REVIEW 13th Post-ECTRIMS Meeting: review of the new developments presented at the 2020 ECTRIMS Congress (I) Óscar Fernández, Xavier Montalban, Yolanda Aladro, Ana Alonso, Rafael Arroyo, Carmen Calles, Tamara Castillo-Triviño, Manuel Comabella, Lucienne Costa-Frossard, Lucía Forero, Ricardo Ginestal, Lamberto Landete, Miguel Llaneza, Sara Llufriu, M. Luisa Martínez-Ginés, José Meca-Lallana, Mar Mendibe, Celia Oreja-Guevara, Agustín Oterino, José M. Prieto, Lluís Ramió-Torrentà, Lucía Romero-Pinel, Nieves Téllez, Alfredo Rodríguez-Antigüedad Introduction. For more than a decade, following the ECTRIMS Congress, the Post-ECTRIMS Meeting has been held in Hospital Regional Universitario de Málaga, Málaga (Ó. Fernández; Spain, where neurologists with expertise in multiple sclerosis (MS) from all over the country meet to review the most rele- A. Alonso). Hospital Universitario vant latest developments presented at the ECTRIMS congress (on this occasion held together with ACTRIMS). Vall d’Hebron- CEMCAT (X. Montalban, M. Comabella); Aim. This article, published in two parts, summarises the presentations that took place at the Post-ECTRIMS Meeting, held Hospital Clínic de Barcelona e online on 16 and 17 October 2020. IDIBAPS (S. Llufriu); Hospital Universitario de Bellvitge, Development. This first part includes the latest results regarding the impact of the environment and lifestyle on risk of MS Barcelona (L. Romero-Pinel). and its clinical course, and the role of epigenetics and genetic factors on these processes. Findings from preclinical and Hospital Universitario de Getafe (Y. Aladro); Hospital Universitario clinical research on the lymphocyte subtypes identified and the involvement of lymphoid follicles and meningeal involve- Quirónsalud (R. Arroyo); Hospital ment in the disease are discussed. Changes in brain structure are addressed at the microscopic and macroscopic levels, Universitario Ramón y Cajal (L. Costa-Frossard); Hospital including results from high-resolution imaging techniques. The latest advances on biomarkers for the diagnosis and prog- Universitario Clínico de Madrid nosis of MS, and on the involvement of the microbiome in these patients are also reported. Finally, results from patient (R. Ginestal); Hospital General Universitario Gregorio Marañón registries on the impact of COVID-19 in MS patients are outlined. (M.L. Martínez-Ginés); Hospital Conclusions. There have been new data on MS risk factors, the impact of MS at the cellular and structural level, the role of Clínico San Carlos-IdISSC-UCM, Madrid (C. Oreja-Guevara). the microbiome in the disease, biomarkers, and the relationship between COVID-19 and MS. Hospital Universitario Son Espases, Palma de Mallorca Key words. ACTRIMS. Congress. ECTRIMS. MS. Multiple sclerosis. Post-ECTRIMS. (C. Calles). Hospital Universitario Donostia, San Sebastián (T. Castillo-Triviño). Hospital Universitario Puerta del Mar, Introduction ganic solvents, passive smoking, shift work, alcohol Cádiz (L. Forero). Hospital and dietary factors on the development of the dis- Universitario Doctor Peset, Valencia (L. Landete). Complejo The 13th edition of the annual Post-ECTRIMS ease, as well as an effect of smoking on its progres- Hospitalario Universitario de Meeting was held on 16 and 17 October 2020. It sion [2]. Ferrol (M. Llaneza); Complejo Hospitalario Universitario was attended by neurologists with expertise in mul- Obesity and some components of metabolic syn- de Santiago de Compostela, tiple sclerosis (MS) from different Spanish centres drome are also associated with increased delay in La Coruña (J.M. Prieto). Hospital who presented the latest developments addressed diagnosis, attack rate, brain and retinal atrophy, and Clínico Universitario Virgen de la Arrixaca, Murcia (J. Meca- at the ECTRIMS-ACTRIMS Congress. This is the disability progression [3-5], with important implica- Lallana). Hospital Universitario first of two articles that summarise the Post-EC- tions for MS management [6]. Cardiovascular risk de Cruces, Bilbao (M. Mendibe, A. Rodríguez-Antigüedad). TRIMS presentations. factors are already associated with brain atrophy in Hospital Universitario Central patients under 50 years of age and have a synergistic de Asturias, Oviedo (A. Oterino). Hospital Universitario Dr. Josep effect if present in combination, even when they Trueta y Hospital Santa Impact of the environment and lifestyle on would be considered mild in isolation [7]. Caterina-IDIBGI, Girona (L. Ramió-Torrentà). Hospital Clínico the risk of MS and its clinical course Air pollutants also play an important role in the Universitario de Valladolid, aetiology of MS. There is an additive interaction be- Valladolid (N. Téllez). Although the aetiology of MS remains unclear, it is tween increased ozone exposure and DRB1 alleles Correspondence: known that the disease is the result of an interac- in the susceptibility to develop paediatric MS [8]. Dr. Óscar Fernández. Instituto de tion between genetic susceptibility and certain en- All these environmental factors appear to interact Investigación Biomédica de Málaga (IBIMA). Hospital vironmental aspects. Along with the risk factors with human leukocyte antigen (HLA) genes, con- Universitario Regional de Málaga. that have already been established [1], there is ferring an increased risk of MS among genetically Universidad de Málaga. Av. de Carlos Haya, s/n. E-29010 Málaga. strong evidence of the influence of exposure to or- susceptible individuals.  