A One-Two Punch in the Gut May Trigger Multiple Sclerosis.

The microbiome plays an important role in multiple sclerosis. In a recent issue of Nature, Miyauchi et al. report that gut microbial molecular mimicry in concert with gut microbes that enhance Th17 cells act synergistically to worsen CNS autoimmunity.

Gut Microbiome in Progressive Multiple Sclerosis.

OBJECTIVE: This study was undertaken to investigate the gut microbiome in progressive multiple sclerosis (MS) and how it relates to clinical disease. METHODS: We sequenced the microbiota from healthy controls and relapsing-remitting MS (RRMS) and progressive MS patients and correlated the levels of bacteria with clinical features of disease, including Expanded Disability Status Scale (EDSS), quality of life, and brain magnetic resonance imaging lesions/atrophy. We colonized mice with MS-derived Akkermansia and induced experimental autoimmune encephalomyelitis (EAE). RESULTS: Microbiota ß-diversity differed between MS patients and controls but did not differ between RRMS and progressive MS or differ based on disease-modifying therapies. Disease status had the greatest effect on the microbiome ß-diversity, followed by body mass index, race, and sex. In both progressive MS and RRMS, we found increased Clostridium bolteae, Ruthenibacterium lactatiformans, and Akkermansia and decreased Blautia wexlerae, Dorea formicigenerans, and Erysipelotrichaceae CCMM. Unique to progressive MS, we found elevated Enterobacteriaceae and Clostridium g24 FCEY and decreased Blautia and Agathobaculum. Several Clostridium species were associated with higher EDSS and fatigue scores. Contrary to the view that elevated Akkermansia in MS has a detrimental role, we found that Akkermansia was linked to lower disability, suggesting a beneficial role. Consistent with this, we found that Akkermansia isolated from MS patients ameliorated EAE, which was linked to a reduction in RORγt+ and IL-17-producing γδ T cells. INTERPRETATION: Whereas some microbiota alterations are shared in relapsing and progressive MS, we identified unique bacteria associated with progressive MS and clinical measures of disease. Furthermore, elevated Akkermansia in MS may be a compensatory beneficial response in the MS microbiome. ANN NEUROL 2021;89:1195-1211.

γδ T Cell-Secreted XCL1 Mediates Anti-CD3-Induced Oral Tolerance.

Oral tolerance is defined as the specific suppression of cellular and/or humoral immune responses to an Ag by prior administration of the Ag through the oral route. Although the investigation of oral tolerance has classically involved Ag feeding, we have found that oral administration of anti-CD3 mAb induced tolerance through regulatory T (Treg) cell generation. However, the mechanisms underlying this effect remain unknown. In this study, we show that conventional but not plasmacytoid dendritic cells (DCs) are required for anti-CD3-induced oral tolerance. Moreover, oral anti-CD3 promotes XCL1 secretion by small intestine lamina propria γδ T cells that, in turn, induces tolerogenic XCR1+ DC migration to the mesenteric lymph node, where Treg cells are induced and oral tolerance is established. Consistent with this, TCRδ-/- mice did not develop oral tolerance upon oral administration of anti-CD3. However, XCL1 was not required for oral tolerance induced by fed Ags, indicating that a different mechanism underlies this effect. Accordingly, oral administration of anti-CD3 enhanced oral tolerance induced by fed MOG35-55 peptide, resulting in less severe experimental autoimmune encephalomyelitis, which was associated with decreased inflammatory immune cell infiltration in the CNS and increased Treg cells in the spleen. Thus, Treg cell induction by oral anti-CD3 is a consequence of the cross-talk between γδ T cells and tolerogenic DCs in the gut. Furthermore, anti-CD3 may serve as an adjuvant to enhance oral tolerance to fed Ags.

Circadian rhythm sleep disorders in patients with multiple sclerosis and its association with fatigue: A case-control study.

