REVIEW 13th Post-ECTRIMS Meeting: review of the new developments presented at the 2020 ECTRIMS Congress (II) 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, after the ECTRIMS Congress, Spain has hosted the Post-ECTRIMS meeting, where Hospital Regional Universitario de Málaga, Málaga (Ó. Fernández; neurologists with expertise in multiple sclerosis (MS) meet to review the new developments presented at the ECTRIMS. A. Alonso). Hospital Universitario Aim. This article, published in two parts, summarises the presentations of the post-ECTRIMS meeting, held online on 16 Vall d’Hebron- CEMCAT (X. Montalban, M. Comabella); and 17 October 2020. Hospital Clínic de Barcelona e IDIBAPS (S. Llufriu); Hospital Development. This second part highlights the importance of gender and age in understanding the pathology of the dis- Universitario de Bellvitge, ease and optimising its management. The advances made in paediatric MS, from a neuropsychological and neuroimaging Barcelona (L. Romero-Pinel). Hospital Universitario de Getafe point of view, are presented. In turn, special attention is paid to the findings that contribute to a more personalised ap- (Y. Aladro); Hospital Universitario proach to therapy and to choosing the best treatment strategy (pharmacological and non-pharmacological) for each pa- Quirónsalud (R. Arroyo); Hospital tient. Similarly, results related to possible strategies to promote remyelination are addressed. Although there are no ma- Universitario Ramón y Cajal (L. Costa-Frossard); Hospital jor advances in the treatment of progressive forms, some quantitative methods for the classification of these patients are Universitario Clínico de Madrid highlighted. In addition, the study also includes results on potential tools for the assessment and treatment of cognitive (R. Ginestal); Hospital General Universitario Gregorio Marañón deficits, and some relevant aspects observed in neuromyelitis optica spectrum disorders. Finally, the results of the papers (M.L. Martínez-Ginés); Hospital considered late breaking news at the ECTRIMS-ACTRIMS are detailed. Clínico San Carlos-IdISSC-UCM, Madrid (C. Oreja-Guevara). Conclusions. Most of the advances presented were related to the knowledge of paediatric MS, remyelination strategies Hospital Universitario Son and cognitive assessment in MS. Espases, Palma de Mallorca (C. Calles). Hospital Universitario Key words. ACTRIMS. Congress. ECTRIMS. MS. Multiple sclerosis. Post-ECTRIMS. Donostia, San Sebastián (T. Castillo-Triviño). Hospital Universitario Puerta del Mar, Cádiz (L. Forero). Hospital Introduction lapse, while the decrease in hormones in the post- Universitario Doctor Peset, partum period leads to a rebound in activity, al- Valencia (L. Landete). Complejo Hospitalario Universitario de This article is the second part of the summary of though these attacks have been reduced with the Ferrol (M. Llaneza); Complejo the papers presented at the 13th post-ECTRIMS use of disease-modifying therapies (DMT) [3]. In a Hospitalario Universitario de Santiago de Compostela, Meeting, held online on 16-17 October 2020. study using data from 1,640 pregnancies from the La Coruña (J.M. Prieto). Hospital MSBase registry, it was concluded that the use of Clínico Universitario Virgen de la Arrixaca, Murcia (J. Meca- highly effective DMT before conception can pre- Lallana). Hospital Universitario Gender-associated factors in pathogenesis vent relapses during pregnancy [4]. Menarche, de Cruces, Bilbao (M. Mendibe, and management pregnancy and lactation do not appear to influence A. Rodríguez-Antigüedad). Hospital Universitario Central long-term disability [5]. After menopause, however, de Asturias, Oviedo (A. Oterino). Although differences in drug metabolism and ad- a more progressive phase does appear, although it Hospital Universitario Dr. Josep Trueta y Hospital Santa verse events (AEs) have been observed between may be associated with ageing per se [6]. Caterina-IDIBGI, Girona (L. men and women, gender is often not taken into ac- Multiple sclerosis (MS) is two to three times Ramió-Torrentà). Hospital Clínico Universitario de Valladolid, count in the design of clinical trials, nor in the re- more common in women [7] perhaps because the X Valladolid (N. Téllez). porting of AEs in studies and on drug product data chromosome expresses multiple genes with an im- Correspondence: sheets [1]. mune function, with the brain being the organ Dr. Óscar Fernández. Instituto de Among the factors that may influence suscepti- where they are expressed the most [8]. Also, differ- Investigación Biomédica de bility to the disease due to gender are the hormonal ences in X chromosome DNA methylation between Málaga (IBIMA). Hospital Universitario Regional de Málaga. changes that occur in women throughout their lives the parents may lead to differences in gene expres- Universidad de Málaga. Av. de [2]. The