www.neurologia.com Rev Neurol 2021; 72 (11): 397-406 397 Ó. Fernández, et al and increased nuclear translocation of HHEX. The Figure 1. Latest developments related to the study of B and T cells. Ag: antigen; CNS: central nervous higher values in some mitochondrial respiration system; EAE: experimental autoimmune encephalitis; GlcNAc: N-acetylglucosamine; mAB: monoclonal parameters observed in patients were more pro- antibody. nounced in rs7923837*AA carriers [14]. The polygenic risk score (PRS) is a quantifiable measure to identify groups of people with increased susceptibility to certain diseases. In an analysis of a cohort of 41,505 MS patients and 26,703 controls, and another cohort of 34 families with one parent and at least one child affected, the PRS differed be- tween patients and controls (first cohort) and clas- sified affected siblings in each family with an accu- racy of 72% (second cohort). The PRS is an effective measure to identify individuals with a high risk of MS at both the population and intra-family levels [15]. Lymphocyte subgroups As of the early stages of MS, the central nervous system (CNS) is infiltrated by cells from the adap- E-mail: Epigenetics and genetic factors tive and innate immune system, including mainly oscar.fernandez.sspa@gmail.com CD8+ T-cells and CD20+ lymphocytes, and to a Acknowledgements: The epigenome as a mediator of external variables lesser extent CD4+ T-cells. Figure 1 shows conclu- The authors would like to thank sions derived from recent findings on T-cell re- Laura Prieto del Val of Dynamic Science for her help in drafting this One of the modes of epigenetic regulation is DNA sponse in MS and in the animal model of experi- article. methylation. In MS patients, external factors such mental autoimmune encephalitis (EAE) [16], po- Funding: as disease-modifying treatment (DMT) or body tential targets for reducing T-cell pathogenesis [17], The drafting of this article was mass index have been shown to affect different cell B-cell mechanisms of action [18, 19] and the B-cell funded by Teva. types by creating cell-specific DNA methylation antigen repertoire in as yet untreated patients [20]. Conflicts of interest: patterns, and epigenetic variations have been found Advances in this field are crucial to understand the OF has received payment for to be present in axonal signalling pathways [9-11]. pathogenesis of the disease and to develop more ef- consultancy work on advisory boards and as a speaker at Epigenome-wide association studies conducted us- fective treatments. meetings, and has also ing deconvolution analysis revealed that epigenetic participated or participates in clinical trials or other research variations in axonal signalling pathways were pres- projects promoted by Biogen-Idec, ent in early stages of MS in specific cells –T-cells, Involvement of lymphoid follicles and Bayer-Schering; Merck-Serono, Teva, Novartis, Roche, Sanofi- B-cells and natural killer cells (NK)– [12]. meningeal compromise Genzyme, Actelion, Almirall, A potential drawback of epigenetic studies is Araclon, Orizon and Ala- confounding bias, as exposure and outcome may Meningeal inflammation is one of the key compo- Diagnostics; XM has received payment for consultancy work, have a common cause. To avoid this, it is proposed nents underlying MS. This inflammation, high in B- travel expenses to attend scientific to use the Mendelian randomisation methodology, cells and compartmentalised within the cerebral meetings, and to participate on Advisory Boards for clinical trials which improves causality inferences and could be sulci, is associated with elevated demyelination and from Actelion, Alexion, Bayer, used when designing clinical trials [13]. damage to the adjacent subpial cortical grey matter Biogen, Celgene-BMS, Excemed, Merck, Sanofi-Genzyme, MedDay (GM). High meningeal inflammation is associated Pharmaceuticals, Multiple Sclerosis Contribution of genetic variants with increased loss of cortical neurons and microg- International Federation, NervGen, National Multiple Sclerosis Society, lia activation in the outer layers of the cortex, close Novartis, Roche-Genentech, Teva Genome-wide association