pediatric-onset MS versus controls, including higher prevalence of a methane-producing pathway from Archaea and depletion of the lactate fermentation pathway. DMD exposure was associated with butyrate-producing enzyme enrichment. Together these ﬁndings indicate that the gut microbiome of individuals with MS may have a disturbed functional potential.
• PMID: 34748672
Eur J Neurol. 2021 Dec 22. doi: 10.1111/ene.15226. Online ahead of print.
Authors: Pauline Bosco-Lévy, Caroline Foch, Angela Grelaud, Meritxell Sabidó, Clémentine Lacueille, Jérémy Jové, Emmanuelle Boutmy, Patrick Blin
Background: Studies have not yet found conclusive results on the risk of cancer in patients with Multiple Sclerosis (MS). This study aimed to compare the incidence of all cancers and of speciﬁc types of cancer between MS patients and the general population by age and by sex.
Methods: All prevalent MS patients identiﬁed between 2008-2014 in the nationwide French healthcare database (SNDS) and without history of malignancy, were included in a cohort study followed-up until cancer occurrence, date of death or 31 December 2015, whichever came ﬁrst. MS patients were matched based on sex and year of birth, to non-MS controls from the general population without cancer before index date. Incidence rate was reported per 100,000 person-year (PY) and risk of cancer was estimated by type of cancer, age and sex using a Cox model (Hazard Ratio, HRs and its 95% conﬁdence intervals, 95%CI).
Results: Overall, 576 cancers per 100,000 PY were observed in MS patients versus 424 per 100,000 PY in the control population. The risk of cancer was higher among MS patients than among population controls whether considered overall (HR: 1.36, 95%CI: 1.29-1.43) or for prostate (HR: 2.08, 95%CI: 1.68-2.58), colorectal and anal (HR: 1.35, 95%CI: 1.16-1.58), trachea bronchus and lung (HR: 2.36, 95%CI: 1.96-2.84), and to a lesser extent, breast cancer (HR: 1.12, 95%CI: 1.03-1.23).
Conclusion: MS patients were associated with increased risk of cancer compared to population controls.
• PMID: 34936169
Eur J Neurol. 2021 Dec 20. doi: 10.1111/ene.15220. Online ahead of print.
Authors: Marcus W Koch , Jop Mostert, Pavle Repovic, James D Bowen, Jerry S Wolinsky, Fred D Lublin, Eva Strijbis, Gary Cutter
Background and purpose: Treatment success in relapsing-remitting multiple sclerosis (RRMS) is generally determined using relapse frequency and magnetic resonance imaging (MRI) activity in the ﬁrst 6 or 12 months on treatment. The association of these deﬁnitions of short-term treatment success with disability worsening and disease activity in the longer term is unclear. In this study, we investigated risk factors associated with early ﬁrst-line treatment failure in RRMS, and the association of early treatment failure with subsequent disability worsening or "no evidence of disease activity" (NEDA-3) status.
Methods: We used data from CombiRx (clinicaltrials.gov identiﬁer NCT00211887) to investigate risk factors associated with early treatment failure, and the association of early treatment failure at 6 and 12 months with subsequent disability worsening or NEDA-3 at 36 months.
Results: CombiRx included 1008 treatment-naïve participants with RRMS, who were randomly assigned to treatment with glatiramer acetate, interferon beta, or the combination of both. Early treatment failure at 6 or 12 months by several deﬁnitions was associated with NEDA-3 failure at 36 months, but not with subsequent disability worsening at 36 months. Expanded Disability Status Scale (EDSS) was the only baseline characteristic associated with the risk of disability worsening at 36 months. Approximately 70% of NEDA-3 failures occurred due to MRI activity, and <10% occurred due to EDSS worsening.
Conclusions: Our investigation shows that current deﬁnitions of early treatment failure in RRMS are unrelated to patient-relevant disability worsening at 36 months of follow-up. Further research into useful deﬁnitions of treatment success and failure in RRMS is needed.
• PMID: 34927308
J Neuroimmunol. 2022 Jan 15;362:577788. doi: 10.1016/j.jneuroim.2021.577788. Epub 2021 Dec 13.
Authors: Ivan Adamec, Dunja Rogić, Monika-Gabriele Penz, Carola Braun, Mario Habek
Objectives: TTo report clinical outcome, development of humoral and T-cell mediated immunity in convalescent COVID-19 people with multiple sclerosis (pwMS) treated with ofatumumab in the ALITHIOS study from a single center.
Methods: Testing for SARS-Cov2 IgG antibodies was performed on two occasions with at least three months apart between the two testing. During the second antibody testing, interferon-γ ELISpot was used to assess cellular immunity.
