Systematic Review of Clinical Practice Guidelines Related to Multiple Sclerosis

Background

High quality clinical practice guidelines (CPGs) can provide clinicians with explicit recommendations on how to manage health conditions and bridge the gap between research and clinical practice. Unfortunately, the quality of CPGs for multiple sclerosis (MS) has not been evaluated.

Objective

To evaluate the methodological quality of CPGs on MS using the AGREE II instrument.

Methods

According to the inclusion and exclusion criteria, we searched four databases and two websites related to CPGs, including the Cochrane library, PubMed, EMBASE, DynaMed, the National Guideline Clearinghouse (NGC), and Chinese Biomedical Literature database (CBM). The searches were performed on September 20th 2013. All CPGs on MS were evaluated by the AGREE II instrument. The software used for analysis was SPSS 17.0.

Results

A total of 27 CPGs on MS met inclusion criteria. The overall agreement among reviews was good or substantial (ICC was above 0.70). The mean scores for each of all six domains were presented as follows: scope and purpose (mean ± SD: 59.05±16.13), stakeholder involvement (mean ± SD: 29.53±17.67), rigor of development (mean ± SD: 31.52±21.50), clarity of presentation (mean ± SD: 60.39±13.73), applicability (mean ± SD: 27.08±17.66), editorial independence (mean ± SD: 28.70±22.03).

Conclusions

The methodological quality of CPGs for MS was acceptable for scope, purpose and clarity of presentation. The developers of CPGs need to pay more attention to editorial independence, applicability, rigor of development and stakeholder involvement during the development process. The AGREE II instrument should be adopted by guideline developers.     

Regional Brain Atrophy and Functional Connectivity Changes Related to Fatigue in Multiple Sclerosis

Fatigue is one of the most frequent symptoms in multiple sclerosis (MS), and recent studies have described a relationship between the sensorimotor cortex and its afferent and efferent pathways as a substrate of fatigue. The objectives of this study were to assess the neural correlates of fatigue in MS through gray matter (GM) and white matter (WM) atrophy, and resting state functional connectivity (rs-FC) of the sensorimotor network (SMN). Eighteen healthy controls (HCs) and 60 relapsing-remitting patients were assessed with the Fatigue Severity Scale (FSS). Patients were classified as fatigued (F) or nonfatigued (NF). We investigated GM and WM atrophy using voxel-based morphometry, and rs-FC changes with a seed-based method and independent component analysis (ICA). F patients showed extended GM and WM atrophy focused on areas related to the SMN. High FSS scores were associated with reductions of WM in the supplementary motor area. Seed analysis of GM atrophy in the SMN showed that HCs presented increased rs-FC between the primary motor and somatosensory cortices while patients with high FSS scores were associated with decreased rs-FC between the supplementary motor area and associative somatosensory cortex. ICA results showed that NF patients presented higher rs-FC in the primary motor cortex compared to HCs and in the premotor cortex compared to F patients. Atrophy reduced functional connectivity in SMN pathways and MS patients consequently experienced high levels of fatigue. On the contrary, NF patients experienced high synchronization in this network that could be interpreted as a compensatory mechanism to reduce fatigue sensation.     

Interaction between HLA-DRB1-DQB1 Haplotypes in Sardinian Multiple Sclerosis Population

We performed a case-control study in 2,555 multiple sclerosis (MS) Sardinian patients and 1,365 healthy ethnically matched controls, analyzing the interactions between HLA-DRB1-DQB1 haplotypes and defining a rank of genotypes conferring a variable degree of risk to the disease. Four haplotypes were found to confer susceptibility (*13∶03-*03∶01 OR = 3.3, Pc 5.1×10⁻⁵, *04∶05-*03∶01 OR = 2.1, Pc 9.7×10⁻⁸, *15∶01-*06∶02 OR = 2.0, Pc = 9.1×10⁻³, *03∶01-*02∶01 OR = 1.7 Pc = 7.9×10⁻²²) and protection (*11, OR = 0.8, Pc = 2.7×10⁻², *16∶01-*05∶02 OR = 0.6, Pc = 4.8×10⁻¹⁶, *14∶01-4-*05∶031 = OR = 0.5, Pc = 9.8×10⁻⁴ and *15∶02-*06∶01 OR = 0.4, Pc = 5.1×10⁻⁴). The relative predispositional effect method confirms all the positively associated haplotypes and showed that also *08 and *04 haplotypes confers susceptibility, while the *11 was excluded as protective haplotype. Genotypic ORs highlighted two typologies of interaction between haplotypes: i) a neutral interaction, in which the global risk is coherent with the sum of the single haplotype risks; ii) a negative interaction, in which the genotypic OR observed is lower than the sum of the OR of the two haplotypes. The phylogenic tree of the MS-associated DRB1 alleles found in Sardinian patients revealed a cluster represented by *14∶01, *04∶05, *13∶03, *08∶01 and *03∶01 alleles. Sequence alignment analysis showed that amino acids near pocket P4 and pocket P9 differentiated protective from predisposing alleles under investigation. Furthermore, molecular dynamics simulation performed on alleles revealed that position 70 is crucial in binding of MBP 85–99 peptide. All together, these data suggest that propensity to MS observed in Sardinian population carried by the various HLA-DRB1-DQB1 molecules can be due to functional peculiarity in the antigen presentation mechanisms.     

