Modeling and simulation for prediction of multiple sclerosis progression.

In light of extensive work that has created a wide range of techniques for predicting the course of multiple sclerosis (MS) disease, this paper attempts to provide an overview of these approaches and put forth an alternative way to predict the disease progression. For this purpose, the existing methods for estimating and predicting the course of the disease have been categorized into clinical, radiological, biological, and computational or artificial intelligence-based markers. Weighing the weaknesses and strengths of these prognostic groups is a profound method that is yet in need and works directly at the level of diseased connectivity. Therefore, we propose using the computational models in combination with established connectomes as a predictive tool for MS disease trajectories. The fundamental conduction-based Hodgkin-Huxley model emerged as promising from examining these studies. The advantage of the Hodgkin-Huxley model is that certain properties of connectomes, such as neuronal connection weights, spatial distances, and adjustments of signal transmission rates, can be taken into account. It is precisely these properties that are particularly altered in MS and that have strong implications for processing, transmission, and interactions of neuronal signaling patterns. The Hodgkin-Huxley (HH) equations as a point-neuron model are used for signal propagation inside a small network. The objective is to change the conduction parameter of the neuron model, replicate the changes in myelin properties in MS and observe the dynamics of the signal propagation across the network. The model is initially validated for different lengths, conduction values, and connection weights through three nodal connections. Later, these individual factors are incorporated into a small network and simulated to mimic the condition of MS. The signal propagation pattern is observed after inducing changes in conduction parameters at certain nodes in the network and compared against a control model pattern obtained before the changes are applied to the network. The signal propagation pattern varies as expected by adapting to the input conditions. Similarly, when the model is applied to a connectome, the pattern changes could give an insight into disease progression. This approach has opened up a new path to explore the progression of the disease in MS. The work is in its preliminary state, but with a future vision to apply this method in a connectome, providing a better clinical tool.

Effects of photobiomodulation therapy on muscle function in individuals with multiple sclerosis.

BACKGROUND: In people with multiple sclerosis (pwMS), muscle fatigue and weakness are common issues that can interfere with daily activities. Photobiomodulation therapy (PBMT), comprising light in a 600-1100 nm bandwidth, is a low-level laser therapy thought to improve muscle performance in non-disease populations, in part, by improving mitochondrial function and thus, might be beneficial in pwMS. Given this potential, we aimed to investigate the effects of PBMT on muscle performance in pwMS, both in the short-term and over an extended period. METHODS: This study consisted of two parts with a randomized double-blind crossover design. In study I, muscle function was assessed in four sessions before and after PBMT in ambulatory pwMS (N = 17, F = 14) as follows: maximal voluntary contraction (MVC) and muscle fatigue of the right tibialis anterior (TA) muscle was compared at baseline and following a two-min submaximal fatiguing contraction. Then, PBMT was administered to the belly of TA muscle at different doses of energy of an active device (40 J, 80 J, 120 J) or placebo. The muscle function assessment was then repeated. OUTCOME VARIABLES: muscle force recovery (%), muscle fatigue (%). Statistical tests included McNemar's exact test, Wilcoxon signed-rank test, and the Friedman test. In study II, a subgroup from study I (N = 12, F = 11) received individualized doses (i.e., best dose-effect observed in study I) of active, or placebo PBMT, which was administered on the TA muscle for two weeks. Muscle function assessments were performed pre- and post-PBMT in four sessions similar to study I. OUTCOME VARIABLES: Baseline strength (N), endurance time (s), and muscle fatigue (%). The Wilcoxon signed-rank test was used for statistical analysis. Values are reported as mean (SD). RESULTS: In study I, participants who received a high dose of PBMT showed significant improvement in force recovery (101.89 % (13.55 %)) compared to the placebo group (96.3 % (18.48 %); p = 0.03). Muscle fatigue did not significantly improve with either active PBMT or placebo. In study II, active PBMT resulted in a significant improvement in muscle strength compared to both the baseline (pre-PBMT = 162.70 N (37.52 N); post-PBMT = 185.56 N (33.95 N); p = 0.01) and the placebo group (active PBMT: mean-change = 22.87 N (23.67 N); placebo: mean-change = -4.12 N (31.95 N); p = 0.02). Endurance time and muscle fatigue did not show significant improvement with either active PBMT or placebo. CONCLUSION: Our findings suggest that an individualized dose of PBMT might improve muscle performance, including force recovery and strength in individuals with mild-moderate MS. Therefore, PBMT might be a novel therapeutic modality, either as a standalone treatment or in combination with other interventions, to improve muscle performance in pwMS.