Results: All four subjects had mild COVID-19 infection without any sequelae. In all subjects except subject 2, COVID-19 was conﬁrmed with PCR. Subjects 1, 2 and 4 had normal levels of IgM and IgG without measurable counts of CD19 cells prior to COVID-19. Subject 3 administered the last dose of ofatumumab 24 days prior to COVID-19 symptoms, but had a gap of 28 weeks of ofatumumab application beforehand due to low IgM levels. Subject 4 received COVID-19 vaccinations before second testing, so second testing and T-cell immunity testing were not performed. Subjects who were CD19 depleted did not had measurable levels of SARS-Cov2 IgG antibodies. Subject 3 had ﬁrst and second SARS-COV2 titer of 118 U/ml and > 250 U/ml, respectively. All three pwMS showed T cell immunity against SARS-CoV-2. Quotient of basal spots divided by interferon-γ secreting spot forming units were 4, 8 and 14.7 SI in subjects 1, 2 and 3, respectively (>3 considered reactive).
Conclusion: While no antibody response was observed in pwMS who were CD19+ lymphocyte depleted, T cell immunity against SARS-CoV-2 was observed in all three pwMS treated with ofatumumab.
• PMCID: PMC8667348
J Neuroimmunol. 2022 Jan 15;362:577760. doi: 10.1016/j.jneuroim.2021.577760. Epub 2021 Nov 5.
Authors: E Mascia, F Clarelli, A Zauli, C Guaschino, M Sorosina, N Barizzone, C Basagni, S Santoro, L Ferrè,
S Bonﬁglio, D Biancolini, M Pozzato , F R Guerini, A Protti, M Liguori, L Moiola, D Vecchio, N Bresolin, G Comi, M Filippi, F Esposito, S D'Alfonso, F Martinelli-Boneschi
Background: Multiple Sclerosis (MS) is a chronic inﬂammatory and neurodegenerative demyelinating disease of the central nervous system. It is a complex and heterogeneous disease caused by a combination of genetic and environmental factors, and it can cluster in families.
Objective: to evaluate at gene-level the aggregate contribution of predicted damaging low-frequency and rare variants to MS risk in multiplex families.
Methods: We performed whole exome sequencing (WES) in 28 multiplex MS families with at least 3 MS cases (81 affected and 42 unaffected relatives) and 38 unrelated healthy controls. A gene-based burden test was then performed, focusing on two sets of candidate genes: i) literature-driven selection and ii) data-driven selection.
Results: We identiﬁed 11 genes enriched with predicted damaging low-frequency and rare variants in MS compared to healthy individuals. Among them, UBR2 and DST were the two genes with the strongest enrichment (p = 5 × 10-4 and 3 × 10-4, respectively); interestingly enough the association signal in UBR2 is driven by rs62414610, which was present in 25% of analysed families.
Conclusion: Despite limitations, this is one of the ﬁrst studies evaluating the aggregate contribution of predicted damaging low-frequency and rare variants in MS families using WES data. A replication effort in independent cohorts is warranted to validate our ﬁndings and to evaluate the role of identiﬁed genes in MS pathogenesis.
• PMID: 34922125
Brain. 2021 Dec 17;awab454. doi: 10.1093/brain/awab454. Online ahead of print.
Authors: Antonio Carotenuto, Laura Cacciaguerra, Elisabetta Pagani, Paolo Preziosa, Massimo Filippi, Maria A Rocca
Recent evidences showed the existence of a central nervous system 'waste clearance' system, deﬁned as glymphatic system. Glymphatic abnormalities have been described in several neurodegenerative conditions, including Alzheimer's and Parkinson's disease. Glymphatic function has not been thoroughly explored in multiple sclerosis, where neurodegenerative processes are intermingled with inﬂammatory processes. We aimed to investigate glymphatic system function in multiple sclerosis and to evaluate its association with clinical disability, disease course, demyelination and neurodegeneration, quantiﬁed using different MRI techniques. In this retrospective study, we enrolled 71 multiple sclerosis patients (49 relapsing-remitting and 22 progressive multiple sclerosis) and 32 age- and sex- matched healthy controls. All subjects underwent neurological and MRI assessment including high-resolution T1, T2 and double inversion recovery sequences, diffusion- and susceptibility weighted imaging. We calculated the diffusion along perivascular space index, a proxy for glymphatic function, cortical and deep gray matter volume, white and cortical gray matter lesion volume and normal appearing white matter microstructural damage. Multiple sclerosis patients showed an overall lower diffusion along perivascular space index vs healthy controls (estimated mean difference: -0.09, P = 0.01). Both relapsing-remitting and progressive multiple sclerosis patients had lower diffusion along perivascular space index vs healthy controls (estimated mean difference: -0.06, P = 0.04 for relapsing-remitting and -0.19, P =
0.001 for progressive multiple sclerosis patients). Progressive multiple sclerosis patients showed lower diffusion along perivascular space index vs relapsing-remitting multiple sclerosis patients (estimated mean difference: -0.09, P = 0.03). In multiple sclerosis patients, lower diffusion along perivascular space index was associated with more severe clinical disability (r = -0.45, P = 0.001) and longer disease duration (r = -0.37, P = 0.002). Interestingly, we detected a negative association between diffusion along perivascular space index and disease duration in the ﬁrst 4.13 years of the disease course (r = -0.38, P = 0.04) without any association thereafter (up to 34 years of disease duration). Lower diffusion along perivascular space index was associated with higher white (r = -0.36, P = 0.003) and cortical (r = -0.41, P = 0.001) lesion volume, more severe cortical (r
= 0.30, P = 0.007) and deep (r = 0.42, P = 0.001) gray matter atrophy, reduced fractional anisotropy (r = 0.42, P
= 0.001) and increased mean diffusivity (r = -0.45, P = 0.001) in the normal-appearing white matter. Our results suggest that the glymphatic system is impaired in multiple sclerosis, especially in progressive stages. Impaired glymphatic function was associated with measures of both demyelination and neurodegeneration and reﬂects a more severe clinical disability. These ﬁndings suggest that glymphatic impairment may be a pathological mechanism underpinning multiple sclerosis. The dynamic interplay with other pathological substrates of the disease deserves further investigation.