Environmental Factors Related to Enterobiasis in a Southeast Region of Korea

Pinworm infection can occur through contact with contaminated surfaces followed by ingestion or even through inhalation of infective eggs. We have limited information regarding environmental contamination by eggs of Enterobius vermicularis. In order to determine environmental risk factors associated with the rate of E. vermicularis infection, we investigated possible environmental risk factors using a questionnaire from 46 kindergartens in 3 different cities of the southeast area of Korea. In total, using the cellotape anal swab technique, 3,422 children were examined for E. vermicularis infection. We evaluated E. vermicularis egg of books, educational materials, toys, room door handles, dusts of window edges, desks, chairs, tables, and dusts of classrooms. The overall egg-positive rate for E. vermicularis was 6.0%, and the prevalence of enterobiasis in each kindergarten ranged between 0% and 16.9%. We found that 78.9% of egg positive kindergartens were managed by private foundations, which was significantly higher, compared with kindergartens managed by public foundations or the nation. Compared with public or national kindergartens, most private kindergartens were located in residential areas and the number of children in these areas was significantly higher. In conclusion, numbers of children in kindergartens was found to be an environmental risk factor associated with transmission of enterobiasis in Korea.     

多发性硬化疾病及模型小鼠中疾病相关细胞因子和转录因子研究进展

多发性硬化症（multiple sclerosis,MS）是一种原发于中枢神经系统的炎症性脱髓鞘疾病。实验性自身免疫性脑脊髓炎（experimental autoimmune encephalomyelitis,EAE）与MS有相似的临床症状和病理特征,是被广泛应用于人类疾病研究的动物模型。MS确切的发病机制尚不清楚,但普遍认为是在易感基因的基础上,受环境因素触发,由CD4＋T细胞介导的中枢神经系统（centralnervous system,CNS）自身免疫性疾病。初始CD4＋T细胞在T细胞受体介导下活化,继而可分化为至少4个主要亚型,分别为TH1、TH2、TH17和iTreg细胞,参与不同类型的免疫应答。细胞因子和转录因子网络对CD4＋T细胞分化和效应细胞因子产物有重要意义。该文综述了各相关细胞因子和转录因子在CD4＋T细胞向不同亚型分化及MS/EAE发病过程中的相互作用和调控,揭示各因子在这些过程中的作用,有助于进一步研究和治疗MS。     

A Further TWEAK to Multiple Sclerosis Pathophysiology

Tumor necrosis factor (TNF)-like weak inducer of apoptosis (TWEAK) is a member of the TNF super family that controls many cellular activities including proliferation, migration, differentiation, apoptosis, and inflammation by binding to fibroblast growth factor-inducible 14 (Fn14), a highly inducible cell surface receptor. Recent studies have indicated that TWEAK–Fn14 axis signaling may contribute to chronic autoimmune diseases. TWEAK expression via microglia in cortical lesions, presence of TWEAK⁺ macrophages in inflamed leptomeninges, and absence of TWEAK/Fn14 expression in healthy brain implicates importance of this pathway in pathogenesis of multiple sclerosis lesions. TWEAK–Fn14 axis blockade has also shown promise in various multiple sclerosis animal models. Stimulation of the TWEAK/Fn14 pathway can result in activation of both canonical and noncanonical NF-κB signaling and could also stimulate mitogen-activated protein kinase (MAPK) signaling pathways. Here, we have reviewed evidence of the possible role of TWEAK–Fn14 axis in pathophysiology of multiple sclerosis and experimental autoimmune encephalomyelitis (EAE) via neuroinflammation, tissue remodeling, blood–brain barrier (BBB) disruption, neurodegeneration, and astrogliosis.     

Tumefactive Multiple Sclerosis in Taiwan

Background

Multiple sclerosis (MS) is less common in Asia, including Taiwan, and some characteristics of MS in Asians differ from those of Caucasians. Tumefactive brain lesion is even rarer in MS patients.

Objective

To review patients with tumefactive MS and compare them with those in other studies investigating tumefactive demyelinating lesions and our Taiwanese typical MS patients.

Methods

Twelve patients (6.3%) from the 190 MS patients visiting Taipei Veterans General Hospital from 1985 to 2010 were enrolled. They all fulfilled the McDonald or Poser criteria for MS and had at least one brain lesion larger than 2 centimeters with or without a mass effect.