Virus de Epstein-Barr: más que una mononucleosis infecciosa / Epstein-Barr virus: more than infectious mononucleosis

El virus de Epstein-Barr (VEB) fue el primer virus asociado a neoplasias en humanos. Infecta el 95 % de la población mundial, y aunque usualmente es asintomático, puede causar mononucleosis infecciosa y se relaciona con más de 200.000 casos de neoplasias al año. De igual forma, se asocia con esclerosis múltiple y otras enfermedades autoinmunes. A pesar de ser catalogado como un virus oncogénico, solo un pequeño porcentaje de los individuos infectados desarrollan neoplasias asociadas a VEB. Su persistencia involucra la capacidad de alternar entre una serie de programas de latencia, y de reactivarse cuando tiene la necesidad de colonizar nuevas células B de memoria, con el fin de sostener una infección de por vida y poder transmitirse a nuevos hospederos. En esta revisión se presentan las generalidades del VEB, además de su asociación con varios tipos de neoplasias, como son el carcinoma nasofaríngeo, el carcinoma gástrico, el linfoma de Hodgkin y el linfoma de Burkitt, y la esclerosis múltiple. Adicionalmente, se describen los mecanismos fisiopatológicos de las diferentes entidades, algunos de ellos no completamente dilucidados

Epstein-Barr virus (EBV) was the first virus associated with human cancer. It infects 95% of the world's population, and although it is usually asymptomatic, it causes infectious mononucleosis. It is related to more than 200,000 cases of cancer per year, and is also associated with multiple sclerosis and other autoimmune diseases. Despite being classified as an oncogenic virus, only a small percentage of infected individuals develop EBV-associated cancer. Its persistence involves the ability to alternate between a series of latency programs, and the ability to reactivate itself when it needs to colonize new memory B cells, in order to sustain a lifelong infection and be able to transmit to new hosts. In this review, the general characteristics of EBV are presented, in addition to its association with various types of cancers, such as nasopharyngeal carcinoma, gastric carcinoma, Hodgkin's lymphoma and Burkitt's lymphoma, and multiple sclerosis. Additionally, the pathophysiological mechanisms of the different entities are described, some of them not completely elucidated yet

Sex differences in the inflammatory response of the mouse DRG and its connection to pain in experimental autoimmune encephalomyelitis.

Multiple Sclerosis (MS) is an autoimmune disease with notable sex differences. Women are not only more likely to develop MS but are also more likely than men to experience neuropathic pain in the disease. It has been postulated that neuropathic pain in MS can originate in the peripheral nervous system at the level of the dorsal root ganglia (DRG), which houses primary pain sensing neurons (nociceptors). These nociceptors become hyperexcitable in response to inflammation, leading to peripheral sensitization and eventually central sensitization, which maintains pain long-term. The mouse model experimental autoimmune encephalomyelitis (EAE) is a good model for human MS as it replicates classic MS symptoms including pain. Using EAE mice as well as naïve primary mouse DRG neurons cultured in vitro, we sought to characterize sex differences, specifically in peripheral sensory neurons. We found sex differences in the inflammatory profile of the EAE DRG, and in the TNFα downstream signaling pathways activated intracellularly in cultured nociceptors. We also found increased cell death with TNFα treatment. Given that TNFα signaling has been shown to initiate intrinsic apoptosis through mitochondrial disruption, this led us to investigate sex differences in the mitochondria's response to TNFα. Our results demonstrate that male sensory neurons are more sensitive to mitochondrial stress, making them prone to neuronal injury. In contrast, female sensory neurons appear to be more resistant to mitochondrial stress and exhibit an inflammatory and regenerative phenotype that may underlie greater nociceptor hyperexcitability and pain. Understanding these sex differences at the level of the primary sensory neuron is an important first step in our eventual goal of developing sex-specific treatments to halt pain development in the periphery before central sensitization is established.

Cochlear implantation of a patient with multiple sclerosis: case report and systematic review.

