Iron in multiple sclerosis - from pathophysiology to disease progression - a narrative literature review.

Emerging role of neuregulin-1beta1 in pathogenesis and progression of multiple sclerosis

Although the involvement of immune mechanisms in multiple sclerosis (MS) is undisputed, some argue that there is insufficient evidence to support the hypothesis that MS is an autoimmune disease, and that the difference between immune- and autoimmune disease mechanisms has yet to be clearly delineated. Uncertainties surrounding MS disease pathogenesis and the modest efficacy of currently used disease modifying treatments (DMTs) in the prevention of disability, warrant the need to explore other possibilities. It is evident from the literature that people diagnosed with MS differ widely in symptoms and clinical outcome - some patients have a benign disease course over many years without requiring any DMTs. Attempting to include all patients into a single entity is an oversimplification and may obscure important observations with therapeutic consequences. In this review we advocate an individualised approach named Pathology Supported Genetic Testing (PSGT), in which genetic tests are combined with biochemical measurements in order to identify subgroups of patients requiring different treatments. Iron dysregulation in MS is used as an example of how this approach may benefit patients. The theory that iron deposition in the brain contributes to MS pathogenesis has caused uncertainty among patients as to whether they should avoid iron. However, the fact that a subgroup of people diagnosed with MS show clinical improvement when they are on iron supplementation emphasises the importance of individualised therapy, based on genetic and biochemical determinations.

Multiple sclerosis (MS) is a common chronic inflammatory disease of the central nervous system which most frequently appears in early adulthood [1]. Since MS usually affects people in the most active and productive phase of their lives and since the frequency and severity of attacks are largely unpredictable, the impact of the disease on patients and their caregivers’ health-related quality of life is important [2,3,4,5,6,7,8]. Therefore, it is essential to elucidate the etiology of this disease, and to this end, epidemiological studies are essential. It has become obvious that the epidemiology of MS has changed over time. Indeed, data over recent years have challenged the traditional view that there is a north-to-south gradient in occurrence in the northern hemisphere and a south-to-north gradient in the southern hemisphere [9]. Furthermore, recent epidemiological studies of MS suggest a trend of increasing disease prevalence and incidence in the same populations worldwide, mainly in women [10,11,12,13,14,15]. The current study from the rural areas of the Black Sea regions of Turkey reveals a high prevalence of MS in a survey of the general population [16]. The authors examined the prevalence of MS in two rural areas (Kandira and Geyve) near Istanbul, and half the population of Erbaa, all near 40° north latitude on the Black Sea coast [16]. The study had several strengths, including the large sample size, the design (door-to-door survey) and the methods used for case finding which are carefully described [16]. The most interesting observation was that the prevalence was 51/100,000 and this is of special interest for two reasons [16]. Aside from the fact that little information exists on MS in Turkey, the results suggest that this geographical region is currently a high-risk area for MS. In addition, the results are in line with the prevalence rates reported from other countries in the area such as Greece (prevalence 119.6 per 100,000) [17], Iran (50.6 per 100,000) [15] or the Turkish community in Cyprus (55 per 100,000) [18]. The study again demonstrates that the prevalence of MS has increased in the last years. How can these findings be explained? The Mediterranean basin and Asia have been classically considered as medium- (5–29 per 100,000 population) and low-frequency (<5 per 100,000 population) areas, respectively [19]. In the 1970s and early 1980s, the lower prevalence rates could be partially explained by the lack of advanced diagnostic techniques such as magnetic resonance. It is also possible that increasing awareness, either by physicians or patients, could result in the improved diagnosis of mild cases that previously might have gone unnoticed. Moreover, there has been an important change in patients’ behavior (i.e. patients tend to seek medical advice more often and with milder symptoms than they did 2 decades ago). Likewise, the increase in prevalence may be due to an improved probability of survival [20]. However, although the quality of the surveys tends to vary between countries, the increase in the prevalence and incidence of MS in the last years worldwide is probably real and not solely due to improved diagnostic techniques or more extensive evaluations. Recent changes in disease incidence and prevalence are likely to be the result of environmental factors that could have been operative in the past few decades. There is evidence to support the view that MS is a complex trait determined by both genetic and environmental factors. Indeed, this disease may be mediated by an autoimmune reaction among susceptible people to a widespread pathogen (Epstein-Barr virus or Candida species?) [21,22]. Furthermore, the biologically most plausible explanations for a disproportional increase in MS among women in some populations may be the role of vitamin D in MS pathogenesis [14]. Indeed, vitamin D insufficiency or deficiency has been shown to affect T-cell differentiation and regulation, which may influence cellular immune responses against autoantigens and pathogens that have been associated with the etiology of MS [14]. One recent theory is that vitamin D and Epstein-Barr virus may be biologically interacting to increase the risk of MS. This hypothesis is supported by the recent observation that a statistical interaction between infectious mononucleosis prevalence and ultraviolet B radiation could explain 72% of the variance in MS prevalence across England [23]. In spite of all the recent advances in the search of the involved factors in the etiology of MS, there is still no consensus among researchers. In this way, new epidemiological research regarding etiological factors is necessary for a better approach of the patients, promoting preventive programs for the disease and improving the health-related quality of life of both patients and their caregivers.