BACKGROUND: Circadian rhythm sleep disorders are a presentation of sleep disorders in patients with multiple sclerosis (MS). This study aims to compare this problem in MS patients with healthy people and to determine its association with chronic fatigue in MS patients. MATERIALS AND METHODS: A case-control study was performed on 120 MS patients and 60 healthy subjects matched for age and sex, in 2009 in MS Clinic Alzahra Hospital. Sleep quality, rhythm and fatigue severity were assessed using PSQI (Pittsburgh sleep quality index) and FSS (Fatigue severity Scale) questionnaires, respectively. Its reliability and validity has been confirmed in several studies (Cronbach's alpha = 0.83). This index has seven sections including patient's assessment of his/her sleep, sleep duration, efficacy of routine sleep, sleep disorders, use of hypnotic medication, and dysfunction in daily activities. RESULTS: Circadian rhythm sleep disorder was more frequent in MS patients relative to healthy subjects (P: 0.002). It was higher in MS patients with severe fatigue relative to MS patients with mild fatigue (P: 0.05). Fatigue severity was 49.9 ± 8.2 and 22.5 ± 7.4 in the first and second group, respectively. PSQI index was 7.9 ± 4.5 in patients with severe fatigue and 5.9 ± 4.5 in patients with mild fatigue and 4.5 ± 2.4 in the control group (P: 0.0001). CONCLUSION: Circadian rhythm sleep disorders are more frequent in MS patients and those with fatigue. Recognition and management of circadian rhythm sleep disorders in MS patients, especially those with fatigue may be helpful in improving care of these patients.

Vγ1 and Vγ4 gamma-delta T cells play opposing roles in the immunopathology of traumatic brain injury in males.

Traumatic brain injury (TBI) is a leading cause of morbidity and mortality. The innate and adaptive immune responses play an important role in the pathogenesis of TBI. Gamma-delta (γδ) T cells have been shown to affect brain immunopathology in multiple different conditions, however, their role in acute and chronic TBI is largely unknown. Here, we show that γδ T cells affect the pathophysiology of TBI as early as one day and up to one year following injury in a mouse model. TCRδ-/- mice are characterized by reduced inflammation in acute TBI and improved neurocognitive functions in chronic TBI. We find that the Vγ1 and Vγ4 γδ T cell subsets play opposing roles in TBI. Vγ4 γδ T cells infiltrate the brain and secrete IFN-γ and IL-17 that activate microglia and induce neuroinflammation. Vγ1 γδ T cells, however, secrete TGF-ß that maintains microglial homeostasis and dampens TBI upon infiltrating the brain. These findings provide new insights on the role of different γδ T cell subsets after brain injury and lay down the principles for the development of targeted γδ T-cell-based therapy for TBI.

Multiple sclerosis and amyotrophic lateral sclerosis: is there a link?

To date, there are no reports studying the rate of amyotrophic lateral sclerosis (ALS) in relatives of multiple sclerosis (MS) patients and vice versa. This study was designed to look into this issue using two population-based databases of MS and ALS in Isfahan province of Iran. We have searched for any first, second or third degree familial kinship between the Isfahan MS Society database and Isfahan ALS population. We compared the rate of ALS among the population of first degree relatives of MS patients, with the crude prevalence of ALS in the general population of Isfahan. On the other hand, a reverse analysis was carried out to compare the prevalence of MS in Isfahan with its rate amongst the first degree relatives of ALS patients. We found 10 families among which five had first degree kinship. The rate of the diseases was significantly higher in both comparisons among the family members (p < 0.00001) and an odds ratios of more than 67 in both calculations showed a several-fold increase of ALS occurrence in the first degree relatives of MS patients and vice versa. In our study relatives of MS patients were significantly more prone to ALS and vice versa. This could give clues about the common features that the two disease share. Both diseases have an environmental and genetic component and these results mostly point toward genetic similarities.

Cesarean delivery may increase the risk of multiple sclerosis.