BACKGROUND: Cochlear implantation can be used when a patient's hearing cannot satisfactorily be improved after optimised hearing aid fitting. However, in patients with a cochlear nerve or brain disorder affecting hearing, the benefits of cochlear implants are not so straightforward. METHODS: This paper describes a 58-year-old patient suffering from multiple sclerosis and profound sensorineural hearing loss, rehabilitated with a cochlear implant. Literature concerning cochlear implantation in demyelinating conditions was systematically reviewed using PubMed/Medline and Web of Science databases. RESULTS: The patient's cochlear implantation was successful, with speech discrimination scores remaining above 90 per cent for eight years post-operatively. No previous cases of cochlear implantation with multiple sclerosis related hearing loss have been reported, despite the high incidence of hearing loss in multiple sclerosis patients. CONCLUSION: This paper demonstrates that multiple sclerosis lesions should not be an exclusion criterion in an otherwise suitable candidate for cochlear implantation.

Neurostructural and Neurophysiological Correlates of Multiple Sclerosis Physical Fatigue: Systematic Review and Meta-Analysis of Cross-Sectional Studies.

Fatigue is one of the most debilitating symptoms for people with multiple sclerosis (PwMS). By consolidating a diverse and conflicting evidence-base, this systematic review and meta-analysis aimed to gain new insights into the neurobiology of MS fatigue. MEDLINE, ProQuest, CINAHL, Web of Science databases and grey literature were searched using Medical Subject Headings. Eligible studies compared neuroimaging and neurophysiological data between people experiencing high (MS-HF) versus low (MS-LF) levels of perceived MS fatigue, as defined by validated fatigue questionnaire cut-points. Data were available from 66 studies, with 46 used for meta-analyses. Neuroimaging studies revealed lower volumetric measures in MS-HF versus MS-LF for whole brain (-22.74 ml; 95% CI: -37.72 to -7.76 ml; p = 0.003), grey matter (-18.81 ml; 95% CI: -29.60 to -8.03 ml; p < 0.001), putamen (-0.40 ml; 95% CI: -0.69 to -0.10 ml; p = 0.008) and acumbens (-0.09 ml; 95% CI: -0.15 to -0.03 ml; p = 0.003) and a higher volume of T1-weighted hypointense lesions (1.10 ml; 95% CI: 0.47 to 1.73 ml; p < 0.001). Neurophysiological data showed reduced lower-limb maximum voluntary force production (-19.23 N; 95% CI: -35.93 to -2.53 N; p = 0.02) and an attenuation of upper-limb (-5.77%; 95% CI:-8.61 to -2.93%; p < 0.0001) and lower-limb (-2.16%; 95% CI:-4.24 to -0.07%; p = 0.04) skeletal muscle voluntary activation, accompanied by more pronounced upper-limb fatigability (-5.61%; 95% CI: -9.57 to -1.65%; p = 0.006) in MS-HF versus MS-LF. Results suggest that MS fatigue is characterised by greater cortico-subcortical grey matter atrophy and neural lesions, accompanied by neurophysiological decrements, which include reduced strength and voluntary activation. Prospero registration Prospero registration number: CRD42016017934.

Associação entre o número de deglutições, resíduo faríngeo e broncoaspiração na esclerose múltipla / Association between the number of swallowing, pharyngeal residue and bronchopulmonary aspiration in multiple sclerosis

RESUMO Objetivo verificar a associação entre o número de deglutições e presença de resíduo faríngeo e broncoaspiração em pessoas com esclerose múltipla. Métodos estudo transversal observacional de exames de videofluoroscopia de 231 deglutições de indivíduos com esclerose múltipla. Três fonoaudiólogas avaliaram as deglutições de IDDSI 1 (International Dysphagia Diet Standardisation Initiative) (5 ml e 10 ml) e IDDSI 4 (8 ml) quanto à presença de resíduo faríngeo e de penetração/aspiração. Deglutições que não apresentaram resíduo faríngeo foram classificadas como deglutições sem resíduos faríngeos (DSR) e as que apresentaram, como deglutições com resíduos faríngeos (DCR), sendo estas últimas subdivididas em resíduos faríngeos em todas as ofertas ou eventuais (DCR1 e DCR2). O número de deglutições foi analisado por um avaliador cego e comparado com os dados demográficos e clínicos. Resultados das 231 deglutições, 73 (31,6%) apresentaram resíduos faríngeos. O número médio de deglutições foi semelhante nas deglutições sem e com resíduos faríngeos em cada consistência e volume e nas variáveis idade, gênero, tipo de esclerose múltipla e incapacidade funcional. Houve associação entre a média do número de deglutições e a ausência de penetração/aspiração, quando comparada às deglutições sem e com resíduos faríngeos, nas DCR2 e em indivíduos acima de 50 anos. Ao analisar intragrupo, observou-se associação nas DCR, sendo maior na ausência de penetração/aspiração e nas DCR2. Conclusão não houve correlação entre o número de deglutições e a presença de resíduos em recessos faríngeos na esclerose múltipla. Todavia, o número de deglutições foi maior quando houve resíduo e ausência de disfagia e de penetração/aspiração, em indivíduos mais velhos.