strongest evidence comes from data col- sion in the two sexes during the immune response Carlos Haya, s/n. E-29010 Málaga. lected during pregnancy, where increased sex hor- [9]. Transcriptional regulation may differ depend- E-mail: mones are accompanied by a decreased risk of re- ing on the sex. In experimental autoimmune en- oscar.fernandez.sspa@gmail.com  www.neurologia.com Rev Neurol 2021; 72 (12): 433-442 433 Ó. Fernández, et al Acknowledgements: cephalomyelitis (EAE) p38 signalling in microglia the age, the longer the time to recovery from the The authors would like to thank appears to be protective only in males [10]. relapse, the greater the disability if initiation of Laura Prieto del Val of Dynamic Science for her help in drafting this DMT is delayed, and the lesser the effect of the article. DMT will be [17]. Additionally, the pre-progression Funding: Advances in paediatric multiple sclerosis stage depends only on age, and not on the previous This article was funded by Teva. clinical stage [18]. The changes in biological mech- Conflicts of interest: Results from the Swedish multiple sclerosis register anisms that take place during ageing play against OF has received payment for MS. Senescence of genetic-epigenetic mechanisms consultancy work on advisory boards and as a speaker at The prevalence of paediatric MS is 5-10% [11]. The would modulate senescence of the immune system, meetings, and has also prognosis of this disease is not as favourable as pre- microglia, the neuron-astrocyte complex and oligo- participated or participates in viously believed. They take around 10 years longer to dendrocyte functions. The future development of clinical trials or other research projects promoted by Biogen-Idec, reach progressive stages, but they do so at an earlier treatments should take into account these mecha- Bayer-Schering; Merck-Serono, age. The course of the disease is different, with a nisms affected by ageing [17]. Teva, Novartis, Roche, Sanofi-Genzyme, Actelion, higher number of relapses in the first five years, and Almirall, Araclon, Orizon and a faster and more complete recovery from them [12]. Neuroimaging Ala-Diagnostics; XM has received payment for consultancy work, Using the Swedish MS register (SMSreg), a slow- travel expenses to attend scientific ing of information processing and impairment of ex- Age also modifies the radiological phenotype [19]. meetings, and to participate on ecutive functions was observed as of early stages of Age is one of the endogenous factors that increas- Advisory Boards for clinical trials from Actelion, Alexion, Bayer, the disease. This cognitive impairment is early and es the likelihood of conversion [20], and is associ- Biogen, Celgene-BMS, Excemed, independent of age and disease duration [13]. ated with a lower likelihood of gadolinium (Gd+)- Merck, Sanofi-Genzyme, MedDay Pharmaceuticals, Multiple The impact of early-onset MS also has community enhancing T1 lesions and a greater likelihood of Sclerosis International Federation, health implications. These people are less likely to pur- atrophy. NervGen, National Multiple Sclerosis Society, Novartis, sue higher education studies than the general popula- An age-brain paradigm has been established Roche-Genentech, Teva and TG tion, and require more disability pensions at a younger with which the age of a patient’s brain can be pre- Therapeutics; YA declares no conflict of interest; AA has been age [11]. This spills over to the next generation, where dicted on the basis of its degree of cerebral atrophy. paid fees from Biogen, children of people with MS have fewer higher qualifi- The difference between the calculated age and the Merck-Serono, Teva, Novartis, cations and lower purchasing power [11]. actual age has been termed brain-PAD (brain-pre- Roche, BMS, Sanofi-Genzyme and Almirall; RA has been paid fees by dicted age difference) and the greater the differ- Teva, Sanofi-Genzyme, Merck, Neuroimaging ence, the older the brain is. A high brain-PAD oc- Novartis, Biogen, Roche, Almirall, Celgene and Bayer; CC has curs in patients with MS and is associated with a received payment of fees for work Paediatric patients have a high inflammatory activ- faster disability progression [21]. as a speaker or on advisory boards from Genzyme, Biogen, Roche, ity. Already at a very early age, black holes and atro- Novartis, Merck, Teva; TC has been phy can be observed, even despite a short disease Immunological perspective and intervention paid professional fees for duration and the absence of progression [13]. One consultancy services, as a speaker or to cover travel expenses from of the great challenges is to find correlations be- The concept of ‘inflammaging’ describes chronic Almirall, Bayer, Biogen, Merck, tween the changes observed with neuroimaging inflammation that increases with age and, together Novartis, Roche, Sanofi-Genzyme