BACKGROUND: Prenatal and perinatal factors are believed to contribute to the risk of developing multiple sclerosis (MS). OBJECTIVE: This study was designed to evaluate whether mode of delivery (vaginal versus cesarean section), as a perinatal factor, affects susceptibility to MS. METHODS: MS patients were recruited from the MS registry of Isfahan Multiple Sclerosis Society (IMSS) and were compared with their healthy siblings. Data regarding mode of delivery, birth order, and gestation week of birth were obtained through a specially designed questionnaire. Preterm or post term deliveries were excluded. We used conditional logistic regression statistics and adjusted for gender and birth order. RESULTS: This study included 1349 participants (449 MS patients and 900 controls). Subjects who were born by cesarean section had significant risk of MS (odds ratio, OR = 2.51; 95% confidence interval, CI: 1.43-4.41; p = 0.001). There was significant MS risk for females who were born by cesarean section (OR = 2.69, 95% CI: 1.30-5.58; p = 0.008), but not for males (OR = 2.25, 95% CI: 0.90-5.63; p = 0.082). The mean age at onset was lower in MS patients born by cesarean section (24.58 ± 6.33) compared with that of patients born by vaginal delivery (27.59 ± 7.97; p = 0.041). There was no significant difference between the two groups for birth order (p = 0.417). CONCLUSION: Our results suggest that those born by vaginal delivery are at a lower risk of subsequent MS. These preliminary findings will need to be addressed in a much larger and preferably prospective study.

CD24 gene allele variation is not associated with oligoclonal IgG bands and IgG index of multiple sclerosis patients.

OBJECTIVE: Multiple sclerosis (MS) shows evidence of many distinctive aspects of an autoimmune disorder, including a polygenic inheritance. A recent candidate gene for susceptibility to MS is CD24, which has also been shown to be associated with disease progression. This study was designed to examine whether there is a relationship between the CD24 genotype, oligoclonal band (OCB) status and IgG index in the cerebrospinal fluid (CSF) of MS patients. METHODS: A total of 27 definite MS patients were enrolled in this cross-sectional study. Blood samples were collected from a peripheral vein, and CSF was obtained by lumbar puncture. The CD24 gene was sequenced in the blood specimen, and albumin and IgG concentrations were measured in both CSF and serum. We compared both IgG index and OCB status in patients with and without CD24V/V. The correlation between MS severity score (MSSS), OCB status, CD24 genotype and IgG index was studied. RESULTS: Only 15 patients were OCB positive. Among patients with negative OCBs, only 2 patients had the V/V genotype. Furthermore, in those with the V/V genotype, IgG index was not significantly elevated (p = 0.322). Patients with the V/V genotype had a significantly higher MSSS (p = 0. 04), but neither the presence of OCBs nor the IgG index showed significant correlation with MSSS (p = 0.379 and 0.20, respectively). CONCLUSION: We could not show any relationship between the CD24V/V genotype, OCB status and IgG index. This could be interpreted as indicating that the CD24V/V allele exerts its effects on the disease course independently of CSF IgG synthesis.

Effect of Dimethyl Fumarate vs Interferon ß-1a in Patients With Pediatric-Onset Multiple Sclerosis: The CONNECT Randomized Clinical Trial.

Importance: With few approved multiple sclerosis therapies in the pediatric population, there is a need for further approved treatment options. Limited data exist for dimethyl fumarate (DMF) treatment in pediatric-onset multiple sclerosis (POMS). Objective: To compare the efficacy, safety, and tolerability of DMF vs intramuscular interferon ß-1a (IFNß-1a) in POMS. Design, Setting, and Participants: The CONNECT study was an active-controlled, open-label, rater-blinded 96-week randomized clinical trial in patients with POMS aged 10 to less than 18 years treated between August 2014 and November 2020. Data were analyzed from January through October 2021. Interventions: Patients were randomized to DMF or IFNß-1a. Main Outcomes and Measures: The primary end point was the proportion of patients free of new or newly enlarging (N or NE) T2 hyperintense lesions at week 96 among trial completers. Secondary end points included number of N or NE T2 lesions, proportion of patients free of relapse, annualized relapse rate (ARR), and safety. The estimated proportion of participants who were relapse free up to week 96 was calculated based on the Kaplan-Meier method. Adjusted ARR was obtained from a negative binomial regression adjusted for baseline relapse rate, baseline Expanded Disability Status Scale (EDSS) score, and age group. Results: Among 150 patients with POMS in the intention-to-treat (ITT) population (median [range] age, 15 [10-17] years; 101 [67.3%] female patients), 78 individuals received DMF and 72 individuals received IFNß-1a. At week 96, the proportion of patients with no N or NE T2 hyperintense lesions among 103 trial completers was 16.1% (95% CI, 8.0%-27.7%) for DMF vs 4.9% (95% CI, 0.6%-16.5%) for IFNß-1a, and in a sensitivity analysis among the ITT population, the proportions were 10 patients receiving DMF (12.8%) vs 2 patients receiving IFNß-1a (2.8%). The estimated proportion of patients who remained relapse free at week 96 was 66.2% for DMF vs 52.3% for IFNß-1a. Adjusted ARR (95% CI) at week 96 was 0.24 (95% CI, 0.15-0.39) for DMF vs 0.53 (95% CI, 0.33-0.84) for IFNß-1a; the rate ratio for DMF vs IFNß-1a was 0.46 (95% CI, 0.26-0.80; P = .006). The number of treatment-emergent adverse events (TEAEs; 74 patients [94.9%] vs 69 patients [95.8%]), serious TEAEs (18 patients [23.1%] vs 21 patients [29.2%]), and treatment discontinuations due to TEAEs (5 patients [6.4%] vs 8 patients [11.1%]) was similar for DMF vs IFNß-1a. Conclusions and Relevance: This study found that more pediatric patients with POMS treated with DMF were free of new or newly enlarging T2 lesions and that the adjusted ARR was lower among these patients compared with those treated with interferon ß-1a. DMF was well tolerated. Trial Registration: ClinicalTrials.gov Identifier: NCT02283853.