ABSTRACT Purpose To verify the association between the number of swallows and the presence of pharyngeal residue and bronchoaspiration in people with Multiple Sclerosis. Methods An observational cross-sectional study of videofluoroscopic examinations of 231 swallows from individuals with Multiple Sclerosis. Three speech therapists evaluated IDDSI 1 (International Dysphagia Diet Standardisation Initiative) (5ml and 10ml) and IDDSI 4 (8ml) deglutitions for pharyngeal residue and penetration/ aspiration. Swallows with no pharyngeal residue were classified as swallows without pharyngeal residue (SWTR) and those with pharyngeal residue (SWR), the latter subdivided into pharyngeal residue in all or occasional offerings (SWR1 e SWR2). The number of swallows was analyzed by a blind evaluator and compared with demographic and clinical data. Results Of the 231 swallows, 73 (31.6%) showed pharyngeal residues. The mean number of swallows was similar in the deglutitions with and without pharyngeal residues in each consistency and volume and in the variables age, gender, type of Multiple Sclerosis and functional disability. There was an association between the mean number of swallows and the absence of penetration/aspiration when comparing deglutitions with and without pharyngeal residues, in SWR2 and in individuals over 50 years of age. When analyzing intragroup, an association was observed in SWR, being higher in the absence of penetration/aspiration and in SWR2. Conclusion There was no correlation between the number of swallows and the presence of residues in pharyngeal recesses in multiple sclerosis. However, the number of swallows was higher when there was residue and absence of dysphagia and penetration/aspiration, and in older individuals.

Crotalphine Attenuates Pain and Neuroinflammation Induced by Experimental Autoimmune Encephalomyelitis in Mice.

Multiple sclerosis (MS) is a demyelinating disease of inflammatory and autoimmune origin, which induces sensory and progressive motor impairments, including pain. Cells of the immune system actively participate in the pathogenesis and progression of MS by inducing neuroinflammation, tissue damage, and demyelination. Crotalphine (CRO), a structural analogue to a peptide firstly identified in Crotalus durissus terrificus snake venom, induces analgesia by endogenous opioid release and type 2 cannabinoid receptor (CB2) activation. Since CB2 activation downregulates neuroinflammation and ameliorates symptoms in mice models of MS, it was presently investigated whether CRO has a beneficial effect in the experimental autoimmune encephalomyelitis (EAE). CRO was administered on the 5th day after immunization, in a single dose, or five doses starting at the peak of disease. CRO partially reverted EAE-induced mechanical hyperalgesia and decreased the severity of the clinical signs. In addition, CRO decreases the inflammatory infiltrate and glial cells activation followed by TNF-α and IL-17 downregulation in the spinal cord. Peripherally, CRO recovers the EAE-induced impairment in myelin thickness in the sciatic nerve. Therefore, CRO interferes with central and peripheral neuroinflammation, opening perspectives to MS control.

The Role of Nutritional Lifestyle and Physical Activity in Multiple Sclerosis Pathogenesis and Management: A Narrative Review.

Studies on the role of nutritional factors and physical activity (PA) in the pathogenesis of multiple sclerosis (MS) go back a long time. Despite the intrinsic difficulty of studying their positive or negative role in MS, the interest of researchers on these topics increased during the last few decades, since the role of diet has been investigated with the perspective of the association with disease-modifying drugs (DMD). The association of DMD, diets, and PA might have an additive effect in modifying disease severity. Among the various diets investigated (low-carbohydrate, gluten-free, Mediterranean, low-fat, fasting-mimicking, and Western diets) only low-carbohydrate, Mediterranean, and fast-mimicking diets have shown both in animal models and in humans a positive effect on MS course and in patient-reported outcomes (PROs). However, the Mediterranean diet is easier to be maintained compared to fast-mimicking and low-carbohydrate diets, which may lead to detrimental side effects requiring careful clinical monitoring. Conversely, the Western diet, which is characterized by a high intake of highly saturated fats and carbohydrates, may lead to the activation of pro-inflammatory immune pathways and is therefore not recommended. PA showed a positive effect both in animal models as well as on disease course and PROs in humans. Training with combined exercises is considered the more effective approach.

iRhom1 rescues cognitive dysfunction in multiple sclerosis via preventing myelin injury.