studies have identified a to the limit of the cerebrospinal fluid (CSF)/pia ma- and TG Therapeutics; YA declares total of 233 single nucleotide polymorphisms ter, compared to the inner layers (surface-in gradi- no conflict of interest; AA has been paid professional fees by Biogen, (SNPs) that increase MS susceptibility. One of these ent) [21]. It has been hypothesised that meningeal Merck-Serono, Teva, Novartis, SNPs is rs7923837, located near the HHEX gene. In infiltrates could represent one of the main intrathe- Roche, BMS, Sanofi- Genzyme and Almirall; RA has been paid a study of MS patients, the homozygous AA geno- cal sources of inflammatory factors that, released professional fees by Teva, type of rs7923837 (rs7923837*AA) was found to into the CSF, could induce or exacerbate a patholo- Sanofi-Genzyme, Merck, Novartis,  determine low levels of messenger RNA expression gy of the cortex [22]. A study of patients with un- 398 www.neurologia.com Rev Neurol 2021; 72 (11): 397-406 13th Post-ECTRIMS Meeting: review of the new developments presented at the 2020 ECTRIMS Congress (I) treated relapsing remitting MS (RRMS) revealed an dence that variations in their degree of heterogene- Biogen, Roche, Almirall, Celgene and Bayer; CC has received intrathecal inflammatory pattern that predicted ity may contribute to the disease [28]. In EAE, OLs payment of fees for work as a variation in the volume and number of cortical le- have been shown to express genes involved in MS speaker or on advisory boards from sions at diagnosis, and distinguished patients at susceptibility, antigen processing and presentation, Genzyme, Biogen, Roche, Novartis, Merck, Teva; TC has been paid high risk of disease activity after four years with an immunoprotection, phagocytic capacity and im- professional fees for consultancy accuracy higher than 70%. CSF analysis could allow munomodulatory properties [29-31]. In one study a services, as a speaker or to cover travel expenses from Almirall, patients to be stratified after diagnosis while also post-mortem analysis was performed of the WM of Bayer, Biogen, Merck, Novartis, permitting the optimisation of therapeutic man- four individuals with progressive MS and five con- Roche, Sanofi-Genzyme and Teva; MC declares no conflict of interest; agement [23]. trols using single-nucleus RNA-seq (whole tran- LCF has been paid fees for work as a Neuroimaging studies using 7 Tesla (7T) mag- scriptome sequencing). On comparing the tran- speaker or moderator, to cover netic resonance (MR) have also shed light on this scriptional profiles of OLs in both groups, the au- travel expenses and for advisory board consultancy from Biogen, area. One study showed that there is a correlation thors saw that oligodendrial heterogeneity was al- Sanofi, Merck, Bayer, Novartis, between leptomeningeal enhancement (a surrogate tered in MS: while there was a decrease in oligo6 Roche, Teva, Celgene, Ipsen, Biopas and Almirall, LF has received marker of meningeal inflammation) and neuronal intermediate cells, oligo1 and OL precursor cell payment for consultancy services or loss in both the retina –measured with optical co- (OPC) nuclei, there was an increase in oligo2, oli- as a speaker from Novartis, Biogen-Idec, Teva, Merck and herence tomography (OCT)– and the cerebral cor- go3, oligo5 and imOLG [32]. Sanofi; RGMC declares no conflict tex (measured with 7T MRI). Patients with lepto- In relation to astrocytes, a genetic risk variant of interest; LL declares no conflict of interest; ML has received payment meningeal enhancement had greater cortical atro- for MS susceptibility, rs7665090G, has been shown of professional fees from Merck, phy and lower retinal thickness. In addition, a dif- to alter astrocyte function, leading to increased Sanofi, Roche, Teva, Novartis, fuse pattern of leptomeningeal enhancement was lymphocyte infiltration in the CNS [33]. Moreover, Bayer, Almirall, Celgene and Biogen, SL has received payment associated with a faster reduction in the macular positron emission tomography has shown that per- for consultancy services and as a and retinal nerve fibre layer [24]. In another study, ilesional adenosine A2A receptor expression in le- speaker from Biogen Idec, Novartis, Teva, Genzyme, Sanofi and Merck; also using 7T MRI, it was found that patients with sions is associated with progression. Furthermore, MLMG has received payment for leptomeningeal enhancement had increased corti- in vitro studies show that adenosine A2A receptor consultancy services or as a speaker from Merck, Biogen, Novartis, cal and thalamic lesions, while those without lepto- signalling increases oxidative damage in astrocytes Sanofi-Genzyme, Almirall, Bayer, meningeal enhancement only had increased white [34]. These findings suggest that the intrinsic re- Roche and Teva; JML has received matter (WM) lesions [25]. These results suggest an sponses of astrocytes could be therapeutic targets, payment of fees for scientific work and consultancy services from involvement of meningeal inflammation in the de- particularly in the progression phase. Almirall, Biogen, Bristol-Meyers velopment of neuronal atrophy. Its potential use as Squibb, Genzyme, Merck, Novartis, Roche and Teva; MM declares no a surrogate marker in studies evaluating drugs tar- Remyelination mechanisms conflict of interest; COG has geting meningeal inflammation is highlighted, to- received payment for consultancy services and as a speaker from gether with the usefulness of OCT for measuring In order to elucidate the origin of remyelinating Biogen, Sanofi-Genzyme, Merck, such inflammation. OLs in MS, a post-mortem study compared lesions Roche, Teva and Novartis, AO declares no conflict of interest; JMP from patients with early MS and patients with pro- has been paid fees for consultancy gressive MS. The results showed that remyelination services for advisory boards and as Impact of MS on neurons and glia cells was predominantly performed by pre-existing OLs a speaker at meetings, and has also participated in clinical trials or other and was most effective immediately after demyelin- research projects sponsored by Neural vulnerability ation. Furthermore, breast carcinoma amplified se- Biogen-Idec, Bayer-Schering, Merck-Serono, Teva, Novartis, quence 1 (BCAS1)-positive satellite cells in the ce- Roche, Sanofi-Genzyme, Actelion Neuronal damage and cortical pathology play a key rebral cortex were found to promote remyelination and Almirall; LRT has received payment of consultancy fees, role in the progression of MS. Transcriptomic stud- after demyelination [35]. remuneration for participating in ies [26] have shown that a selective change in gene Given the absence of remyelinating therapies, ef- educational programmes, and has expression occurs in certain subtypes of neurons, forts to find therapeutic targets that allow for the been involved in clinical trials and other research projects sponsored with excitatory neurons in subpial layers 2-3 shar- development of therapies are particularly impor- by Biogen-Idec, Bayer-Schering, ing the highest level of cortical vulnerability, with tant. Two potential targets have been identified: Merck-Serono, Teva, Novartis, Roche, Sanofi-Genzyme and an outside-in pattern of progression. These neuron oncostatin M (OSM), a member of the interleu- Almirall; LRP has been paid populations also showed increased gene pathways kin-6 family, and its mediator tissue inhibitor ma- consultancy fees or received payment for participating in related to cellular stress, protein accumulation, en- trix metalloproteinase 1 (TIMP-1). While remye- advisory services, collaborative ergy metabolism and oxidative stress [27]. lination was completely abrogated in mice with in- consultancy work and scientific communications, and has received activation of the OSM receptor (OSMRβ), over-ex- financial support for research, Contribution of oligodendrocytes and astrocytes pression of OSM in the chronically demyelinated travel costs and attendance at CNS triggered remyelination. Astrocyte-derived conferences from TEVA, Biogen Idec, Novartis, Merck-Serono, The role of oligodendrocytes (OLs) in the patho- TIMP-1 drove OPC differentiation in mature OLs Genzyme, Almirall, Bayer and genesis of MS remains an enigma, but there is evi- in vitro [36]. Roche; NT has received payment for  www.neurologia.com Rev Neurol 2021; 72 (11): 397-406 399 Ó. Fernández, et al consultancy services and as a Grey matter pathology a summary of the most prominent studies on bio- speaker from Biogen Idec, markers that were presented. Merck-Serono, Novartis, Roche, Sanofi-Genzyme, Teva Cortical and WM damage are concomitant patho- Neuroscience and Bristol Myers; logical processes, but do not appear to be distrib- ARA declares no conflict of interest. uted exclusively according to a specific cortical- Radiological advances fascicular pattern. An in vivo study of the spatial How to cite this article: Fernández O, Montalban X, specificity of the interdependence between intra- Spinal cord Aladro Y, Alonso A, Arroyo R, cortical and WM integrity suggests that there is Calles C, et al. 13th Post-ECTRIMS Meeting: review of the new a common, phase-dependent mechanism [37]. The spinal cord is frequently affected in MS, caus- developments presented at the With the follow-up of patients using 7T MRI, it ing motor, autonomic and sensory dysfunction. The 2020 ECTRIMS Congress (I). has been shown that, in the early stages of the dis- importance of the spinal cord for the diagnosis of Rev Neurol 2021; 72: 397-406. doi: 10.33588/rn.7211.2021172. ease, cortical lesions primarily affect the sulci, fol- CIS [45] and differential diagnosis of MS [46] has lowed by the convolutions; the rate of cortical le- become more firmly established in recent years. Versión en español disponible en neurología.com sion formation is higher in secondary progressive Pathological abnormalities in the spinal cord, such MS (SPMS) than in RRMS, and there is no corre- as demyelination and neuroaxonal loss, can be ob- © 2021 Revista de Neurología lation between the accumulation of WM and GM served in vivo with MRI. Recent advances include: lesions [38]. (i) recommendations for standardised protocols for GM demyelination is a heterogeneous process diagnosis, prognosis and follow-up [47]; (ii) recom- that results in loss of neurons [26] and synaptic mendations on the use of spinal atrophy in clinical density, as well as changes in the mitochondria. practice [48]; (iii) the development of registry- Based on the observation that in subpial lesions based methods to assess spinal atrophy; (iv) quanti- there is an alteration between the ratio of miRNAs tative and multimodal MR imaging to measure mi- and the expression of certain genes and metabolic crostructural damage to the spine; and (v) neuraxis pathways, serum miRNAs that regulate gene ex- assessment to understand the pathological changes pression in cortical lesions could be detected and in disability [49]. Figure 2 shows the conclusions of used as a marker of the prognosis of cortical dam- the MAGNIMS-CMSC-NAIMS consensus guide- age [39]. Although the relationship between subpial line and recommended protocols for carrying out demyelination and neuronal loss is unclear, it has MR imaging of the spinal cord. been postulated that there is a selective vulnerabil- Spinal cord MRI is important for diagnosis in ity of cortical neurons and OLs to this subpial de- CIS, and for prognosis in radiologically isolated myelination, and that neuronal loss is independent syndrome (RIS), CIS and the early stages of MS. In of demyelination [39]. patients with CIS, gadolinium enhancement (Gd+) A study of over 1,000 patients with radiological and spinal cord lesions were independently associ- (15 years) and clinical (19 years) follow-up has ated with the development of SPMS. In the pres- shown that atrophy begins in adolescence, before ence of spinal lesions and together with two or the onset of symptoms, and progresses in a linear more Gd+ lesions there was a 45% risk of SPMS at manner. Its appearance is independent of the time 15 years; whereas in the absence of spinal lesions of onset of MS, diagnosis, gender or subtype. This and Gd+ lesions the risk of SPMS was only 5% [50]. suggests that assessments of neurodegeneration Spinal cord volume also predicts progression. In should be analysed in relation to patient age rather another study, each 1% increase in annual loss of than disease duration. However, the study did not spinal volume was associated with a 28% increased include healthy controls, so the influence of ageing risk of progressing in the following year [51]. itself on atrophy is unknown [40]. High resolution image: 7-T Biomarkers 7T MR images have several advantages over 1.5T and 3T, such as superior image clarity, resolution The development of biomarkers sensitive to MS- and perception of anatomical details. Increased associated changes and applicable in clinical prac- resolution is crucial in the detection of the sign of tice remains a challenge. Several biomarkers of the central vein, which is important in the diagno- conversion from clinically isolated syndrome (CIS) sis and occurs in 80% of patients [52]. The use of 7T to MS and of disability progression have been iden- MR also allows for a better characterisation of cor- tified, including genetic, clinical, fluid (CSF and tical [38] and thalamic lesions [53], which are po- blood) and neuroimaging biomarkers. Table I shows tential diagnostic and prognostic biomarkers. 400 www.neurologia.com Rev Neurol 2021; 72 (11): 397-406 13th Post-ECTRIMS Meeting: review of the new developments presented at the 2020 ECTRIMS Congress (I) Table I. MS biomarker studies presented at ECTRIMS 2020. Aim Methodology Results Conclusions miRNA in serum Classify patients Quantification of T2LV and BPF of 1.5T • MR: 1/3 of patients showed a dissociation MRI MS phenotypes with high atrophy and MRI [41] according to miRNA MR in cross-sectional (n = 1088) and between T2LV and severity of atrophy, (with or without ongoing inflammation) profiles and MR longitudinal cohorts at 5 years disproportionately in type II. Only type IV show high conversion rates, supporting phenotypesa (T2LV and (n = 153). experienced a worse EDSS. Older age at baseline the partial independence of these BPF). miRNA evaluated in patients with and lower BPF predicted phenotype conversion processes. miRNA is a promising stable MR phenotype for 2 years at five years biomarker for its usefulness