Sharp increase in the incidence and prevalence of multiple sclerosis in Isfahan, Iran.

BACKGROUND: The epidemiology of multiple sclerosis (MS) has changed in recent decades. OBJECTIVES: This study aimed to give an update on the prevalence and incidence of MS in Isfahan, Iran. METHODS: The study population was all residents of Isfahan province during the period from April 2003 to July 2010. In April 2003, a registry of MS patients was created at the Isfahan MS Society (IMSS), which is the only referral center for MS patients in the province. Nearly all MS patients in Isfahan province are now registered with IMSS and were included in the analysis. RESULTS: Among the 3522 registered patients, 2716 were female and 806 were male (sex ratio: 3.37 : 1), and 431 were diagnosed in 2009. This results in a prevalence figure of 73.3 (95% CI: 70.9-75.8) and an incidence of 9.1 (95% CI: 8.3-10.0) per 100,000. CONCLUSION: The reported prevalence and incidence figures in our study were higher than in our previous report of 2007, in which the prevalence and incidence of MS were reported to be 43.8 and 3.64 per 100,000, respectively. This dramatic increase in the prevalence of MS puts Isfahan amongst the regions with the highest prevalence of MS in Asia and Oceania and is mostly due to changing environmental factors, amongst which vitamin D deficiency seems an important factor in our population.

A case-control study of risk factors for multiple sclerosis in Iran.

BACKGROUND: Numerous studies have assessed risk factors for multiple sclerosis (MS), although none have been conducted previously in Iran. OBJECTIVE: The objective of this study was to study lifestyle and environmental risk factors of MS in the Iranian population. METHODS: A case-control study, including 394 MS cases and 394 matched controls, was conducted in MS clinics in different Iranian cities. Information on lifestyles, environmental exposures, and past medical history was obtained from medical charts and phone interviews. RESULTS: In multivariable analysis, sunlight exposure was associated with a lower risk of MS: the odds ratio (OR) and 95% confidence interval (CI) of MS associated with a 1-h increment in daily sunlight was 0.62 (0.53-0.73). Smoking was associated with MS risk in women (OR: 6.48, 95% CI: 1.46-28.78), but not in men (OR: 0.72, 95% CI: 0.31-1.68) (p=0.002 for interaction). Finally, past history of common surgical procedures, infectious disorders, or exposure to pets and farm animals was not associated with MS risk. CONCLUSIONS: Different modifiable lifestyles, including sunlight exposure and smoking, were associated with lower MS risk in Iran. Interventions aimed at promoting smoking cessation and, more importantly, at increasing exposure to sunlight might contribute to the prevention of MS.

Cigarette smoking and the risk of multiple sclerosis: a sibling case-control study in Isfahan, Iran.