Results

Eleven patients (91.7%) were female and presented tumefactive brain lesions during the first attack. The clinical course of all patients was relapsing-remitting with a second attack within 2 years. Their initial extended disability status score was higher, but the prognosis was better after more than 2 years of follow-up, than in other studies. Moreover, our patients did not have optic or spinal involvement as well as positive neuromyelitis optica immunoglobulin or aquaporin-4 antibody, which is very common in Taiwanese MS patients.

Conclusion

Tumefactive MS is not common in Taiwan. Although the tumefactive demyelinating lesions seem to be terrible initially, their prognosis is relatively more favorable than expected.     

Nutrition Facts in Multiple Sclerosis

The question whether dietary habits and lifestyle have influence on the course of multiple sclerosis (MS) is still a matter of debate, and at present, MS therapy is not associated with any information on diet and lifestyle. Here we show that dietary factors and lifestyle may exacerbate or ameliorate MS symptoms by modulating the inflammatory status of the disease both in relapsing-remitting MS and in primary-progressive MS. This is achieved by controlling both the metabolic and inflammatory pathways in the human cell and the composition of commensal gut microbiota. What increases inflammation are hypercaloric Western-style diets, characterized by high salt, animal fat, red meat, sugar-sweetened drinks, fried food, low fiber, and lack of physical exercise. The persistence of this type of diet upregulates the metabolism of human cells toward biosynthetic pathways including those of proinflammatory molecules and also leads to a dysbiotic gut microbiota, alteration of intestinal immunity, and low-grade systemic inflammation. Conversely, exercise and low-calorie diets based on the assumption of vegetables, fruit, legumes, fish, prebiotics, and probiotics act on nuclear receptors and enzymes that upregulate oxidative metabolism, downregulate the synthesis of proinflammatory molecules, and restore or maintain a healthy symbiotic gut microbiota. Now that we know the molecular mechanisms by which dietary factors and exercise affect the inflammatory status in MS, we can expect that a nutritional intervention with anti-inflammatory food and dietary supplements can alleviate possible side effects of immune-modulatory drugs and the symptoms of chronic fatigue syndrome and thus favor patient wellness.     

Progress in Multiple Sclerosis Genetics

A genetic component in the susceptibility to multiple sclerosis (MS) has long been known, and the first and major genetic risk factor, the HLA region, was identified in the 1970’s. However, only with the advent of genome-wide association studies in the past five years did the list of risk factors for MS grow from 1 to over 50. In this review, we summarize the search for MS risk genes and the latest results. Comparison with data from other autoimmune and neurological diseases and from animal models indicates parallels and differences between diseases. We discuss how these translate into an improved understanding of disease mechanisms, and address current challenges such as genotype-phenotype correlations, functional mechanisms of risk variants and the missing heritability.     

Lymphocyte Transformation in Multiple Sclerosis

Lymphocytes in cultures of peripheral blood cells from patients with multiple sclerosis showed significant blastogenic transformation in the presence of human brain extract, encephalitogenic myelin basic protein, or human cerebrospinal fluid, but not in the presence of kidney extract. There was no correlation between the degree of activity of the patients'' disease and the percentage transformation of their lymphocytes.     

Rickettsial Antibodies in Multiple Sclerosis

The serum of subjects with multiple sclerosis or other degenerative neurological diseases and that of normal controls does not differ significantly in its content of antibodies to several rickettsial antigens. There is no evidence for a rickettsial aetiology of multiple sclerosis, and no grounds for an extended clinical trial of Le Gac''s full method of treatment with antibiotics.     

备孕二胎女性人群中MTHFR基因多态性及相关环境因素的调查分析

目的:调查评估备孕二胎女性人群中MTHFR基因多态性及其生活习惯、一胎孕期情况等相关环境因素,以发挥孕前检查在子代先心病一级预防中的作用。方法:选取江苏部分地区参加备孕二胎优生健康检查妇女共402名进行问卷调查,并检测外周血中MTHFR基因rs1801131、rs1801133两个位点的突变情况。结果:收回有效问卷389份,其中备孕二胎女性平均年龄为27.04±2.68,最大43岁,最小19岁。MTHFR rs1801131纯合突变(CC型)为3.5%、杂合突变(AC型)为29.1%;rs1801133纯合突变(TT型)22.9%、杂合突变(CT型)48.5%;rs1801131、rs1801133双杂合突变为16.7%。结论:备孕二胎女性人群中存在一定的先心病环境危险因素暴露和MTHFR相关位点基因多态性。加强女性孕前保健,为高危人群制定个性化叶酸增补方案并降低先心病危险因素的暴露,从而做好出生缺陷一级预防,提高出生人口质量。