in (n = 98). • miRNA by phenotype: miR-22-39 and miR-345- immunological characterisation, 50 (pathogenic) over-expressed in types II and but requires methodological IV. miR-365-59 (protective) increased in type I. standardisation t protein and Assess whether t Clinical and radiological variables were • Patients with higher t levels at diagnosis t may play a role as a predictive β-amyloid in CSF and β-amyloid at collected in 109 patients (82 RRMS) developed greater disability as assessed by MSSS biomarker in identifying early [42] diagnosis predict early at diagnosis and during follow-up. and ARMSS disability. This is the 1st study to report MS disability and if Radiological markers: >9 T2 WM • No correlations were found between β-amyloid a correlation between t and MSSS they correlate with lesions, and spinal cord lesions and markers of early disability and ARMSS. The exact role of t and radiological markers • No differences were found in the levels of t β-amyloid in the pathophysiology of MS protein or β-amyloid and the clinical forms is unknown, and hence studies with a • There was a (non-significant) trend of higher t longer follow-up, larger sample size and levels and lower β-amyloid levels with higher T2 more data analyses are needed WM lesion burden and spinal cord involvement Transcriptomic Investigate the PBMC analysis was obtained with the • Patients with RIS and CIS were characterised RIS and CIS have a similar profiling [43] transcriptional profile of high-throughput RNA-Seq platform in by 455 and 125 DEGs, respectively. Among the transcriptomic profile associated with PBMC from patients with RIS (n = 14), CIS (n = 26) and controls CIS-associated DEGs, 65 (52%) were common the inflammatory response. The RIS- RIS vs. CIS vs. controls (n = 16) with RIS specific PBMC transcriptome suggests • The transcriptional profile of RIS was high the occurrence of an initial infection in genes associated with the inflammatory that triggers the immune mechanisms response and with the activation of the receptor of preclinical stages mechanism of the virus and bacteria pattern recognition GFAP, S100B and Assessing sGFAP, sS100B 47 serum samples were obtained from • High levels of GFAP during the remission phase GFAP could be a prognostic biomarker NfL in serum [44] and sNfL levels as a 18 patients in remission, followed were associated with an increased risk of future of relapses in stable NMOSD that could biomarker of future up for up to 10 years. Patients were relapses and of experiencing them earlier guide the monitoring of treatment relapses in NMOSD with stratified according to high/low GFAP • High levels of S100B and NfL during the response. The absence of NfL as a aquaporin-4-IgG (141.6 pg/mL), S100B (8.6 pg/mL) and remission phase were not associated with an neural marker in NMOSD reflects NfL (33.9 pg/mL) increased risk of future relapses differences in pathogenesis with MS ARMSS: age-related MSSS score; β-amyloid: beta-amyloid; BFP: brain parenchymal fraction; CSF: cerebrospinal fluid; DEGs: differentially expressed genes; EDSS: Expanded Disability Status Scale; GFAP: glial fibrillary acidic protein; miRNA, microRNA; MSSS: MS severity score; NfL: serum neurofilaments light chain; NMOSD: neuromyelitis optica spectrum disorders); PBMC: periph- eral blood mononuclear cells; RIS: radiologically isolated syndrome; S100B: serum s100 calcium-binding protein B; T2LV: T2-hyperintense lesion volume; WM: white matter. a Type I: low T2LV, low atrophy; type II: high T2LV, low atrophy; type III: low T2LV, high atrophy; type IV: high T2LV, high atrophy. Meningeal enhancement patterns lates with T1/T2 lesion load, with ventricular CSF and with GM brain atrophy [54]. Alongside leptomeningeal enhancement, uptake in the dura mater/falx cerebri and the wall of the meningeal vessels are other, less studied, meningeal Gut-CNS axis and microbiome enhancement patterns, which are identified with 3D FLAIR (fluid attenuated inversion recovery) Microbiome compromise MRI and could contribute to the stratification of the MS subgroups. One study has shown that pa- The study of the microbiome is very complex and tients with leptomeningeal enhancement have ad- research in MS patients has been rather limited. ditional vascular wall contrast uptake, compared to Gut bacterial populations appear to be similar in those without meningeal enhancement. Dura ma- patients and controls in terms of diversity, while the ter/falx cerebri enhancement is the most frequent abundance of certain bacteria is not [55]. However, meningeal enhancement pattern in MS, and corre- these differences are not always consistent across www.neurologia.com Rev Neurol 2021; 72 (11): 397-406 401 Ó. Fernández, et al ed, the role of the ENS in other CNS diseases, such Figure 2. Acquisition protocol and recommendations for spinal