Multiple sclerosis (MS) is characterized by myelin sheath injury. A disintegrin and metalloprotease-17 (ADAM17), a disintegrin and metalloproteinase, is essential in regulating oligodendrocyte (OL) regeneration and remyelination under demyelinating conditions. iRhom1, a highly conserved inactive protease that belongs to the rhomboid family, is one of key regulators for ADAM17 maturation. However, it is unknown whether iRhom1 also plays a role in central neuron system myelination under demyelinating conditions like MS. In this study, we investigated the function of iRhom1/ADAM17 in cognitive capability in MS by establishing the mice with iRhom1 overexpression in the hippocampus.

Risk Factors and Time to Clinical Symptoms of Multiple Sclerosis Among Patients With Radiologically Isolated Syndrome.

Importance: Younger age, oligoclonal bands, and infratentorial and spinal cord lesions are factors associated with an increased 10-year risk of clinical conversion from radiologically isolated syndrome (RIS) to multiple sclerosis (MS). Whether disease-modifying therapy is beneficial for individuals with RIS is currently unknown. Objectives: To evaluate the 2-year risk of a clinical event (onset of clinical symptoms of MS) prospectively, identify factors associated with developing an early clinical event, and simulate the sample size needed for a phase III clinical trial of individuals with RIS meeting 2009 RIS criteria. Design, Setting, and Participants: This cohort study used data on prospectively followed-up individuals with RIS identified at 1 of 26 tertiary centers for MS care in France that collect data for the Observatoire Français de la Sclérose en Plaques database. Participants were aged 10 to 80 years with 2 or more magnetic resonance imaging (MRI) scans after study entry and an index scan after 2000. All diagnoses were validated by an expert group, whose review included a double centralized MRI reading. Data were analyzed from July 2020 to January 2021. Exposure: Diagnosis of RIS. Main Outcomes and Measures: Risk of clinical event and associated covariates at index scan were analyzed among all individuals with RIS. Time to the first clinical event was compared by covariates, and sample size estimates were modeled based on identified risk factors. Results: Among 372 individuals with RIS (mean [SD] age at index MRI scan, 38.6 [12.1] years), 354 individuals were included in the analysis (264 [74.6%] women). A clinical event was identified among 49 patients (13.8%) within 2 years, which was associated with an estimated risk of conversion of 19.2% (95% CI, 14.1%-24.0%). In multivariate analysis, age younger than 37 years (hazard ratio [HR], 4.04 [95% CI, 2.00-8.15]; P < .001), spinal cord lesions (HR, 5.11 [95% CI, 1.99-13.13]; P = .001), and gadolinium-enhancing lesions on index scan (HR, 2.09 [95% CI, 1.13-3.87]; P = .02) were independently associated with an increased risk of conversion to MS. Having 2 factors at the time of the index MRI scan was associated with a risk of 27.9% (95% CI, 13.5%-39.9%) of a seminal event within 2 years, increasing to 90.9% (95% CI, 41.1%-98.6%) for individuals with all 3 factors (3 risk factors vs none: HR, 23.34 [95% CI, 9.08-59.96]; P < .001). Overall, with 80% power to detect an effect size of 60% within 24 months, a total of 160 individuals with RIS were needed assuming an event rate of 20%. Conclusions and Relevance: This study found that age younger than age 37 years, spinal cord involvement, and gadolinium-enhancing lesions on index MRI scan were associated with earlier clinical disease and relevant to the number of enrolled patients needed to detect a potential treatment effect.

Antipsychotic drugs counteract autophagy and mitophagy in multiple sclerosis.