Keywords: glymphatic system; multiple sclerosis; neurodegeneration; pathology; progression.
• PMID: 34
Radiology. 2021 Dec 14;211528. doi: 10.1148/radiol.211528. Online ahead of print.
Authors: Anitha Priya Krishnan, Zhuang Song, David Clayton, Laura Gaetano, Xiaoming Jia, Alex de Crespigny, Thomas Bengtsson, Richard A D Carano
Background: Deep learning-based segmentation could facilitate rapid and reproducible T1 lesion load assessments, which is crucial for disease management in multiple sclerosis (MS). T1 unenhancing and contrast-enhancing lesions in MS are those that enhance or do not enhance after administration of a gadolinium-based contrast agent at T1-weighted MRI.
Purpose: To develop deep learning models for automated assessment of T1 unenhancing and contrast-enhancing lesions; to investigate if joint training improved performance; to reproduce a known ocrelizumab treatment response; and to evaluate the association of baseline T1-weighted imaging metrics with clinical outcomes in relapsing MS clinical trials.
Materials and Methods: Joint and individual deep learning models (U-Nets) were developed retrospectively on multimodal MRI data sets from large multicenter OPERA trials of relapsing MS (August 2011 to May 2015). The joint model included cross-network connections and a combined loss function. Models were trained on OPERA I data sets with three-fold cross-validation. OPERA II data sets were the internal test set. Dice coefﬁcients, lesion true-positive and false-positive rates, and areas under the receiver operating characteristic curve (AUCs) were used to evaluate model performance. Association of baseline imaging metrics with clinical outcomes was assessed with Cox proportional hazards models.
Results: A total of 796 patients (3030 visits; mean age, 37 years ± 9; 521 women) from the OPERA II trial were evaluated. The joint model achieved a mean Dice coefﬁcient of 0.77 and 0.74, lesion true-positive rate of 0.88 and 0.86, and lesion false-positive rate of 0.04 and 0.19 for T1 contrast-enhancing and T1 unenhancing lesion segmentation, respectively. Joint training improved performance for smaller T1 contrast-enhancing lesions (≤0.06 mL; individual training AUC: 0.75; joint training AUC: 0.87; P < .001). A signiﬁcant ocrelizumab treatment effect (P < .001) was seen in reducing the mean number of T1 contrast-enhancing lesions at 24, 48, and 96 weeks (manual assessment at 24 weeks: 10 lesions in 366 patients with ocrelizumab, 141 lesions in 355 patients with interferon, 93% reduction; manual assessment at 48 weeks: six lesions in 355 patients with ocrelizumab, 150 lesions in 317 patients with interferon, 96% reduction; manual assessment at 96 weeks: ﬁve lesions in 340 patients with ocrelizumab, 157 lesions in 294 patients with interferon, 97% reduction; joint model assessment at 24 weeks: 19 lesions in 365 patients with ocrelizumab, 128 lesions in 354 patients with interferon, 86% reduction; joint model assessment at 48 weeks: 14 lesions in 355 patients with ocrelizumab, 121 lesions in 317 patients with interferon, 90% reduction; joint model assessment at 96 weeks: 10 lesions in 340 patients with ocrelizumab, 144 lesions in 294 patients with interferon, 94% reduction) and the mean number of new T1 unenhancing lesions across all follow-up examinations (manual assessment: 504 lesions in 1060 visits for ocrelizumab-treated patients, 1438 lesions in 965 visits for interferon-treated patients, 68% reduction; joint model assessment: 205 lesions in 1053 visits for ocrelizumab-treated patients, 661 lesions in 957 visits for inter
CNS Drugs. 2021 Dec 11. doi: 10.1007/s40263-021-00875-0. Online ahead of print.