cord MR imaging. CIS: clinically isolat- as Parkinson’s or Alzheimer’s, suggests that there ed syndrome; DIT: dissemination in time; MAGNIMS-CMSC-NAIMS: European-based Magnetic Reso- may be a common denominator in neurodegenera- nance Imaging in MS-Consortium of Multiple Sclerosis Centers-North American Imaging in Multiple Sclerosis Cooperative; PD: proton density; PSIR: phase-sensitive inversion recovery; STIR: short t inver- tive disorders. sion recovery. Table II outlines the studies presented on the microbiome in paediatric MS [59], the effect of vancomycin on gut permeability in EAE [60], and gut dysbiosis in neuromyelitis optica [61]. COVID-19 Data from a UK registry have shown that the inci- dence of COVID-19 in MS patients is the same as in the rest of the population [62]. Another registry study, in this case from North America (CO- ViMS), found that when MS patients are classified by ethnicity, African-American COVID-19 pa- tients with MS were younger, more likely to have comorbidities and had a higher risk of worse out- comes compared to Caucasians, even after adjust- studies, possibly due to variability in geographic re- ing for comorbidities in the diagnosis of COV- gion of origin, diet, comorbidities, medication use ID-19 [63]. The French registry COVISEP identi- and age. Very little is known about the relationship fied the Expanded Disability Status Scale and age between the microbiome and the risk of relapses, as independent risk factors for severe COVID-19, and hardly anything is known about how it is relat- while exposure to immunomodulatory DMTs was ed to disability. Analyses of the main metabolic independently associated with lower severity of pathways involved will be essential to identify po- COVID-19 [64]. tential targets for intervention. Some studies show Using the largest international cohort of people that disruption of up to nine metabolic pathways is with MS and COVID-19 available, an association associated with risk of relapses and, of these, four between anti-CD20 DMTs (ocrelizumab and involve methane metabolism [56]. Ongoing clinical rituximab) and hospitalisation, ICU admission trials evaluating the effect of probiotic supplements and use of artificial ventilation was demonstrated, or microbiome transplantation will determine the suggesting that their use among MS patients may feasibility of these interventions as disease modifi- be a risk factor for more severe COVID-19 disease ers [56]. [65]. Yet, data from the ocrelizumab pharmaco- vigilance programme showed that mortality in pa- Enteric nervous system tients treated with this drug (5.5%) can be super- imposed on that observed in the general popula- There is currently a debate under way as to whether tion, and in COVID-19 and MS registries, such as MS starts in the CNS or whether other peripheral COViMS [66]. organs, such as the gut, could be considered as a Finally, increased humoural immunity in CSF starting point. This possible paradigm shift is sup- and plasma has been identified in patients with ported, for example, by a study showing that 31.6% COVID-19 presenting with neurological disorders, of MS patients reported gastrointestinal symptoms although its pathogenic significance is unknown prior to diagnosis [57]. [67]. In a study on EAE, enteric nervous system (ENS) pathology was seen to occur prior to degen- eration of the CNS, in the myenteric plexus. The Conclusions pathology was accompanied by reduced intestinal motility. Furthermore, analysis of colon samples This latest edition of the Post-ECTRIMS presented from MS patients revealed nerve fibre degenera- advances in our understanding of the mechanisms tion and enterogliosis of the myenteric plexus [58]. underlying the onset and development of MS, as Although studies with more MS patients are need- well as the role of the epigenome in mediating the 402 www.neurologia.com Rev Neurol 2021; 72 (11): 397-406 13th Post-ECTRIMS Meeting: review of the new developments presented at the 2020 ECTRIMS Congress (I) Table II. Studies presented on the microbiome in MS. Aim Methodology Results Conclusions Mirza Examine the functional Patients ≤21 years old who met There was no difference in functional diversity between Differences in the functional potential et al [59] potential of the McDonald criteria and with paediatric MS vs. controls But MS patients showed of the gut microbiome in paediatric gut microbiome by symptoms at onset <18 years higher levels of archaeal-related methanogenesis, MS vs. controls are observed in metagenomic analysis old, with no previous treatment vitamin B2 production, viral activity, heavy metal several metabolic pathways, including of stool samples in or exposed only to IFNB or metabolism and L-glutamate degradation; and lower enrichment of tryptophan-related paediatric MS GA. Illumina NextSeq, Enzyme