and Teva; MC declares no conflict techniques in the white matter and in the grey mat- with immunosenescence, contributes to neurode- of interest; LCF has been paid fees ter, as well as, in turn, between each of these chang- generative diseases [22]. Premature immunosenes- for work as a speaker or moderator, to cover travel es and cognitive function or fatigue [14]. cence plays an important role in the progression of expenses and for advisory board MS. Levels of nerve growth factor β differ depend- consultancy from Biogen, Sanofi, Merck, Bayer, Novartis, Roche, Neuropsychological profile ing on age, and pro-inflammatory interleukins (IL- Teva, Celgene, Ipsen, Biopas and 18) are increased in older patients, especially in un- Almirall, LF has received payment Cognitive impairment in paediatric patients is not treated males [23]. Possible interventions suggested for consultancy services or as a speaker from Novartis, limited to a slowing of processing speed. Other cog- to decrease ‘inflammaging’ include calorie restric- Biogen-Idec, Teva, Merck and nitive domains such as episodic memory, visuospa- tion and reduced methionine intake [24]. Sanofi; RGMC declares no conflict of interest; LL declares no conflict tial and visuomotor function and language are also of interest; ML has received impaired, regardless of the time course of MS [15]. payment of professional fees from Merck, Sanofi, Roche, Teva, Personalised treatment approaches Novartis, Bayer, Almirall, Celgene and Biogen, SL has received payment for consultancy services Ageing Identification of the optimal treatment for each and as a speaker from Biogen patient Idec, Novartis, Teva, Genzyme, Sanofi and Merck; MLMG has Ageing and multiple sclerosis phenotypes received payment for consultancy Personalised medicine aims to tailor treatment to services or as a speaker from  Age modifies the clinical phenotype [16]. The older individual patient characteristics, taking into ac- 434 www.neurologia.com Rev Neurol 2021; 72 (12): 433-442 13th Post-ECTRIMS Meeting: review of the new developments presented at the 2020 ECTRIMS Congress (II) count various factors (Fig. 1). As the therapeutic arsenal grows, and it is unknown whether a patient Figure 1. Factors to be considered in a personalised approach to medicine. EDSS: Expanded Disability Status Scale; MR: magnetic resonance; MS: multiple sclerosis. will respond favourably to a given treatment [25], choosing which one to use becomes quite a chal- lenge [26]. For this reason, several prediction mod- els have been developed, including the two-stage model, which takes the risk variables of each pa- tient into account. This model was applied to 3,590 patients receiving natalizumab, dimethyl fumarate, glatiramer acetate or placebo in several clinical tri- als and results showed that the baseline risk of re- lapses modifies the relative and absolute effects of the drugs [27]. Specific biomarkers of treatment response The implementation of certain biomarkers will allow for an increasingly personalised form of medicine. A prospective follow-up study in relaps- ing remitting MS (RRMS) has shown that, in pa- tients with similar demographic and clinical char- acteristics, low percentages of CD19+ B cells in blood or plasmablasts before starting alemtuzumab Discontinuation of treatment Merck, Biogen, Novartis, treatment predicted a lower risk of autoimmune Sanofi-Genzyme, Almirall, Bayer, Roche and Teva; JML has received AEs [28]. It appears that discontinuation of DMT in older pa- payment of fees for scientific work The predictive value of serum neurofilament tients may be safe [33]. The combination of an age and consultancy services from Almirall, Biogen, Bristol-Meyers light chains (NfL) for disease activity has been stud- ≥ 45 years with no relapses or radiological activity Squibb, Genzyme, Merck, Novartis, ied in patients with clinically isolated syndrome for ≥ 4 years has been associated with a high prob- Roche and Teva; MM declares no conflict of interest; COG has (CIS) and RRMS with DMT. The results showed ability of continuing without relapses after discon- received payment for consultancy that NfL levels are predictive of activity and could tinuation of DMT; while ≥ 45 years with long dis- services and as a speaker from therefore be used to monitor the patient [29]. ease duration and high EDSS predicted risk of pro- Biogen, Sanofi-Genzyme, Merck, Roche, Teva and Novartis, AO gression [34]. It should also be noted that almost declares no conflict of interest; JMP half of elder people are very satisfied with their has been paid fees for advisory board consultancy, and as a Disease-modifying strategies DMT and do not consider discontinuing it, even if speaker at meetings, and has also their disease is inactive [35]. participated in clinical trials or other research projects sponsored by Escalation vs. induction