P015 - Epidemiology of multiple sclerosis in the Middle East: A systematic review and meta analysis

Background: Multiple sclerosis (MS) is the most common non-traumatic cause of central nervous system disorders in young people worldwide, leading to cognitive and physical disability. About 20,000 of adult Ukrainians suffer from MS. Prospective studies, taking into account the prevalence and incidence, combined with environmental, territorial and urbanization factors can optimize medical care for patients with MS. A prospective study of MS within Volyn Polissia and Opillya zones has not been conducted before. Objective: To evaluate prospectively the prevalence and morbidity rates of MS among the adult population of Volyn region within the physical-geographical zones. Materials and methods: Epidemiological and medical-statistical methods of morbidity study were used to study features of MS prevalence in the Volyn region. The standard descriptive statistics and factor analysis (principal component method) were used to estimate the variation of a set of indicators. Factor analysis included incidence and prevalence rates of MS in Volyn region since 1999. Results: A statistically significant difference in MS prevalence at the significance level p &lt;0.05 was found in the MS prevalence in 2014 and at the p = 0.005 level in the 2015–2017 section. Also, a statistically significant difference in the incidence of MS at a significance level of p &lt;0.1 was detected in the incidence of MS in 2015 and at the level of p = 0.001 in 2013. Thus, comparing the prevalence and incidence rates, we can conclude that the prevalence of MS in the Volyn Opillya region is significantly higher than in the Volyn Polissia area. Factor analysis (principal component method) was conducted to identify latent factors. As a result, it was found that the 3-factor model allows to describe more than 88% of the variation of the set of indicators: the 1st (main) factor describes 69%, the 2nd - 12,6%, the 3rd - 6,6% (together 88,2%). Conclusions: The prevalence and incidence rates of MS in the Volyn Oblast were found to be uneven. The prevalence of MS in the Volyn Polissia area is lower than in the Volyn Opillia region. The developed 3-factor model allows to describe more than 88% of the variation of the population prevalence of MS. In our opinion, it is advisable to consider the incidence and prevalence rates of MS comprehensively, taking into account environmental, territorial, urban and, not excluded, industrial indicators.