Authors: Serena Palmeri, Marta Ponzano, Federico Ivaldi, Alessio Signori, Caterina Lapucci , Valentina Casella, Maria Teresa Ferrò, Tiziana Vigo, Matilde Inglese, Giovanni Luigi Mancardi, Antonio Uccelli, Alice Laroni
Background: Deﬁning immune mechanisms leading to multiple sclerosis (MS) is difﬁcult, due to the great inter-individual difference in immune system responses. The anti-CD52 antibody alemtuzumab transiently abolishes differences in immune parameters among individuals, allowing analysis of subsequent immune cell repopulation patterns, and their possible role in MS.
Objective: To evaluate the correlation between innate and adaptive immune cell subsets and disease activity in MS in the context of treatment with alemtuzumab.
Methods: A two-center observational cohort of patients treated with alemtuzumab underwent immune proﬁling of T, B, and natural killer (NK) cells, biomarker, clinical and radiological follow-up.
Results: After treatment, the percentage of NK and B cells increased; NK, T- and B-cell populations underwent a profound rearrangement. Within the effector T-cell compartment, treatment led to a transient decrease, followed by an increase, of T-helper 1 cells, and to a transient decrease of T-helper 17 cells. Within the T-regulatory compartment, naïve T-regulatory cells increased. Within the B-cell compartment, memory B cells and mature B cells decreased, whereas transitional B cells increased. Within the NK cell compartment, CD56bright NK cells increased. Subjects without disease activity had a greater decrease in serum NfL and greater NK cell/CD3+ T cell ratio. NK cell numbers at baseline and after treatment inﬂuenced reconstitution of T and B cells, being inversely correlated with the reconstitution of proinﬂammatory CD3+ T cells and mature B cells, and directly correlated to the increase in transitional B cells.
Conclusions: The results of this study provide novel evidence that NK cells inﬂuence reconstitution of adaptive immune cells upon alemtuzumab and that patients with a successful response to alemtuzumab have an early immune reconstitution dominated by NK cells.
• PMID: 34894339
Brain. 2021 Dec 11;awab320. doi: 10.1093/brain/awab320. Online ahead of print.
Authors: Achilles Ntranos, Hye-Jin Park, Maureen Wentling, Vladimir Tolstikov, Mario Amatruda, Benjamin Inbar, Seunghee Kim-Schulze, Carol Frazier, Judy Button, Michael A Kiebish 3 , Fred Lublin, Keith Edwards, Patrizia Casaccia
The identiﬁcation of intestinal dysbiosis in patients with neurological and psychiatric disorders has highlighted the importance of gut-brain communication and yet, the question regarding the identity of the components responsible for this cross talk remains open. We previously reported that relapsing remitting multiple sclerosis patients (RRMS) treated with dimethyl fumarate have a prominent depletion of the gut microbiota, thereby suggesting that studying the composition of plasma and cerebrospinal ﬂuid (CSF) samples from these patients may help to identify microbially derived metabolites. We used a functional xenogeneic assay consisting of cultured rat neurons exposed to CSF samples collected from multiple sclerosis patients before and after dimethyl fumarate treatment to assess neurotoxicity and then conducted a metabolomic analysis of plasma and CSF samples to identify metabolites with differential abundance. A weighted correlation network analysis, allowed us to identify groups of metabolites, present in plasma and CSF samples, whose abundance correlated with the neurotoxic potential of the CSF. This analysis identiﬁed the presence of phenol and indole group metabolites of bacterial origin (e.g. p-cresol-sulfate, indoxyl-sulfate and N-phenylacetylglutamine) as potentially neurotoxic and decreased by treatment. Chronic exposure of cultured neurons to these metabolites impaired their ﬁring rate and induced axonal damage, independent from mitochondrial dysfunction and oxidative stress, thereby identifying a novel pathway of neurotoxicity. Clinical, radiological and cognitive test metrics were also collected in treated patients at follow-up visits. Improved MRI metrics, disability and cognition were only detected in dimethyl fumarate -treated RRMS patients. The levels of the identiﬁed metabolites of bacterial origin (p-cresol-sulfate, indoxyl-sulfate and N-phenyl-acetyl-glutamine) were inversely correlated to MRI measurements of cortical volume and directly correlated to the levels of neuroﬁlament light chain, an established biomarker of neurodegeneration. Our data suggest that phenol and indole derivatives from the catabolism of tryptophan and phenylalanine are microbially derived metabolites, which may mediate gut-brain communication and induce neurotoxicity in multiple sclerosis.
• PMID: 34894211
Rev Neurol (Paris). 2021 Dec 7;S0035-3787(21)00766-9. doi: 10.1016/j.neurol.2021.09.008. Online ahead of print.