Biogen-Idec, Bayer-Schering, Radiologically isolated syndrome Merck-Serono, Teva, Novartis, The choice between moderately effective and safe Roche, Sanofi-Genzyme, Actelion and Almirall; LRT has received drugs with subsequent escalation or more effec- Radiologically isolated syndrome continues to give payment of consultancy fees, tive drugs from the outset is a key issue in clini- rise to a large amount of controversy and there is remuneration for participating in educational programmes, and has cal practice [30]. No information from clinical tri- insufficient information on its evolution, risk of been involved in clinical trials and als on the efficacy of different treatment strate- progression and long-term prognosis [36]. The cur- other research projects sponsored by Biogen-Idec, Bayer-Schering, gies is available, although randomised clinical rent recommendation is not to treat these patients, Merck-Serono, Teva, Novartis, trials (TREAT-MS and DELIVER-MS) are under and to consider this period as a window of oppor- Roche, Sanofi-Genzyme and Almirall; LRP has been paid way to determine whether a given treatment strat- tunity in which changes in lifestyle can be imple- consultancy fees or received egy best prevents long-term disability and atro- mented [36]. There are two ongoing phase III clini- payment for participating in phy [31]. cal trials that aim to unify criteria in the manage- advisory services, collaborative consultancy work and scientific A study with more than five years’ follow-up ment of these patients. communications, and has received showed that the induction strategy was more effec- financial support for research, travel costs and attendance at tive than the escalation strategy in controlling dis- Treatment dosage conferences from TEVA, Biogen ability progression. This effect increased in the long Idec, Novartis, Merck-Serono, Genzyme, Almirall, Bayer and term (up to 10 years), even though patients in the A study conducted at two centres in Catalonia with Roche; NT has received payment for escalation group had been switched to more effec- patients treated with rituximab has shown that low consultancy services and as a tive drugs [32]. doses of rituximab had the same effectiveness and a speaker from Biogen Idec,  www.neurologia.com Rev Neurol 2021; 72 (12): 433-442 435 Ó. Fernández, et al Merck-Serono, Novartis, Roche, better safety profile than higher doses, with both axonal degeneration. These lesions occur even in Sanofi-Genzyme, Teva Neuroscience and Bristol Myers; groups being demographically and clinically homo- patients treated with DMT [42]. In EAE, an in- ARA declares no conflict of geneous [37]. The RIDOSE-MS phase III clinical crease in essential amino acids has been detected interest. trial, which is evaluating two rituximab dosing regi- around the lesion, especially early on in the disease. Accepted: mens (500 mg every 6 months vs. every 12 months), The protein Slc7a5 (large neutral amino acid trans- 06.05.21. is currently under way. porter; LAT1), which regulates the flow of amino How to cite this article: acids from the inside to the outside of the cell, is Fernández O, Montalban X, over-expressed within the microglia of the lesion, Aladro Y, Alonso A, Arroyo R, Calles C, et al. XIII Reunión Strategies to promote remyelination suggesting that excess amino acids are introduced Post-ECTRIMS: revisión de las into the cell. Blocking LAT1 regulates the amount novedades presentadas en el Role of astrocytes in remyelination of amino acids within the microglia, which changes Congreso ECTRIMS 2020 (II). Rev Neurol 2021; 72: 433-42. its phenotype from amoeboid-like to branched- doi: 10.33588/rn.7211.2021172. Oligodendrocytes are in close contact with astro- like. Following this intervention, there is an in- Versión en español disponible en cytes from the beginning of brain development, re- crease in oligodendrocyte differentiation and remy- neurologia.com. sulting in an intertwining of the endings of both elination [43]. © 2021 Revista de Neurología cells. Through this junction, astrocytes provide oli- godendrocytes with nutritional support and cho- lesterol molecules that will be used by oligodendro- Pharmacological management of progressive cytes for the synthesis of myelin [38]. Once MS ap- multiple sclerosis pears, astrocyte reactivity increases and astrocyte gene expression changes during the remyelination Treatments available process. In the early stages, genes of the Nrf2 path- way are over-expressed. Later, this pathway is miti- The number of drugs approved to treat the progres- gated and at the end of the process another type of sive forms is still limited. For secondary progressive genes associated with the biosynthesis of choles- MS (SPMS) with active disease, siponimod has terol are over-expressed. These two pathways com- been approved. In addition, interferons, ocrelizum- pete; when the