We have proposed that the myelin damage observed in multiple sclerosis (MS) may be partly mediated through the long-term release and degradation of extracellular hemoglobin (Hb) and the products of its oxidative degradation [Cellular and Molecular Life Sciences, 71, 1789-1798, 2014]. The protein haptoglobin (Hpt) binds extracellular Hb as a first line of defense, and can serve as a vascular antioxidant. Humans have two different Hpt alleles: Hpt1 and Hpt2, giving either homozygous Hpt1-1 or Hpt2-2 phenotypes, or a heterozygous Hpt1-2 phenotype. We questioned whether those geographic regions with higher frequency of the Hpt2 allele (conversely, lower frequency of Hpt1 allele) would correlate with an increased incidence of MS, because different Hpt phenotypes will have variable anti-oxidative potentials in protecting myelin from damage inflicted by extracellular Hb and its degradation products. To test this hypothesis, we undertook a systematic analysis of the literature on reported geographic distributions of Hpt alleles to compare them with data reported in the World Health Organization Atlas of worldwide MS prevalence. We found the frequency of the Hpt1 allele to be low in European and North American countries with a high prevalence of MS, consistent with our hypothesis. However, this correlation was not observed in China and India, countries with the lowest Hpt1 frequencies, yet low reported prevalence of MS. Nevertheless, this work shows the need for continued refinement of geographic patterns of MS prevalence, including data on ethnic or racial origin, and for new clinical studies to probe the observed correlation and evaluate Hpt phenotype as a predictor of disease variability and progression, severity, and/or comorbidity with cardiovascular disorders.

Background The prevalence of multiple sclerosis (MS) appears to be increasing worldwide. However, data on the pediatric onset of MS is lacking, particularly in developing countries. Objective This study is aimed at reporting the current burden of the pediatric onset of MS in the five regions of Saudi Arabia. Methods This study used relevant data from the National Saudi MS Registry that was operational between 2015 and 2018. The data on patients with pediatric onset MS from all the hospitals included in the registry was retrospectively analyzed using the age of diagnosis. Patients who were 1-18 years old when diagnosed were included in the analysis. Results The registry included 287 patients with pediatric onset MS, with a mean age of diagnosis at 15.7 (SD: 2.06). 74.2% of the participants were females. For the included hospitals, the estimated prevalence of pediatric MS was at 2.73/100,000 pediatric Saudi population. The prevalence of pediatric MS in the remaining nonparticipant hospitals was then projected taking into account both the size of pediatric population in the Kingdom per region and the number of facilities treating and managing MS in each of the corresponding regions. The overall projected prevalence was found to be 14.33/100,000 Saudi pediatric population. Conclusion To the best of our knowledge, this study reported the latest epidemiological data of pediatric onset of MS in Saudi Arabia. The current prevalence of MS among the pediatric Saudi population was found to be 2.73/100,000, and the overall projected prevalence was estimated at 14.33/100,000. Our findings were similar to those in other pediatric MS cohorts. Further studies are needed to understand the long-term prognosis, response to treatment, and disease course.

France is located in an area with a medium to high prevalence of multiple sclerosis, where its epidemiology is not well known. We estimated the national and regional prevalence of multiple sclerosis in France on 31 October 2004 and the incidence between 31 October 2003 and 31 October 2004 based on data from the main French health insurance system: the Caisse Nationale d'Assurance Maladie des Travailleurs Salariés. The Caisse Nationale d'Assurance Maladie des Travailleurs Salariés insures 87% of the French population. We analysed geographic variations in the prevalence and incidence of multiple sclerosis in France using the Bayesian approach. On the 31 October 2004, 49 417 people were registered with multiple sclerosis out of the 52 359 912 insured with the Caisse Nationale d'Assurance Maladie des Travailleurs Salariés. Among these, 4497 were new multiple sclerosis cases declared between 31 October 2003 and 31 October 2004. After standardization for age, total multiple sclerosis prevalence in France was 94.7 per 100,000 (94.3-95.1); 130.5 (129.8-131.2) in females and 54.8 (54.4-55.3) in males. The national incidence of multiple sclerosis between 31 October 2003 and 31 October 2004 was 7.5 per 100,000 (7.3-7.6); 10.4 (10.2-10.6) in females and 4.2 (4.0-4.3) in males. The prevalence and incidence of multiple sclerosis were higher in North-Eastern France, but there was no obvious North-South gradient. This study is the first performed among a representative population of France (87%) using the same method throughout. The Bayesian approach, which takes into account spatial heterogeneity among geographical units and spatial autocorrelation, did not confirm the existence of a prevalence gradient but only a higher prevalence of multiple sclerosis in North-Eastern France and a lower prevalence of multiple sclerosis in the Paris area and on the Mediterranean coast.