AIMS: We aimed to study the smoking habits of multiple sclerosis (MS) patients and their healthy siblings in Isfahan province in Iran. METHODS: MS patients registered with the Isfahan MS society database were compared to their healthy siblings who served as controls. Data regarding the smoking habits of patients and their siblings were collected using a specially designed questionnaire. Conditional logistic regression was adopted to analyze the association of smoking with the risk of MS, adjusting for age and sex. RESULTS: There were 1,606 participants with 516 cases and 1,090 controls. After adjustments for age and sex, subjects who were ever-smokers had a significant risk of developing MS [odds ratio (OR) 2.67; 95% confidence interval (CI) 1.70-4.21; p <0.001]. Past smokers (OR 8.83; 95% CI 3.98-19.60; p < 0.001) and current smokers (OR 1.84; 95% CI 1.10-3.10; p = 0.021) had a significant risk for developing MS. Disease progression (current expanded disability status scale/disease duration) was not different between smokers and nonsmokers (0.54 ± 0.42 vs. 0.49 ± 0.48; p = 0.61). CONCLUSION: Using a sibling pair method our data confirm the association between smoking and MS. A degree of confounding due to overmatching between siblings was unavoidable, but any bias would be conservative and should have lessened the effect of smoking.

Torque teno mini virus infection and multiple sclerosis.

Multiple sclerosis (MS) is a disease of young adults which is characterized by autoimmune demyelination of the central nervous system. Interaction of genetics and environmental factors are required to cause MS. Among the proposed environmental factors for MS, viral infections are thought to play a role in the pathogenesis of the disease. Torque teno mini virus (TTMV), which has recently been shown to infect humans, is a member of circoviridae, and has a circular DNA with 2860 nucleotides. Since there are a few data about the pathogenicity of this virus, this study sought to investigate the presence of TTMV in sera from MS patients and healthy individuals. We studied 149 serum samples from MS patients and 150 sera of healthy individuals. Serum DNA was extracted using phenol-chloroform and was subjected to nested polymerase chain reaction. TTMV-DNA was detected in 24 (16%) sera of the healthy blood donors and in 21 (14.1%) samples of the MS patients, where the difference did not reach significance (p > .05). The result of this study could not establish an association between TTMV infection and MS.

COVID-19 Among Patients With Multiple Sclerosis: A Systematic Review.

OBJECTIVE: We systematically reviewed the literature on COVID-19 in patients with multiple sclerosis (MS). METHODS: We searched PubMed, Scopus, EMBASE, CINAHL, Web of Science, Google Scholar, and World Health Organization database from December 1, 2019, to December 18, 2020. Three conference abstract databases were also searched. We included any types of studies that reported characteristics of patients with MS with COVID-19. RESULTS: From an initial 2,679 publications and 3,138 conference abstracts, 87 studies (67 published articles and 20 abstracts) consisting of 4,310 patients with suspected/confirmed COVID-19 with MS met the inclusion criteria. The female/male ratio was 2.53:1, the mean (SD) age was 44.91 (4.31) years, the mean disease duration was 12.46 (2.27), the mean Expanded Disability Status Scale score was 2.54 (0.81), the relapsing/progressive ratio was 4.75:1, and 32.9% of patients had at least 1 comorbidity. The most common symptoms were fever (68.8%), followed by cough (63.9%), fatigue/asthenia (51.2%), and shortness of breath (39.5%). In total, 837 of 4,043 patients with MS with suspected/confirmed COVID-19 (20.7%) required hospitalization, and 130 of 4,310 (3.0%) died of COVID-19. Among suspected/confirmed patients, the highest hospitalization and mortality rates were in patients with no disease-modifying therapies (42.9% and 8.4%), followed by B cell-depleting agents (29.2% and 2.5%). CONCLUSION: Our study suggested that MS did not significantly increase the mortality rate from COVID-19. These data should be interpreted with caution as patients with MS are more likely female and younger compared with the general population where age and male sex seem to be risk factors for worse disease outcome.

Oropharyngeal dysphagia in multiple sclerosis.