Authors: D Veillard, E Le Page, J Epstein, S Wiertlewski, P Gallien, S Hamonic, M Debouverie, G Edan
Introduction: Evaluating the quality of the care pathway for patients with chronic diseases, such as multiple sclerosis (MS), is an important issue. Process indicators are a recognized method for evaluating professional practices. However, these tools have been little developed in the ﬁeld of MS, and few data are available. The aim of this study was to describe, retrospectively, with validated indicators, the quality of the care pathway in a population-based cohort of 700 patients with the ﬁrst manifestations of the disease occurring between January 1, 2000 and December 31, 2001 and during the ﬁrst 10 years of disease.
Method: This assessment was based on 48 indicators speciﬁc to MS. The information required for the calculation of each indicator was collected from the source ﬁles of the 700 patients of the cohort.
Results: Data for the 10 years of follow-up were collected for 80% of the patients. In total, 36 indicators were calculated. These results reveal that there is room for improvement, particularly in terms of the initial assessment, access to ophthalmological evaluation, employment, obtaining an evaluation of the need for rehabilitation and access to such care.
Conclusion: The results of this survey provide access to unprecedented new data in France, that professionals and patients can appropriate to improve the targeting of actions, to improve the quality of care further for patients with MS in France. We propose to continue this process by submitting, for discussion, a targeted list of updated indicators relating to changes in guidelines, and in issues concerning the quality of patient management.
• PMID: 34893353
Neurology. 2021 Dec 8;10.1212/WNL.0000000000013045. doi: 10.1212/WNL.0000000000013045. Online ahead of print.
Authors: Prince Sebastian, Nicolas Cherbuin, Lisa F Barcellos, Shelly Roalstad, Charles Casper, Janace Hart, Gregory S Aaen, Lauren Krupp, Leslie Benson, Mark Gorman, Meghan Candee, Tanuja Chitnis, Manu Goyal, Benjamin Greenberg, Soe Mar, Moses Rodriguez, Jennifer Rubin, Teri Schreiner, Amy Waldman, Bianca Weinstock-Guttman, Jennifer Graves, Emmanuelle Waubant, Robyn Lucas, US Network of Pediatric Multiple Sclerosis Centers
Objective: This study aims to determine the contributions of sun exposure and ultraviolet radiation (UVR) exposure to risk of paediatric-onset multiple sclerosis (MS).
Methods: Children with MS and controls recruited from multiple centres in the USA were matched on sex and age. Multivariable conditional logistic regression was used to investigate the association of time spent outdoors daily in summer, use of sun protection, and ambient summer UVR dose in the year prior to birth and the year prior to diagnosis, with MS risk, adjusting for sex, age, race, birth season, child's skin colour, mother's education, tobacco smoke exposure, being overweight, and Epstein-Barr virus infection.
Results: 332 children with MS (median disease duration: 7.3 months) and 534 controls were included after matching on sex and age. In a fully adjusted model, compared to spending <30 minutes outdoors daily during the most recent summer, greater time spent outdoors was associated with a marked reduction in the odds of developing MS, with evidence of dose-response (30 minutes to 1 hour: adjusted odds ratio (AOR)=0.48, 95% conﬁdence interval [95%CI] 0.23-0.99, p=0.05; 1-2 hours: AOR=0.19, 95%CI 0.09-0.40, p<0.001). Higher summer ambient UVR dose was also protective for MS (AOR=0.76 per kJ/m2, 95%CI 0.62-0.94, p=0.01).
Conclusions: If this is a causal association, spending more time in the sun during summer may be strongly protective against developing paediatric MS, as well as residing in a sunnier location.
• PMID: 34880094
PLoS One. 2021 Dec 8;16(12):e0261050. doi: 10.1371/journal.pone.0261050. eCollection 2021.
Authors: Gustavo Saposnik, Beatriz Del Río, Guillermo Bueno-Gil, Ángel P Sempere, Alejandro Lendínez-Mesa, Alfredo Rodríguez-Antigüedad, María Terzaghi, Nicolás Medrano, Jorge Maurino
Background: Nurse practitioners (NPs) play a critical role in the multidisciplinary management of patients with multiple sclerosis (MS). Neurologists´ behavioral characteristics have been associated with suboptimal clinical decisions. However, limited information is available on their impact among NPs involved in MS care. The aim of this study was to assess nurses´ therapeutic choices to understand behavioral factors inﬂuencing their decision making process.
Methods: A non-interventional, cross-sectional, web-based study was conducted. NPs actively involved in the care of patients with MS were invited to participate in the study by the Spanish Society of Neurology Nursing. Participants answered questions regarding their standard practice and therapeutic management of seven simulated relapsing-remitting MS (RRMS) case scenarios. A behavioral battery was used to measure participants´ life satisfaction, mood, positive social behaviors, feeling of helpfulness, attitudes toward adoption of evidence-based innovations, occupational burnout, and healthcare-related regret. The outcome of interest was therapeutic inertia (TI), deﬁned as the lack of treatment escalation when there is clinical and radiological evidence of disease activity. A score to quantify TI was created based on the number of simulated scenarios where treatment intensiﬁcation was warranted.