Background: The prevalence of multiple sclerosis (MS) is not uniform, with a latitudinal gradient of prevalence present in most studies. Understanding the drivers of this gradient may allow a better understanding of the environmental factors involved in MS pathogenesis. Method: The New Zealand national MS prevalence study (NZMSPS) is a cross-sectional study of people with definite MS (DMS) (McDonald criteria 2005) resident in New Zealand on census night, 7 March 2006, utilizing multiple sources of notification. Capture—recapture analysis (CRA) was used to estimate missing cases. Results: Of 2917 people with DMS identified, the crude prevalence was 72.4 per 100,000 population, and 73.1 per 100,000 when age-standardized to the European population. CRA estimated that 96.7% of cases were identified. A latitudinal gradient was seen with MS prevalence increasing three-fold from the North (35°S) to the South (48°S). The gradient was non-uniform; females with relapsing—remitting/secondary-progressive (RRMS/SPMS) disease have a gradient 11 times greater than males with primary-progressive MS (p < 1 × 10-7). DMS was significantly less common among those of Māori ethnicity. Conclusions: This study confirms the presence of a robust latitudinal gradient of MS prevalence in New Zealand. This gradient is largely driven by European females with the RRMS/SPMS phenotype. These results indicate that the environmental factors that underlie the latitudinal gradient act differentially by gender, ethnicity and MS phenotype. A better understanding of these factors may allow more targeted MS therapies aimed at modifiable environmental triggers at the population level.

To establish the prospective incidence of multiple sclerosis and mortality rates of people with multiple sclerosis in Leeds Health Authority and an updated prevalence of multiple sclerosis on 31 October 1999. A population based prevalence register established on 30 April 1996 was maintained by prospectively registering all new cases of multiple sclerosis, flagging all cases with the National Health Service Central Register for notification of deaths and by registering all new clinical events. General practitioners notified patients with multiple sclerosis moving into or out of the area. 136 incident cases were prospectively registered from 30 April 1996 living in Leeds Health Authority (with an estimated resident population of 728,840). 57 deaths were notified. 792 people with multiple sclerosis were identified living in Leeds on 31 October 1999. The mean annual incidence rate for the three-year period 1996-1998 was 6.1/10(5) (95% CI: 5.1-7.2). The sex ratio of incident cases was 2.3 to 1 women to men. On 31 October 1999 the prevalence of multiple sclerosis in the Leeds Health Authority was 108.7/10(5) (95% CI: 101.2-116.5). This compares with a prevalence of 97.3/10(5) (95% CI: 90.3-104.7) on 30 April 1996. The prevalence of definite and probable multiple sclerosis was 93.3/10(5) (95% CI: 86.4-100.6) and of suspected multiple sclerosis was 15.4/10(5) (95% CI 12.7-18.5). Crude annual mortality rates of people with multiple sclerosis for 1997 and 1998 were 1.9/10(5) (95% CI: 1.1 to 3.2) and 3.2/10(5) (95% CI: 2.0 to 4.7). Multiple sclerosis was noted as the underlying cause of death in 8 (14%) cases. The incidence of multiple sclerosis in the Leeds Health Authority is similar to that in the south of the United Kingdom. The difference in successive prevalence figures is less than that published in other serial studies. Multiple sclerosis was notified as the underlying cause of death in a minority of deaths in people with multiple sclerosis.

The prevalence of multiple sclerosis (MS) in the Persian Gulf countries has been significantly increasing during the past decades. This study was conducted for investigating the prevalence and incidence of MS in Northeast Iran (Khorasan Razavi province). This cross-sectional study was conducted during 1 January 1988 and 23 September 2018. All patients with a clinically definite diagnosis of MS according to the McDonald criteria (2005) and MRI along with the medical diagnosis, recorded in the Khorasan MS society, were considered for calculation of crude and age-standardized prevalence, and incidence rates of MS. The periodic incidence rates were calculated based on the year of onset of MS. Also, we calculated gender ratios for prevalence and incidence rates. The mean age-standardized prevalence and incidence rates of MS in the Khorasan Razavi were 8.69 (95% CI 8.05-9.41) per 100,000 (3.99 (95% CI 3.39-4.74) for males, 13.49 (95% CI 12.37-14.76) for females). Age-standardized prevalence was 48.87 (95% CI 48.37-49.35) per 100,000 (22.47 (95% CI 22.01-22.93) for males, 75.65 (95% CI 74.80-76.51) for females). Also, the mean incidence and prevalence for Mashhad County as capital of province were 11.38 and 59.09 per 100,000 populations, respectively. The female/male ratio was 3.33 for all age groups. Our results showed that this region is a high-risk area for MS like central region of Iran. Our results revealed that the prevalence and incidence of MS in the study area have increased during the recent decades with a sharp slope.