Nrf2 pathway is up-regulated, the ab, cladribine and ozanimod can be used in these cholesterol pathway is down-regulated. Based on patients [44]. Other drugs such as simvastatin and these observations, it is suggested that the study of ibudilast are currently being studied in advanced the neuroprotective and pro-myelinating functions clinical stages. of the Nrf2 pathway should be complemented as a In primary progressive MS (PPMS), the only ap- therapeutic target [39]. proved DMT is ocrelizumab. Study results were not positive for interferons, glatiramer acetate and Remyelination mechanisms rituximab. However, long-term efficacy was seen in a single-centre study in patients treated with inter- In EAE, older mice have a higher number of myelin ferons, and in younger patients with ≥ 1 Gd+ lesion debris-laden lysosomes within the phagocytes, which treated with rituximab. cannot be expelled to the outside. Liver X receptors (LXRs) are involved in this process of removing Time in treatment and progression myelin debris-laden lysosomes. In older mice, this clearance mechanism is impaired because of an ac- One retrospective study [45] found that, in PPMS, cumulation of lysosomes within the cell that cryst- longer exposure to DMT could delay the time to allise and perpetuate a pro-inflammatory environ- reach an EDSS of 7 (note that the patients treated ment around the cell. When older mice are supple- in this case were younger, with a lower EDSS and mented with an LXR agonist, the cells release lyso- shorter disease duration). Treating younger patients somes, and the clearance pathway and capacity for and initiating treatment earlier could improve long- remyelination is restored [40]. Resolution of the in- term disability outcomes. flammatory environment is necessary for oligoden- drocytes to remyelinate [41]. Quantitative methods of classifying RRMS and SPMS Role of amino acids The diagnosis of SPMS is challenging, as there are Chronic active lesions have latent inflammatory de- no clear and agreed diagnostic criteria. Methods myelination at their edge, remyelination failure and for classifying RRMS and SPMS, such as EXPAND 436 www.neurologia.com Rev Neurol 2021; 72 (12): 433-442 13th Post-ECTRIMS Meeting: review of the new developments presented at the 2020 ECTRIMS Congress (II) [46], Melbourne [47] or decision tree [48] differ in several of their criteria, including the number of Table I. Studies on quantitative methods of classifying RRMS and SPMS. EDSS assessments required, demonstration of pro- gression by EDSS or taking age into consideration. Method Results Table I shows the results of a study aimed at vali- Forsberg Data from registries in the Czech Republic The overall classification performance dating these classification methods [49], and of an- et al [49] (11,336 patients), Denmark (10,255), (sensitivity, specificity, accuracy) among other study that determined the characteristics of Germany (23,185), Sweden (11,247) and classifiable patients was – method 1: patients clinically assigned to an RRMS course who the United Kingdom (5,086) were used. (0.47; 0.85; 0.79); method 2: (0.77; 0.87; Three classification methods were applied 0.85); method 3: (0.84; 0.83; 0.84). The were reclassified as SPMS when the decision tree – method 1: EXPAND criteria; method 2: proportions of patients not classifiable with was applied [50]. University of Melbourne definition; method each method were – method 1: 20.0%; 3: Karolinska Institute decision tree. The method 2: 32.2%; method 3: 0% classifications were compared with clinical assignment, and the sensitivity (SPMS as Cognitive dysfunction true positive), specificity (RRMS as true negative) and accuracy were calculated Evaluation and monitoring Hillert The same registry data were used as in Between 5% and 25% of patients were et al [50] Forsberg et al. The Karolinska Institute misclassified: 8,372 RRMS patients were In recent years, tests have been developed in elec- decision tree method was applied reassigned as SPMS, the proportion of SPMS tronic format for neuropsychological evaluation. increasing from 17% to 31%. Reassigned Advantages include their ease of use and reduced patients were younger, of greater age at learning effect, although technical supervision is onset and had undergone a more rapid progression to SPMS. The proportion important during their administration [51]. of patients with DMT was 36% in those Remote administration (by phone) of neuropsy- clinically assigned to SPMS, while it was 69% chological testing appears to be on a par with face- in those reassigned as SPMS to-face administration, providing a valid and reli- EDSS: Expanded Disability Status Scale; RRMS: relapsing-remitting multiple sclerosis; SPMS: secondary progres- able measure of cognitive function. This has been sive multiple sclerosis. demonstrated with the California Verbal Learning