Results: Overall, 331 NPs were invited to participate, 130 initiated the study, and 96 (29%) completed the study. The mean age (SD) was 44.6 (9.8) years and 91.7% were female. Seventy-three participants (76.0%) felt their opinions had a signiﬁcant inﬂuence on neurologists´ therapeutic decisions. Sixteen NPs (16.5%) showed severe emotional exhaustion related to work and 13 (13.5%) had depressive symptoms. The mean (SD) TI score was
0.97 (1.1). Fifty-six of NPs showed TI in at least one case scenario. Higher years of nursing experience (p = 0.014), feeling of helpfulness (p = 0.014), positive attitudes toward innovations (p = 0.046), and a higher intensity of care-related regret (p = 0.021) were associated with a lower risk of TI (adjusted R2 = 0.28). Burnout was associated with higher risk of TI (p = 0.001).
Conclusions: Although NPs cannot prescribe MS treatments in Spain, their behavioral characteristics may inﬂuence the management of patients with RRMS. Continuing education and speciﬁc strategies for reducing occupational burnout may lead to better management skills and improve MS care.
• PMID: 34879095
Ann Neurol. 2021 Dec 8. doi: 10.1002/ana.26281. Online ahead of print.
Authors: Antje Bischof, Nico Papinutto, Anisha Keshavan, Anand Rajesh, Gina Kirkish, Xinheng Zhang, Jacob M Mallott, Carlo Asteggiano, Simone Sacco, Tristan J Gundel, Chao Zhao, William A Stern, Eduardo Caverzasi, Yifan Zhou, Refujia Gomez, Nicholas R Ragan, Adam Santaniello, Alyssa H Zhu,
Jeremy Juwono, Carolyn J Bevan, Riley M Bove, Elizabeth Crabtree, Jeffrey M Gelfand, Douglas S Goodin, Jennifer S Graves, Ari J Green, Jorge R Oksenberg, Emmanuelle Waubant, Michael R Wilson, Scott S Zamvil, University of California, San Francisco MS-EPIC Team; Bruce A Cree, Stephen L Hauser, Roland G Henry
Objective: A major challenge in multiple sclerosis (MS) research is the understanding of silent progression and Progressive MS. Using a novel method to accurately capture upper cervical cord area from legacy brain MRI scans we aimed to study the role of spinal cord and brain atrophy for silent progression and conversion to secondary progressive disease (SPMS).
Methods: From a single-center observational study, all RRMS (n=360) and SPMS (n=47) patients and 80 matched controls were evaluated. RRMS patient subsets who converted to SPMS (n=54) or silently progressed (n=159), respectively, during the 12-year observation period were compared to clinically matched RRMS patients remaining RRMS (n=54) or stable (n=147), respectively. From brain MRI, we assessed the value of brain and spinal cord measures to predict silent progression and SPMS conversion.
Results: Patients who developed SPMS showed faster cord atrophy rates (-2.19 %/year) at least four years before conversion compared to their RRMS matches (-0.88 %/year, p<0.001). Spinal cord atrophy rates decelerated after conversion (-1.63%/year, p=0.010) towards those of SPMS patients from study entry (-1.04%). Each 1% faster spinal cord atrophy rate was associated with 69% (p<0.0001) and 53% (p<0.0001) shorter time to silent progression and SPMS conversion, respectively.
Interpretation: Silent progression and conversion to secondary progressive disease are predominantly related to cervical cord atrophy. This atrophy is often present from the earliest disease stages and predicts the speed of silent progression and conversion to Progressive MS. Diagnosis of SPMS is rather a late recognition of this neurodegenerative process than a distinct disease phase.
• PMID: 34878197
CNS Neurol Disord Drug Targets. 2021 Dec 6. doi: 10.2174/1871527320666211207101113. Online ahead of print.
Authors: Begoña M Escribano, Ana Muñoz-Jurado, Evelio Luque, Cristina Conde, Montse Feijóo, Manuel LaTorre, Manuel E Valdelvira, Paula Buendía, Ana I Giraldo, Javier Caballero-Villarraso, Abel Santamaría, Eduardo Agüera, Isaac Túnez
Background and objectives: Experimental autoimmune encephalomyelitis (EAE) in rats closely reproduces multiple sclerosis (MS), a disease characterized by neuroinﬂammation and oxidative stress, that also appears to extend to other organ compartments. The origin of MS is a matter for discussion, but it would seem that altering certain bacterial populations present in the gut may lead to a proinﬂammatory condition due to the bacterial lipopolysaccharides (LPS) in the so-called brain-gut axis. The casein and lactose in milk confer anti-inﬂammatory properties and immunomodulatory effects. The objectives of this study were: to evaluate the effects of administration of casein and lactose on the oxidative damage and the clinical status caused by EAE, and to verify whether both, casein and lactose, had any effect on the LPS and its transport protein -LBP-.