Multiple sclerosis (MS) is a neuroinflammatory and neurodegenerative disease characterized by myelin damage followed by axonal and ultimately neuronal loss. The etiology and physiopathology of MS are still elusive, and no fully effective therapy is yet available. We investigated the role in MS of autophagy (physiologically, a controlled intracellular pathway regulating the degradation of cellular components) and of mitophagy (a specific form of autophagy that removes dysfunctional mitochondria). We found that the levels of autophagy and mitophagy markers are significantly increased in the biofluids of MS patients during the active phase of the disease, indicating activation of these processes. In keeping with this idea, in vitro and in vivo MS models (induced by proinflammatory cytokines, lysolecithin, and cuprizone) are associated with strongly impaired mitochondrial activity, inducing a lactic acid metabolism and prompting an increase in the autophagic flux and in mitophagy. Multiple structurally and mechanistically unrelated inhibitors of autophagy improved myelin production and normalized axonal myelination, and two such inhibitors, the widely used antipsychotic drugs haloperidol and clozapine, also significantly improved cuprizone-induced motor impairment. These data suggest that autophagy has a causal role in MS; its inhibition strongly attenuates behavioral signs in an experimental model of the disease. Therefore, haloperidol and clozapine may represent additional therapeutic tools against MS.

Central Nervous System Barriers Impact Distribution and Expression of iNOS and Arginase-1 in Infiltrating Macrophages During Neuroinflammation.

In multiple sclerosis (MS) and other neuroinflammatory diseases, monocyte-derived cells (MoCs) traffic through distinct central nervous system (CNS) barriers and gain access to the organ parenchyma exerting detrimental or beneficial functions. How and where these MoCs acquire their different functional commitments during CNS invasion remains however unclear, thus hindering the design of MS treatments specifically blocking detrimental MoC actions. To clarify this issue, we investigated the distribution of iNOS+ pro-inflammatory and arginase-1+ anti-inflammatory MoCs at the distinct border regions of the CNS in a mouse model of MS. Interestingly, MoCs within perivascular parenchymal spaces displayed a predominant pro-inflammatory phenotype compared to MoCs accumulating at the leptomeninges and at the intraventricular choroid plexus (ChP). Furthermore, in an in vitro model, we could observe the general ability of functionally-polarized MoCs to migrate through the ChP epithelial barrier, together indicating the ChP as a potential CNS entry and polarization site for MoCs. Thus, pro- and anti-inflammatory MoCs differentially accumulate at distinct CNS barriers before reaching the parenchyma, but the mechanism for their phenotype acquisition remains undefined. Shedding light on this process, we observed that endothelial (BBB) and epithelial (ChP) CNS barrier cells can directly regulate transcription of Nos2 (coding for iNOS) and Arg1 (coding for arginase-1) in interacting MoCs. More specifically, while TNF-α+IFN-γ stimulated BBB cells induced Nos2 expression in MoCs, IL-1ß driven activation of endothelial BBB cells led to a significant upregulation of Arg1 in MoCs. Supporting this latter finding, less pro-inflammatory MoCs could be found nearby IL1R1+ vessels in the mouse spinal cord upon neuroinflammation. Taken together, our data indicate differential distribution of pro- and anti-inflammatory MoCs at CNS borders and highlight how the interaction of MoCs with CNS barriers can significantly affect the functional activation of these CNS-invading MoCs during autoimmune inflammation.

Current Immunological and Clinical Perspective on Vaccinations in Multiple Sclerosis Patients: Are They Safe after All?

Vaccines work by stimulating the immune system, and their immunogenicity is key in achieving protection against specific pathogens. Questions have been raised whether in Multiple Sclerosis (MS) patients they could induce disease exacerbation and whether vaccines could possibly act as a trigger in the onset of MS in susceptible populations. So far, no correlation has been found between the vaccinations against influenza, hepatitis B, tetanus, human papillomavirus, measles, mumps, rubella, varicella zoster, tuberculosis, yellow fever, or typhoid fever and the risk of MS. Further research is needed for the potential protective implications of the tetanus and Bacillus Calmette-Guerin vaccines in MS patients. Nowadays with the emerging coronavirus disease 2019 (COVID-19) and recent vaccinations approval and arrival, the risk-benefit in MS patients with regards to safety and efficacy of COVID-19 vaccination in those treated with immunosuppressive therapies is of paramount importance. In this manuscript, we demonstrate how different vaccine types could be related to the immunopathogenesis of MS and discuss the risks and benefits of different vaccinations in MS patients.