levels of homolactic fermentation, and bacterial pathways and metabolism of industrial Comission, MetaCyc and Gene carbohydrate degradation. DMT affected the relative chemicals. Exposure to DMT appears Ontology analyses were used abundance of tryptophan degradation to produce an enrichment of pathways involved in promoting remyelination Smith Investigate the activity of Controls treated with vancomycin Vancomycin improved EAE by modulating the gut Vancomycin preserves the integrity et al [60] vancomycin on intestinal and with neomycin. Samples microbiota, so that vancomycin-treated mice developed of intestinal permeability through permeability in the were collected from adult mice milder disease and also preserved the integrity of the inhibition of intestinal trypsin activity, animal model of EAE before and after inducing EAE in intestinal barrier. Proteases, such as trypsin, modulate an effect mediated by the microbiota. controls and vancomycin-treated intestinal barrier function. Vancomycin decreases Identification of gut bacterial mice. Trypsin activity and its role intestinal trypsin activity and lowers immune activation communities that modulate trypsin in intestinal permeability were activity could lead to the development analysed of drugs to prevent and treat MS Moinfar Study whether an Mice were colonised with stool The mean clinical score of mice colonised with The data suggest that the intestinal et al [61] intestinal samples from an untreated NMOSD gut microbiota was significantly higher than microbiota of NMOSD increases dysbiosis promotes NMOSD patient, a household that of mice colonised with HHC gut microbiota or susceptibility to EAE. inflammatory responses healthy control (HHC) and a vehicle vehicle. The frequency of CD4+ Foxp3+ CD25+ cells Decreased Treg contributes to in patients with NMOSD control, and they were examined decreased in NMOSD and HHC vs. vehicle control, and susceptibility to EAE. for susceptibility to EAE induced CD4+Foxp3+Helios+Tregs decreased in NMOSD but not Several mechanisms may be involved by MOG p35-55 30 days after in the HHC group in the worsening of EAE in NMOSD immunisation and HHC DMT: disease-modifying therapy; EAE: experimental autoimmune encephalitis; GA: glatiramer acetate; HHC: household healthy controls; IFNB: interferon beta; MOG: myelin oligodendrocyte glycoprotein; NMOSD: neuromyelitis optica spectrum disorders. effect of external variables. Despite the discoveries References made, the pathological substrate of MS and the re- 1. Munger K. Environmental exposures and MS risk. ECTRIMS- lationship between inflammation, demyelination ACTRIMS; Virtual 2020. and neurodegeneration remain unknown. As for 2. Hedstrom A. 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Effect of vancomycin on intestinal humoral autoimmunity in the CSF and plasma of permeability during experimental autoimmune COVID-19 patients with comorbid neurologic dysfunction. encephalomyelitis. ECTRIMS-ACTRIMS; Virtual 2020. ECTRIMS-ACTRIMS; Virtual 2020. XIII Reunión Post-ECTRIMS: revisión de las novedades presentadas en el Congreso ECTRIMS 2020 (I) Introducción. Desde hace más de una década, tras el congreso ECTRIMS, se celebra en España la reunión Post-ECTRIMS, donde neurólogos expertos en esclerosis múltiple (EM) de toda España se reúnen para revisar las principales novedades presentadas en el ECTRIMS (en esta ocasión, celebrado junto con el ACTRIMS). Objetivo. En el presente artículo, publicado en dos partes, se resumen las ponencias que tuvieron lugar en la reunión Post-ECTRIMS, celebrada los días 16 y 17 de octubre de 2020 de forma virtual. Desarrollo. En esta primera parte se incluyen los últimos resultados acerca del impacto del ambiente y el estilo de vida sobre el riesgo de EM y su curso clínico, y el papel de la epigenética y los factores genéticos sobre estos procesos. Se discu- ten los hallazgos en investigación preclínica y clínica sobre los subtipos de linfocitos identificados, y la implicación de los folículos linfoides y la afectación meníngea en la enfermedad. Los cambios en la estructura cerebral se abordan a nivel microscópico y macroscópico, incluyendo resultados de técnicas de imagen de alta resolución. También se presentan los últimos avances sobre biomarcadores para el diagnóstico y el pronóstico de la EM, y sobre la afectación del microbioma en estos pacientes. Por último, se esbozan los resultados de registros de pacientes sobre el impacto de la COVID-19 en los pacientes con EM. Conclusiones. Ha habido nuevos datos sobre factores de riesgo de la EM, impacto de la EM a nivel celular y estructural, papel del microbioma en la enfermedad, biomarcadores y la relación entre COVID-19 y EM. Palabras clave. ACTRIMS. Congreso. ECTRIMS. EM. Esclerosis múltiple. Post-ECTRIMS. www.neurologia.com Rev Neurol 2021; 72 (11): 397-406 405