Gut-oriented interventions in patients with multiple sclerosis: fact or fiction?

OBJECTIVE: Multiple sclerosis (MS) is a chronic, inflammatory, demyelinating, disimmune disease of the central nervous system whose etiology and pathogenesis remain poorly understood, due to its complex and multifactorial nature. Evidence of a bidirectional connection linking the gut microbiome with the intestinal barrier and the immune system (the gut-brain axis) may have implications for the pathogenesis of inflammatory demyelinating diseases such as MS. This narrative review summarizes the evidence for the gut-brain axis involvement in the pathogenesis of MS and examines the role of gut-oriented interventions in MS. PATIENTS AND METHODS: We reviewed all available studies in PubMed concerning gut-directed interventions and MS. This research was conducted using different combinations of pertinent keywords (multiple sclerosis, immune-mediated inflammatory diseases, autoimmune diseases, first demyelinating event, neurocognition, neurological disorders, neurology practice, risk factors, taxonomic biomarkers, nutrition, diet, dietary additives, complementary treatment, gut bacteria, gut microbiome, microbiome, gut-brain axis, epidemiology, alpha-linolenic acid, fermentative metabolites, fat, saturated fat, monounsaturated fat, polyunsaturated fat, omega-3 fatty acids, calorie restricted diet, fasting, fecal microbiome, fecal microbiota transplantation, animal testing). RESULTS: There is an emerging evidence that alterations in the gut microbiome and increased intestinal permeability may be causative factors in the complex interplay between nutrition, metabolic status and the immune-inflammatory response in patients with MS. This suggests the possibility that modification of lifestyle and the microbiome, for example by specific diets or fecal microbiota transplantation, supplementation with bile acids and intestinal barrier enhancers, may positively influence the pathogenesis of MS. CONCLUSIONS: Although the role of nutritional factors in the pathogenesis of MS remains to be established, there is evidence that appropriate gut-directed interventions such as diet, nutritional supplementation or fecal transplantation may modulate the inflammatory response and improve the course of MS as a complementary treatment in the disease.

Listening to the neurological teams for multiple sclerosis: the SMART project.

OBJECTIVE: Aim of the research was to define the quality of life of Italian neurologists and nurses' professional caring for multiple sclerosis, to understand their living the clinical practice and identify possible signals of compassion fatigue. MATERIAL AND METHODS: One hundred five neurologists and nurses from 30 Italian multiple sclerosis centres were involved in an online quali-quantitative survey on the organization of care, combined with the Satisfaction and Compassion Fatigue Test and a collection of narratives. Descriptive statistics of the quantitative data were integrated with the results obtained by the narrative medicine methods of analysis. RESULTS: Most of the practitioners were neurologists, 46 average years old, 69% women, 43% part time dedicated to multiple sclerosis. An increased number of patients in the last 3 years were referred in 29 centres. Differences were found between neurologists and nurses. Physicians showed higher risks of burnout, reporting intensive working paces, lack of medical personnel, and anxiety caused by the precarious employment conditions. Nurses appeared more satisfied, although the reference to the lack of spaces, and the cross professional roles risk of compassion fatigue. Both positive and negative relationships of care were depicted as influencing the professional quality of life. CONCLUSION: The interviewed neurological teams need to limit the risk of compassion fatigue, which appeared from the first years of the career. The prevalence of the risk among neurologists suggests more awareness among scientific societies and health care managers on the risk for this category, as first step to prevent it.

Safety and efficacy of autologous hematopoietic stem-cell transplantation following natalizumab discontinuation in aggressive multiple sclerosis.

BACKGROUND AND PURPOSE: Natalizumab (NTZ) is a highly effective treatment for relapsing-remitting multiple sclerosis (MS), but its withdrawal is often followed by disease reactivation or rebound, even if other disease-modifying treatments (DMTs) are administered. In this study, for the first time, the safety and efficacy of autologous hematopoietic stem-cell transplantation (aHSCT) performed following NTZ discontinuation were retrospectively compared with conventional DMTs. METHODS: Patients with relapsing-remitting MS treated with NTZ who discontinued the drug after at least six administrations and with at least 6 months of follow-up were included. Patients underwent aHSCT after a minimum of 6 months following NTZ withdrawal, receiving meanwhile cyclophosphamide or corticosteroids, or other DMTs approved for MS (control group) after an adequate wash-out period. Both hematological and neurological follow-up were assessed according to standard policies. RESULTS: A total of 52 patients were included, 11 who received aHSCT and 41 who received DMTs. Baseline clinical and demographic characteristics were similar between the two groups. No fatality or life-threatening complications, including progressive multifocal leukoencephalopathy, were observed. At 3 years following NTZ discontinuation, no evidence of disease activity was reported in 54.5% of the patients in the aHSCT group compared with 11.5% of those in the DMT group (P = 0.0212). Disease reactivation in the patients with aHSCT was observed only during wash-out/bridging therapy and 100% of the cases were free from disease activity after aHSCT. CONCLUSIONS: These data suggest that an aggressive therapy should be established after NTZ with the shortest possible wash-out period. aHSCT after 6 months from NTZ withdrawal appears to be safe.