Microglia: The Missing Link to Decipher and Therapeutically Control MS Progression?

Therapeutically controlling chronic progression in multiple sclerosis (MS) remains a major challenge. MS progression is defined as a steady loss of parenchymal and functional integrity of the central nervous system (CNS), occurring independent of relapses or focal, magnetic resonance imaging (MRI)-detectable inflammatory lesions. While it clinically surfaces in primary or secondary progressive MS, it is assumed to be an integral component of MS from the very beginning. The exact mechanisms causing progression are still unknown, although evolving evidence suggests that they may substantially differ from those driving relapse biology. To date, progression is assumed to be caused by an interplay of CNS-resident cells and CNS-trapped hematopoietic cells. On the CNS-resident cell side, microglia that are phenotypically and functionally related to cells of the monocyte/macrophage lineage may play a key role. Microglia function is highly transformable. Depending on their molecular signature, microglia can trigger neurotoxic pathways leading to neurodegeneration, or alternatively exert important roles in promoting neuroprotection, downregulation of inflammation, and stimulation of repair. Accordingly, to understand and to possibly alter the role of microglial activation during MS disease progression may provide a unique opportunity for the development of suitable, more effective therapeutics. This review focuses on the current understanding of the role of microglia during disease progression of MS and discusses possible targets for therapeutic intervention.

Prognostic factors for relapse and outcome in pediatric acute transverse myelitis.

OBJECTIVE: It may be difficult for clinicians to estimate the prognosis of pediatric acute transverse myelitis (ATM). The aim of this study was to define prognostic factors for relapsing disease and poor outcome in pediatric ATM. METHODS: This prospective cohort study included 49 children, 18 boys and 31 girls (median age 13.1 years, IQR 6.5-16.2) with a first episode of ATM. Factors associated with relapsing disease and poor outcome (Expanded Disability Status Scale (EDSS) ≥ 4) were assessed during a median follow-up of 37 months (IQR 18-75). RESULTS: In total, 14 patients (29%) experienced ≥ 1 relapse(s) and nine patients (18%) had a poor outcome. Factors at onset associated with relapsing disease included higher age (16.1 vs. 11.6 years, p = 0.002), longer time to maximum severity of symptoms (5.5 vs. 3 days, p = 0.01), lower maximum EDSS score (4.0 vs. 6.5, p = 0.003), short lesion on spinal MRI (64 vs. 21%, p = 0.006), abnormalities on brain MRI (93 vs. 44%, p = 0.002) and presence of oligoclonal bands in cerebrospinal fluid (67 vs. 14%, p = 0.004). The only factor associated with poor outcome was presence of a spinal cord lesion on MRI without cervical involvement (56 vs. 14%, p = 0.02). CONCLUSION: Pediatric ATM patients presenting with clinical, radiological and laboratory features associated with multiple sclerosis (MS) are at risk for relapsing disease. In absence of these known MS risk factors at onset of disease these patients are at low risk for relapses. Only a minority of pediatric ATM patients in this cohort have a poor outcome.

Clinical findings and outcomes of uveitis associated with multiple sclerosis.

PURPOSE: To describe the clinical findings and outcomes in patients who presented with uveitis associated with multiple sclerosis. METHODS: Retrospective review of 20 patients (38 eyes). RESULTS: The most frequent ocular finding was multifocal elongated retinal perivenous "sheathing" with focal vascular leakage on fundus fluorescein angiography in 29 eyes followed by vitreous snowballs and debris in 26 eyes, anterior chamber inflammation in 15 eyes, mutton-fat keratic precipitates in 14 eyes, posterior synechiae in 13 eyes, cystoid macular edema in 9 eyes, iris nodules in 4 eyes, and optic neuritis in 3 eyes. Patients with cystoid macular edema were treated successfully with systemic corticosteroids combined with mycophenolate mofetil. Ocular complications were cataract in 6 eyes, glaucoma in 2 eyes and vitreous hemorrhage in 1 eye. CONCLUSIONS: Multifocal elongated retinal perivenous "sheathing" with focal vascular leakage on fundus fluorescein angiography is the most frequent finding in uveitis associated with multiple sclerosis.

Neuroprotective Methodologies in the Treatment of Multiple Sclerosis Current Status of Clinical and Pre-clinical Findings.