Methods: Twenty male dark Agouti rats were divided into: control rats (control), EAE rats and EAE rats to which casein and lactose, EAE+casein and EAE+lactose, respectively, were administered. Fifty-one days after casein and lactose administration, the rats were sacriﬁced and different organs were studied (brain, spinal cord, blood, heart, liver, kidney, small and large intestine). In the latter, products derived from oxidative stress were studied (lipid peroxides and carbonylated proteins) as well as the glutathione redox system, various inﬂammation factors (total nitrite, Nuclear Factor-kappa B p065, the Rat Tumour Necrosis Factor-α) and the LPS and LBP values.
Results and conclusion: Casein and lactose administration improved the clinical aspect of the disease at the same time as reducing inﬂammation and oxidative stress, exerting its action on the glutathione redox system or increasing GPx levels.
• PMID: 34875994
J Neurol Sci. 2021 Nov 27;432:120074. doi: 10.1016/j.jns.2021.120074. Online ahead of print.
Authors: Shay Menascu, Aviva Fattal-Valevski, Adi Vaknin-Dembinsky, Ron Milo, Keren Geva, David Magalashvili, Mark Dolev, Shlomo Flecther, Alon Kalron, Shmulik Miron, Chen Hoffmann, Roy Aloni, Michael Gurevich,
Approximately 40% of young-onset multiple sclerosis (MS) patients experience breakthrough disease, which carries a high risk for long-term disability, and requires using therapies beyond traditional ﬁrst-line agents. Despite the increasing use of newer disease-modifying treatments (DMTs) in this population, data are not available to guide the need for escalating DMTs and there is a scarcity of data on the effects of natalizumab in children and young adults with active disease. We performed a retrospective analysis of the rate of No Evidence of Disease Activity (NEDA), tolerability, and safety of natalizumab in a multi-center cohort of 36 children and young adults with highly active MS. All patients had active disease and initiated treatment with natalizumab. The primary endpoint was the rate of achieving NEDA-3 status, within two years of natalizumab treatment. To examine a possible effect of age on the outcome of treatment, outcomes were also analyzed by pre-pubertal (n = 13 children aged 9-13 years) and pubertal subgroups (n = 23 young adolescents aged 14-20 years). The NEDA-3 status of the pre-pubertal group was 92% in the ﬁrst and second year and in the pubertal group - 96% in the ﬁrst year and 92% in the second year. Natalizumab reduced the number and volume of brain lesions in both pre-pubertal and pubertal groups. Treatment was well-tolerated, only 8 patients (22.2%) had adverse events during the 2-year study period. Our analysis shows that natalizumab is effective and well-tolerated in pre-pubertal and pubertal MS patients.
• PMID: 34875473
PLoS One. 2021 Dec 7;16(12):e0261002. doi: 10.1371/journal.pone.0261002. eCollection 2021.
Authors: Miko Valori, Lilja Jansson, Pentti J Tienari
Somatic mutations have a central role in cancer but their role in other diseases such as common autoimmune disorders is not clear. Previously we and others have demonstrated that especially CD8+ T cells in blood can harbor persistent somatic mutations in some patients with multiple sclerosis (MS) and rheumatoid arthritis. Here we concentrated on CD8+ cells in more detail and tested (i) how commonly somatic mutations are detectable, (ii) does the overall mutation load differ between MS patients and controls, and (iii) do the somatic mutations accumulate non-randomly in certain genes? We separated peripheral blood CD8+ cells from newly diagnosed relapsing MS patients (n = 21) as well as matched controls (n = 21) and performed next-generation sequencing of the CD8+ cells' DNA, limiting our search to a custom panel of 2524 immunity and cancer related genes, which enabled us to obtain a median sequencing depth of over 2000x. We discovered nonsynonymous somatic mutations in all MS patients' and controls' CD8+ cell DNA samples, with no signiﬁcant difference in number between the groups (p = 0.60), at a median allelic fraction of 0.5% (range 0.2-8.6%). The mutations showed statistically signiﬁcant clustering especially to the STAT3 gene, and also enrichment to the SMARCA2, DNMT3A, SOCS1 and PPP3CA genes. Known activating STAT3 mutations were found both in MS patients and controls and overall 1/5 of the mutations were previously described cancer mutations. The detected clustering suggests a selection advantage of the mutated CD8+ clones and calls for further research on possible phenotypic effects.
• PMID: 34874980
BMC Neurol. 2021 Dec 2;21(1):468. doi: 10.1186/s12883-021-02396-1.