Test (CVLT) [52,53] and the Symbol Digit Modali- ties Test (SDMT) [53], both of which are useful tests for identifying cognitive dysfunction [54]. primary variable. Thus, while positive effects have been obtained, the nature of the evidence is not suf- Radiological predictors of cognitive impairment ficiently robust to make concrete recommendations on the use of specific DMT in cognitive impairment. Cognitive impairment in MS is determined by le- This would require randomised clinical trials with sions, structural damage and the degree of efficien- cognition as the primary outcome variable [61]. cy of the neural network [55-59]. Even if structural For the time being (Fig. 2), there is evidence of a damage is significant, the efficiency of the network beneficial effect on certain cognitive processes of prevents this from translating into major cognitive interventions such as dalfampridine treatment [62], symptoms. In patients with CIS, an association has cognitive rehabilitation [63] and physical exercise been found between involvement of the hippocam- [64]. Further studies are needed to confirm this evi- pus and verbal episodic memory [56], and between dence. the posterior lobes of the cerebellum and process- ing speed [58]. From a functional point of view, cognitive impairment could be due to a failure of Innovations in symptomatic therapy and compensatory mechanisms consisting in the re- rehabilitation cruitment of additional brain areas to perform a task. This failure in these mechanisms may be due Although the impact of fatigue on quality of life and to compensation not occurring or its occurring in a social burden is high, it remains one of the most maladaptive manner [60]. difficult symptoms to treat, despite the fact that some pharmacological and non-pharmacological Treatment approaches have been proposed. Non-pharmacological approaches include psy- Several phase III clinical trials with DMT have in- chological therapies such as cognitive training, which cluded cognitive impairment among the study vari- appears to offer an improvement in 50% of patients, ables although, in most cases, it was not defined as a and energy-saving strategies, which have shown a www.neurologia.com Rev Neurol 2021; 72 (12): 433-442 437 Ó. Fernández, et al in the diagnosis of NMOSD. However, not all the Figure 2. Results from studies on pharmacological and non-pharmacological interventions for cognitive techniques used for its detection have the same impairment in multiple sclerosis. SDMT: Symbol Digit Modalities Test. sensitivity and specificity. The cell culture tech- nique appears to be the most accurate. AQP4-IgG- positive paediatric cases respond well to treatment, especially first-line rituximab [70]. Naive B-cell behaviour has been studied in anti- MOG and anti-AQP4 positive patients in different scenarios [71]. In the former, prior to treatment, anti-AQP4 patients showed an increase in transi- tional B cells (CD36+ and CD27-) that was not ob- served in anti-MOG patients. After treatment with steroids, in both anti-MOG and anti-AQP4 pa- tients, there was a decrease in transitional B cells. This suppression was correlated with the time of treatment administration. Late breaking news As usual in recent editions, the event ended with some late breaking news. Table II describes these studies, framed within various themes such as re- moderate favourable impact [65]. Neurofeedback myelination processes and their possible therapeu- may also improve cognition. A pilot study with 14 tic management [72,73] biomarkers in cerebrospi- patients showed that patients who learned to regu- nal fluid (CSF) [74], microstructural and metabolic late the sensory motor EEG rhythm after receiving correlates of the first demyelinating event [75], as- visual feedback showed an improvement in MRI sociation between gut bacteria and relapses in pae- parameters, which in turn correlated with an im- diatric MS [76] and the role of NfLs as a biomarker provement in cognition [66]. in pregnancy [77]. As for pharmacological therapies, the TRI- UMPHANT-MS study on the use of amantadine, modafinil and methylphenidate for five weeks Conclusions showed no change in the Modified Fatigue Impact Scale (MFIS). In addition to not improving fatigue, The importance that demographic factors, particu- these treatments gave rise a higher number of AEs larly age, may have in MS was discussed at the last compared to the placebo group [67]. The COMBO- post-ECTRIMS. Proactive management in paediat- MS study was designed to analyse the effectiveness ric patients was proposed and advances in the study of cognitive behavioural therapy, treatment with of the accuracy of serum prognostic biomarkers, modafinil or a combination of the two. In addition, such as NfL, were highlighted. Quantitative classifi- it aims to identify whether treatment response oc- cation methods were discussed