No proinflammatory signature in CD34+ hematopoietic progenitor cells in multiple sclerosis patients.

Autologous hematopoietic stem cell transplantation (aHSCT) has been used as a therapeutic approach in multiple sclerosis (MS). However, it is still unclear if the immune system that emerges from autologous CD34+ hematopoietic progenitor cells (HPC) of MS patients is pre-conditioned to re-develop the proinflammatory phenotype. The objective of this article is to compare the whole genome gene and microRNA expression signature in CD34+ HPC of MS patients and healthy donors (HD). CD34+ HPC were isolated from peripheral blood of eight MS patients and five HD and analyzed by whole genome gene expression and microRNA expression microarray. Among the differentially expressed genes (DEGs) only TNNT1 reached statistical significance (logFC=3.1, p<0.01). The microRNA expression was not significantly different between MS patients and HD. We did not find significant alterations of gene expression or microRNA profiles in CD34+ HPCs of MS patients. Our results support the use of aHSCT for treatment of MS.

Autologous haematopoietic stem cell transplantation with an intermediate intensity conditioning regimen in multiple sclerosis: the Italian multi-centre experience.

BACKGROUND: Over recent years numerous patients with severe forms of multiple sclerosis (MS) refractory to conventional therapies have been treated with intense immunosuppression followed by autologous haematopoietic stem cell transplantation (AHSCT). The clinical outcome and the toxicity of AHSCT can be diverse, depending on the various types of conditioning protocols and on the disease phase. OBJECTIVES: To report the Italian experience on all the consecutive patients with MS treated with AHSCT with an intermediate intensity conditioning regimen, named BEAM/ATG, in the period from 1996 to 2008. METHODS: Clinical and magnetic resonance imaging outcomes of 74 patients were collected after a median follow-up period of 48.3 (range = 0.8-126) months. RESULTS: Two patients (2.7%) died from transplant-related causes. After 5 years, 66% of patients remained stable or improved. Among patients with a follow-up longer than 1 year, eight out of 25 subjects with a relapsing-remitting course (31%) had a 6-12 months confirmed Expanded Disability Status Scale improvement > 1 point after AHSCT as compared with one out of 36 (3%) patients with a secondary progressive disease course (p = 0.009). Among the 18 cases with a follow-up longer than 7 years, eight (44%) remained stable or had a sustained improvement while 10 (56%), after an initial period of stabilization or improvement with median duration of 3.5 years, showed a slow disability progression. CONCLUSIONS: This study shows that AHSCT with a BEAM/ATG conditioning regimen has a sustained effect in suppressing disease progression in aggressive MS cases unresponsive to conventional therapies. It can also cause a sustained clinical improvement, especially if treated subjects are still in the relapsing-remitting phase of the disease.

[Commuting accidents: the influence of excessive daytime sleepiness. A review of an Italian Police officers population]. / Infortuni in itinere: ruolo della sonnolenza in una popolazione di operatori della Polizia di Stato.

Commuting accidents (CA) play an important role in many systems of workers' compensation insurance and with good reason, as they generally bring about more serious consequences in terms of permanent disablement and death than ordinary occupational accidents; this usually leads to high social costs. Nevertheless, research investigations aimed at studying the possible causes underlying the phenomenon are not available in medical literature. Objective of the present study is to evaluate whether excessive daytime sleepiness (EDS) might influence the occurrence of CA. 463 CA occurred to 411 police officers in northern Italy during the period 1999 - 2002 were collected; 51.9% of the subjects were working on shifts, 48.1% were non-shift workers. The study was carried out by submitting a self-administered questionnaire to gather information on age and physical characteristics, working conditions, sleep-related problems and accidents occurrence; EDS was measured by the Epworth Sleepiness Scale (ESS). A large number of workers (36%) complained of EDS; a strict significant relationship between shift - work condition and the presence of EDS was found, thus suggesting that CA are significantly influenced by EDS. The shift work schedule adopted by Italian Police might be accountable for the disruption of the balance between circadian and homeostatic factors.