Background: Multiple sclerosis (MS) has had a remarkable increase in prevalence during recent years. This study was conducted to evaluate the correlation between prevalence and incidence of MS with the income level and lifestyle condition of countries with considering the effect of latitude. Subjects and Methods: This is an ecological study with secondary data obtained from several sources such as MS International Federation for MS variables data, and World Bank is a reliable source for economic variables. The latitude is also added in all models as an important effective factor. The bivariate correlation and linear regression were used to analyze of data. Results: The prevalence of MS in 2013 (54.06/100,000) increased by 9% in comparison to that in 2008 (49.96/100,000). According to fully adjusted analysis, there were significant positive correlations between income level with the incidence and prevalence of MS in reported 2008 and 2013 (P < 0.05) throughout the world. Our results revealed that the mean MS prevalence estimates in northern hemisphere, especially in North of America and Europe were different with those in the southern hemisphere. Conclusion: MS is more prevalent in high-income countries and the prevalence in developing countries is increasing by economically growth. It seems that environmental factors related to economic determinants are associated with increased incidence and prevalence of MS, further, geographic location continues to influence risk for MS, but these associations require more studies.

Trends in prevalence and incidence of multiple sclerosis in the Israeli Jewish and Arab populations.

Multiple sclerosis (MS) prevalence varies widely by country and world region, variation that is often attributed to latitude and its association with vitamin D exposure. Given that increasing latitude is also associated with higher national wealth, this study investigated associations between MS prevalence and other factors driving regional differences, with a focus on sociodemographic, health systems, and lifestyle factors on a national and regional level. Using data from multilateral organizations and scientific literature, an ecological study was conducted to evaluate associations between age- and sex-adjusted MS prevalence and prespecified sociodemographic (gross domestic product [GDP] per capita and gross national income [GNI] per capita), health systems (current health expenditure per capita and by percentage of GDP, universal health coverage [UHC] index, and medical doctors per capita), neurology-specific (MRI unit density and neurologists per capita), and lifestyle (obesity and tobacco use) factors. National, regional, and income-stratified data were aggregated and employed in relevant univariable and multivariable regression models. Stepwise variable selection techniques identified independent predictors of MS prevalence. Univariable regression analyses showed significant associations at the national level for all investigated factors, except obesity prevalence and tobacco use. Latitude was significantly associated with MS prevalence in all world regions (β = 0.16-2.16), whereas the UHC index was significantly associated in 5 of 6 world regions (β = 0.18-3.17). MS prevalence was significantly associated with all factors except lifestyle factors and MRI unit density in high-income countries, but no associations were observed in low-income countries. Latitude was associated with MS prevalence for all income strata except low-income countries (β = 0.55-1.62). In multivariable analyses, current health expenditure per capita (β = 0.083, 95% CI 0.048-0.12, p < 0.01) and latitude (β = 1.05, 95% CI 0.63-1.47, p < 0.01) remained significantly associated with MS prevalence. Health expenditure per capita is strongly associated with national MS prevalence, suggesting that theories that attribute variations in MS prevalence primarily to latitude effects on vitamin D are incomplete. Health care access significantly contributes to the global variations in MS prevalence, especially since national wealth rises with latitude and likely results in significant underestimation of MS prevalence in countries with lower health expenditure.

Prevalence and Incidence Rates of Multiple Sclerosis in Lebanon