that could help to curs as a function of MS subtypes or other covari- identify RRMS patients who have started a progres- ates, such as sleep and depression. sive course. Regarding remyelination processes, in- flammation has been shown to be relevant, so that control of latent inflammation could favour remye- Global perspectives on neuromyelitis optica lination. spectrum disorders In the near future, the development of electronic devices and scales is expected to change the ap- Neuromyelitis optica spectrum disorders (NMOSD) proach to cognitive screening in MS. Assessment of is still considered a rare disease [68] that is charac- focal damage to structures involved in cognitive terised by more severe relapses with worse recov- impairment by means of MRI could become a sur- ery than MS and a negative impact on quality of rogate marker of the disease. life [69]. The data presented provide information that will The discovery of anti-aquaporin-4 antibodies allow for an increasingly personalised approach to (AQP4-IgG) has been one of the major milestones patients, taking into account both their personal 438 www.neurologia.com Rev Neurol 2021; 72 (12): 433-442 13th Post-ECTRIMS Meeting: review of the new developments presented at the 2020 ECTRIMS Congress (II) Table II. Late breaking news. Aim Methodology Results Conclusions Lohrberg To investigate the effects They studied autopsy There was rapid activation of the parenchymal NG2+ OPC Astrocyte-oligodendrocyte interactions et al [72] of primary astrocytic loss material from patients reservoir in the astrocyte-free lesion, leading to extensive are important for remyelination. The on the regeneration and with CPM; in EAE, they OPC proliferation. One week after the onset of the lesion, the impact of astrocyte dysfunction on remyelination of lesions characterised the activation majority of parenchymal OPC-derived cells expressed BCAS1, remyelination efficiency needs to be and differentiation of OPCs indicating the transition to a pre-myelinating state further determined Brown To evaluate the Double-blind, phase 2a The outcome of the main variable was negative: there was Although the result of the primary et al [73] safety and efficacy of trial of RRMS patients no difference between the groups in the change in the mean variable was negative, the results of bexarotene (an RXR aged 18-50 years treated magnetisation transfer rate of the submedian lesions; there secondary/exploratory variables show agonist used in cutaneous with dimethyl fumarate, were, however, significant changes in the supermedian that bexarotene exerts a small biological T-cell lymphoma) as a randomly assigned to lesions and in the latency of the visual evoked potentials. In effect. Tolerance of bexarotene was poor remyelinating therapy bexarotene or placebo for the bexarotene group, 20% discontinued and 48% required 6 months dose reduction Watanabe To examine the capacity CSF from patients with All the patients had high levels of NfL, although GFAP levels Since all 4 neutrophil granulocyte et al [74] to differentiate NMOSD, NMOSD, MOG and RRMS only elevated in NMOSD. In MOG, Ela, MPO and MMP-8 they biomarkers can be measured within a few MOG and RRMS by 4 was evaluated for Ela, were increased compared to controls and acute RRMS. In hours, compared to a response time of up neurotrophic granulocyte MPO, MMP-8, NGAL and acute NMOSD, the S100B and GFAP levels were increased in to 2 weeks for cell-based assays for AQP4 biomarkers in CSF: Ela, compared with markers 89% and 83% of patients, respectively, compared to mean and MOG, they could support individual MPO, MMP-8 and NGAL of neuronal (NfL) and MOG values. In acute NMOSD, EDSS correlated with all 4 decision-making for acute therapeutic astrocyte (GFAP, S100B) biomarkers and GFAP, but not with NfL and S100B intervention damage with conventional ELISA or SIMOA Collorone To use quantitative multi- In a 3T scan, structural Patients showed higher ODI in the normal-appearing Increased axonal dispersion in the et al [75] parametric MRI techniques scans of the brain and white matter, including the corpus callosum, where they normal-appearing white matter and to detect clinically relevant spinal cord, and NODDI of also showed lower NDI and higher TSC vs. controls. In grey reduced axonal density in the corpus alterations not captured the brain were obtained in matter, controls vs. patients had lower ODI in the frontal, callosum suggests that this structure may by conventional MRI CIS or MS patients (n=46), parietal and temporal cortex; lower NDI in the parietal, be affected early on. NODDI alterations and controls (n=13). NDI temporal and occipital cortex; and higher TSC in the limbic were observed in grey matter in specific and ODI were measured and frontal cortex. There was no difference in brain volumes areas. The 23Na MRI technique could with NODDI, and TSC