Multiple sclerosis is an idiopathic and autoimmune associated motor neuron disorder that affects myelinated neurons in specific brain regions of young people, especially females. MS is characterized by oligodendrocytes destruction further responsible for demyelination, neuroinflammation, mitochondrial abnormalities, oxidative stress and neurotransmitter deficits associated with motor and cognitive dysfunctions, vertigo and muscle weakness. The limited intervention of pharmacologically active compounds like interferon-ß, mitoxantrone, fingolimod and monoclonal antibodies used clinically are majorly associated with adverse drug reactions. Pre-clinically, gliotoxin ethidium bromide mimics the behavioral and neurochemical alterations in multiple sclerosis- like in experimental animals associated with the down-regulation of adenyl cyclase/cAMP/CREB, which is further responsible for a variety of neuropathogenic factors. Despite the considerable investigation of neuroprotection in curing multiple sclerosis, some complications still remain. The available medications only provide symptomatic relief but do not stop the disease progression. In this way, the development of unused beneficial methods tends to be ignored. The limitations of the current steady treatment may be because of their activity at one of the many neurotransmitters included or their failure to up direct signaling flag bearers detailed to have a vital part in neuronal sensitivity, biosynthesis of neurotransmitters and its discharge, development, and separation of the neuron, synaptic versatility and cognitive working. Therefore, the current review strictly focused on the exploration of various clinical and pre-clinical features available for multiple sclerosis to understand the pathogenic mechanisms and to introduce pharmacological interventions associated with the upregulation of intracellular adenyl cyclase/cAMP/CREB activation to ameliorate multiple sclerosis-like features.

Associations between smoking and walking, fatigue, depression, and health-related quality of life in persons with multiple sclerosis.

Smoking is associated with increased multiple sclerosis (MS) risk. In addition, some studies have reported that smoking is associated with anxiety and depression. However, the associations between smoking, walking, and fatigue are needed to be investigated. The objective was to investigate the associations between cigarette smoking and walking, fatigue, depression symptom severity, and health-related quality of life in persons with MS. Two hundred seventy-nine persons with MS were evaluated in this cross-sectional study. Study outcomes were neurological disability level, walking speed, walking endurance, perceived walking impact of MS, fatigue, depression symptom severity, and health-related quality of life. There were 95 (34.1%) current smokers who had significantly higher fatigue (p = 0.003, pη2 = 0.031) and depression (p = 0.044, pη2 = 0.015), and lower health-related quality of life (p = 0.003, pη2 = 0.031) after adjusting for age, gender, neurological disability level, and disease duration compared to non-smokers (n = 184). There was no significant difference between smokers and non-smokers in walking measures (p > 0.05). Smoking intensity was significantly correlated with age (r = 0.487), neurological disability level (r = 0.227), disease duration (r = 0.30), walking speed (r = 0.574), walking endurance (r = - 0.461), perceived walking impact of MS (r = 0.684), fatigue (r = 0.370), health-related quality of life (r = - 0.259), and depression (r = 0.269) in current smokers. Cigarette smokers with MS had significantly more fatigue and depression symptom severity and less health-related quality of life compared to non-smokers. Increased pack-years of cigarette smoking was associated with worse walking ability and health-related quality of life, and greater depression symptom severity and fatigue.

Short-term reproducibility of cystometry in multiple sclerosis patients.

OBJECTIVE: To assess the reproducibility of detrusor activity cystometric pattern in multiple sclerosis (MS) patients, which is poorly documented in the medical literature, by means of successive filling. METHODS: We conducted a prospective study in MS patients; cystometry was repeated twice at 5minutes of interval if a detrusor overactivity before 300mL of filling was observed. Thus, 3 successive cystometries were analysed. The following characteristics were recorded: detrusor maximum pressure (Pmax), volume at the first involuntary detrusor contraction (IDC), maximum cystometric capacity (MCC), pressure at the first IDC, the existence of an overactive detrusor classified as phasic or terminal. RESULTS: We included 31 patients (19 women and 12 men); only 6 patients were naïve-treatment, the mean EDSS was: 5.3 (±1.6) and the mean age was 48.4 (±12.5) years. All the patients had an overactive detrusor for each cystometry. The reproducibility was good for all the parameters (range ICC between 0.7 and 0.83). CONCLUSION: Quantitative and qualitative cystometric data have a good reproducibility in MS patients with detrusor overactivity before 300mL of filling. LEVEL OF PROOF: 3.