Authors: Abril Oliva Ramirez, Alexander Keenan, Olivia Kalau, Evelyn Worthington, Lucas Cohen, Sumeet Singh
Background: Multiple sclerosis (MS) is a chronic, demyelinating disease of the central nervous system that results in progressive and irreversible disability. Fatigue is one of the most common MS-related symptoms and is characterized by a persistent lack of energy that impairs daily functioning. The burden of MS-related fatigue is complex and multidimensional, and to our knowledge, no systematic literature review has been conducted on this subject. The purpose of this study was to conduct a systematic literature review on the epidemiology and burden of fatigue in people with multiple sclerosis (pwMS).
Methods: Systematic searches were conducted in MEDLINE, Embase, and Evidence-Based Medicine Reviews to identify relevant studies of fatigue in pwMS. English-language records published from 2010 to January 2020 that met predeﬁned eligibility criteria were included. We initially selected studies that reported quality of life (QoL) and economic outcomes according to categories of fatigue (e.g., fatigued vs non-fatigued). Studies assessing associations between economic outcomes and fatigue as a continuous measure were later included to supplement the available data.
Results: The search identiﬁed 8147 unique records, 54 of which met the inclusion criteria. Of these, 39 reported epidemiological outcomes, 11 reported QoL, and 9 reported economic outcomes. The supplementary screen for economic studies with fatigue as a continuous measure included an additional 20 records. Fatigue prevalence in pwMS ranged from 36.5 to 78.0%. MS-related fatigue was consistently associated with signiﬁcantly lower QoL. Results on the economic impact of fatigue were heterogeneous, but most studies reported a signiﬁcant association between presence or severity of fatigue and employment status, capacity to work, and sick leave. There was a gap in evidence regarding the direct costs of MS-related fatigue and the burden experienced by caregivers of pwMS.
Conclusion: Fatigue is a prevalent symptom in pwMS and is associated with considerable QoL and economic burden. There are gaps in the evidence related to the direct costs of MS-related fatigue and the burden of fatigue on caregivers. Addressing fatigue over the clinical course of the disease may improve health and economic outcomes for patients with MS.
• PMID: 34856949
PLoS One. 2021 Dec 2;16(12):e0261097. doi: 10.1371/journal.pone.0261097. eCollection 2021.
Authors: Max Mimpen, Linda Rolf, Geert Poelmans, Jody van den Ouweland, Raymond Hupperts, Jan Damoiseaux, Joost Smolders
Introduction: A poor 25-hydroxyvitamin D (25(OH)D) status is a much replicated risk factor for developing multiple sclerosis (MS), and several vitamin D-associated single nucleotide polymorphisms (SNPs) have been associated with a higher risk of MS. However, studies on the beneﬁt of vitamin D supplementation in MS show inconclusive results. Here, we explore whether vitamin D-associated SNPs and MS risk alleles confound serological response to vitamin D supplementation.
Methods: 34 participants from the SOLARIUM study consented to genotyping, of which 26 had vitamin D data available. The SOLARIUM study randomised relapsing-remitting MS patients to placebo or 14,000 IU vitamin D3 for 48 weeks. Participants were categorised as either 'carriers' or 'non-carriers' of the risk allele for 4 SNPs: two related to D binding protein (DBP) and associated with lower 25(OH)D levels (rs4588 and rs7041), and two related to vitamin D metabolism enzymes CYP27B1 and CYP24A1 and associated with a higher risk of MS (rs12368653; rs2248359, respectively). 25(OH)D levels were determined at baseline and after 48 weeks.
Results: The DBP-related SNPs showed no difference in 25(OH)D status at baseline, but carriers of the rs7041 risk allele showed lower 25(OH)D-levels compared to non-carriers after 48 weeks of supplementation (median 224.2 vs. 332.0 nmol/L, p = 0.013). For CYP related SNPs, neither showed a difference at baseline, but carriers of the rs12368653 risk allele showed higher 25(OH)D-levels compared to non-carriers after 48 weeks of supplementation (median 304.1 vs. 152.0 nmol/L, p = 0.014).
Discussion: Vitamin D-related SNPs affect the serological response to high-dose vitamin D supplementation. The effects on more common doses of vitamin D, as well as the clinical consequence of this altered response, need to be investigated further.
• PMID: 34855907
Lancet Neurol. 2022 Jan;21(1):12-13. doi: 10.1016/S1474-4422(21)00417-8.
Authors: Erin S Beck, Daniel S Reich
No abstract available
• PMID: 34942123
Brain. 2021 Dec 31;144(12):3552-3554. doi: 10.1093/brain/awab424.
Author: Ari J Green
No abstract available
• PMID: 34927667
Eur J Neurol. 2021 Dec 10. doi: 10.1111/ene.15210. Online ahead of print.
Author: Hans Lassmann
Afﬁliation: Center for Brain Research, Medical University of Vienna, Vienna, Austria.
No abstract available
• PMID: 34890080