An attempt of identifying MS-associated loci as a follow-up of a genomic linkage study in the Italian population.

Subsequent to a genomic linkage study on Sardinian and Continental Italian families, we considered the possibility that some of the tested microsatellite markers showed association to MS. Markers selected on the basis of the data obtained in the original set of 70 multiplex families were tested for MS association in an additional set of 154 simplex families. A limited set of markers were further tested on an additional set of 100 simplex families. The results indicate the presence of a putative MS gene in 19q13.13.

Disappearance of motor tics after Wernicke's encephalopathy in a patient with Tourette's syndrome.

Tourette's syndrome (TS) is a disease characterized by multiple motor and vocal tics as well as behavioral abnormalities. The anatomic substrates of this syndrome are not defined. We report a 48-year-old man with TS in whom motor tics disappeared after the onset of a midbrain syndrome related to thiamine deficiency (Wernicke's encephalopathy). MRI study showed a lesion in the dorsal area of the midbrain. This case suggests that loops located in the midbrain tegmentum may influence the presence of motor tics in patients with TS.

The natural history of gallstones: the GREPCO experience. The GREPCO Group.

During the cross-sectional studies (February 1981 to July 1984) performed by the Group for Epidemiology and Prevention of Cholelithiasis (GREPCO) in Rome, Italy, 161 subjects were identified as having gallstones. Ten subjects did not participate in the prospective follow-up. At entry, 33 of the 151 remaining subjects were symptomatic, and 118 were asymptomatic. Data on incidence of biliary colics, complications, cholecystectomy, and death were collected at least every 2 years. In the initially asymptomatic group, the cumulative probability (% +/- SE) of developing biliary colic was 11.9 +/- 3.0 at 2 years, 16.5 +/- 3.5 at 4 years, and 25.8 +/- 4.6 at 10 years. None of the variables considered as possible modifiers of the natural history were found to be associated with an increased risk of developing biliary colic. The cumulative probability (% +/- SE) of developing complications after 10 years was 3.0 +/- 1.8 in the initially asymptomatic group and 6.5 +/- 4.4 in the symptomatic group (P = NS). Incidence of cholecystectomy was higher in the initially symptomatic than in the asymptomatic group (log-rank test = 2.27; P = .02). Fifteen (53.6%) of the 28 operated in the initially asymptomatic group were submitted to cholecystectomy, although specific symptoms did not occur. Twelve (10.2%) and 2 (6.1%) of the initially asymptomatic and symptomatic subjects died during the follow-up. One patient in the former group died at age 64 of a histologically proven adenocarcinoma of the gallbladder. In conclusion, this study demonstrates that the natural history of gallstones is less benign than is generally considered.

The effect of ursodeoxycholic acid on serum enzymes and liver histology in patients with chronic active hepatitis. A 12-month double-blind, placebo-controlled trial.

A reduction in serum enzymes has been already observed by administering ursodeoxycholic acid to patients with chronic active hepatitis. The aim of this study was to assess whether the liver histological activity of inflammation was modified by a 12-month treatment with ursodeoxycholic acid. Thirty-six patients with chronic active hepatitis, fulfilling the inclusion criteria, were admitted to the trial. Patients were randomly allocated to receive double blind either 600 mg/day of ursodeoxycholic acid (Group A: 18 patients) or placebo (Group B: 18 patients). Clinical and biochemical follow-up was performed at acid (Group A: 18 patients) or placebo (Group B: 18 patients). Clinical and biochemical follow-up was performed at 3-month intervals. A percutaneous liver biopsy was performed before and after 1 year of treatment. Histological hepatitis activity was assessed using Knodell's numerical scoring system, while biliary damage was evaluated by an appropriate scoring system. Sixteen and 12 patients in Groups A and B, respectively, completed the clinical and biochemical follow-up. Although a reduction in serum enzymes was found in both groups, multifactorial covariance analysis showed that the reductions in alanine aminotransferase, aspartate aminotransferase and gamma glutamyl transpeptidase were significantly higher in Group A than in Group B. Biochemical remission was not observed in either group. Histological analysis showed a dichotomy between the results from the hepatitis and the biliary components of the disease process. No differences were found in the two groups before or after treatment in histological activity index, which measures the "hepatitic" component. Nor were there any significant differences in baseline values.(ABSTRACT TRUNCATED AT 250 WORDS)