Swallowing disorders are commonly observed in multiple sclerosis (MS) patients. The complications of dysphagia are common causes of morbidity and death in late stages of MS. However, dysphagia in MS usually receives limited attention. The purpose of this study was to determine the prevalence of different kinds of swallowing disorders in MS patients with mild to moderate disability; and to identify possible associations between clinical and demographic features of patients and the presence of dysphagia. The swallowing functions of 101 consecutive MS patients were screened by the Northwestern Dysphagia Patient Check Sheet. This is a screening test which identifies patients with pharyngeal stage disorders, aspiration, oral stage disorders and/or pharyngeal delay. 'Dysphagia' was defined as having at least one of the above mentioned four disorders. Among 101 MS patients, 32 (31.7%) were classified as having dysphagia. Pharyngeal stage disorders were the most common observed impairment (28.7%) and aspiration, oral stage disorders, and pharyngeal delay were observed in 6.9%, 5%, and 1% of patients, respectively. Dysphagic patients had a significantly longer disease duration (p = 0.031) and more neurological impairment in cerebellar functional system (p = 0.04) when compared with non-dysphagic patients. Moreover, dysphagia was significantly more prevalent in patients with more neurological disability as measured by Expanded Disability Status Scale (EDSS) scores (p = 0.04). These results emphasize the importance of assessment and management of swallowing function in MS patients, particularly in patients with a high EDSS score; more severe cerebellar dysfunction, and long disease duration.

COVID-19 in teriflunomide-treated patients with multiple sclerosis.

The outbreak of a severe acute respiratory syndrome caused by a novel coronavirus (COVID-19), has raised health concerns for patients with multiple sclerosis (MS) who are commonly on long-term immunotherapies. Managing MS during the pandemic remains challenging with little published experience and no evidence-based guidelines. We present five teriflunomide-treated patients with MS who subsequently developed active COVID-19 infection. The patients continued teriflunomide therapy and had self-limiting infection, without relapse of their MS. These observations have implications for the management of MS in the setting of the COVID-19 pandemic.

Short-term effects of prolonged fasting on multiple sclerosis.

Fasting during Ramadan is mandatory for all healthy Muslim adults. During the fasting month, many physiological and biochemical changes occur that may be due to alterations in eating and sleeping patterns. A concern for Muslim multiple sclerosis (MS) patients is whether prolonged fasting might have an unfavorable impact on the course of their disease. The aim of this prospective study was to determine the effects of prolonged intermittent fasting on the course of MS in a cohort of patients who reside in Isfahan, Iran. The cohort consisted of 40 adult MS patients who fasted during Ramadan and 40 MS patients who did not fast. Only patients with mild disability (expanded disability status scale (EDSS) score 0.05). Fasting had no short-term unfavorable effects on the disease course in MS patients with mild disability. However, larger multi-center prospective studies of longer duration are needed to validate the results of this study.

Frequency of myasthenia gravis in multiple sclerosis: Report of five cases from Isfahan, Iran.

This study was designed to determine the frequency and clinical characteristics of myasthenia gravis (MG) in a large cohort of Persian patients with multiple sclerosis (MS) living in the province of Isfahan. We reviewed the case records of patients with definite MS (McDonald's criteria) registered in the Isfahan MS Society (IMSS) for associated MG. Of the 1,718 patients with MS in the registry, six patients were found to have both MS and MG. The prevalence after excluding one patient with insufficient data, was 291 per 100,000 (0.29%), a higher prevalence than the earlier reports. These results may support the hypothesis that MS and MG share some common immunopathogenic mechanisms.

The sex-specific interaction of the microbiome in neurodegenerative diseases.

Several neurologic diseases exhibit different prevalence and severity in males and females, highlighting the importance of understanding the influence of biologic sex and gender. Beyond host-intrinsic differences in neurologic development and homeostasis, evidence is now emerging that the microbiota is an important environmental factor that may account for differences between men and women in neurologic disease. The gut microbiota is composed of trillions of bacteria, archaea, viruses, and fungi, that can confer benefits to the host or promote disease. There is bidirectional communication between the intestinal microbiota and the brain that is mediated via immunologic, endocrine, and neural signaling pathways. While there is substantial interindividual variation within the microbiota, differences between males and females can be detected. In animal models, sex-specific microbiota differences can affect susceptibility to chronic diseases. In this review, we discuss the ways in which neurologic diseases may be regulated by the microbiota in a sex-specific manner.