was between patients and controls. In patients, higher ODI in the detect clinically relevant pathology in very measured with 23Na MRI corpus callosum was associated with worse performance in early MS the gait test Horton To estimate the Stool samples were Among 270 ASVs included in the analyses, 20 were There are no major differences in the et al [76] association between collected and analysed by significant (p<0.05), e.g. the presence of Blautia stercoris composition of the gut microbiota gut microbiota and 16S rRNA sequencing of was associated with an increased risk of relapses. Six ASV associated with relapses, but there are subsequent disease the V4 region. ASVs were modules were identified. Higher module-specific gene values some bacterial species of the Blautia activity in paediatric-onset identified using DADA2 were associated with a higher risk of relapse. Four ASVs genus that seem to be associated with MS associated with an increased risk of relapses were included relapses in this module: Blautia massiliensis, Dorea longicatena, Coprococcus comes and an unknown species of the genus Subdoligranulum Yaldizli To assess whether the Pregnancies were DMT was discontinued in 13 out of 72 pregnancies. NfL NfL could be a sensitive and minimally et al [77] interruption of DMT due documented prospectively levels were on average 22% higher during vs. outside the invasive measure of disease activity in to pregnancy leads to an from the Swiss MS cohort postpartum period. There were 29 relapses during the pregnancy. Strategies that allow DMT to increase in NfL levels study. Serum samples were postpartum periods, which were associated with 98% more be continued during pregnancy may be collected every 6 to 12 NfL. The effect of the postpartum period on NfL disappeared justified months and analysed using after including exposure to DMT in the model. DMT patients SIMOA had 12% lower NfL levels vs. non-DMT patients ASV: amplicon sequence variants; BCAS1: breast carcinoma amplified sequence 1; CIS: clinically isolated syndrome; CPM: central pontine myelinolysis; CSF: cerebrospinal fluid; DADA2: Divisive Amplicon Denoising Algorithm-2; DMT: disease-modifying therapies; EAE: experimental autoimmune encephalomyelitis; Ela: elastase; MMP-8: matrix metalloproteinase 8; MOG: anti-MOG antibody-associated diseases; MPO: myeloperoxidase; NDI: neurite density index; NGAL: neutrophil gelatinase-associated lipocalin; NMOSD: neuromyelitis optica spectrum disorders; NODDI: neurite orientation dispersion and density imaging; ODI: orientation dispersion index; OPC: oligodendrocyte precursor cells; RM: magnetic resonance; RXR: retinoid X receptor; SIMOA: single molecule array assay; TSC: total sodium concentration. www.neurologia.com Rev Neurol 2021; 72 (12): 433-442 439 Ó. Fernández, et al characteristics and those of their disease, while also 22. 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ECTRIMS- systematic review. CNS Drugs 2020; 34: 599-628. ACTRIMS; Virtual 2020. www.neurologia.com Rev Neurol 2021; 72 (12): 433-442 441 Ó. Fernández, et al XIII Reunión Post-ECTRIMS: revisión de las novedades presentadas en el Congreso ECTRIMS 2020 (II) 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) se reúnen para revisar las novedades presentadas en el ECTRIMS. Objetivo. En el presente artículo, publicado en dos partes, se resumen las ponencias de la reunión post-ECTRIMS, celebrada los días 16 y 17 de octubre de 2020 virtualmente. Desarrollo. En esta segunda parte se destaca la importancia del género y la edad en la compresión de la patología de la enfermedad y la optimización de su manejo. Se exponen los avances realizados en la EM pediátrica desde un punto de vista neuropsicológico y de neuroimagen. Por su parte, cobran especial protagonismo los hallazgos que contribuyen a realizar un enfoque del tratamiento más personalizado y a elegir la mejor estrategia de tratamiento (farmacológica y no farmacológica) para cada paciente. De igual forma, se abordan los resultados relacionados con las estrategias posibles que promuevan la remielinización. Aunque no hay grandes avances en el tratamiento de formas progresivas, se destacan algunos métodos cuantitativos para la clasificación de estos pacientes. Además, se incluyen los resultados sobre herramientas potenciales de evaluación y tratamiento de los déficits cognitivos, y algunos aspectos relevantes observados en el espectro de los trastornos de la neuromielitis óptica. Por último, se detallan los resultados de las ponencias consideradas como noticias de última hora en el ECTRIMS-ACTRIMS. Conclusiones. Se presentaron avances principalmente sobre el conocimiento de la EM pediátrica, las estrategias de remielinización y la evaluación cognitiva en la EM. Palabras clave. ACTRIMS. Congreso. ECTRIMS. EM. Esclerosis múltiple. Post-ECTRIMS. 442 www.neurologia.com Rev Neurol 2021; 72 (12): 433-442