Multiple Sclerosis (MS) is a complex chronic neuro inflammatory, demyelinating disorder of the Central Nervous System (CNS), and both genetic and environmental factors have been implicated in MS etiology [1]. MS sclerosis prevalence was increased in the last few decades. However, this statement cannot be attributed to the advances in neuroimaging of changes in diagnostic criteria [2]. Evidences demonstrate that a large number of environmental factors are important in the development and course of MS. The disease is triggered by environmental and lifestyle risk factors in individuals with susceptible genetic background, precipitated an aberrant autoimmune attack resulting in damage to myelin and axons [3,4].  It is not clear at present which factors are responsible for the different clinical presentations and disease courses [5]. Oxidative stress (OS), female gender, type 2 diabetes mellitus (T2DM), metabolic syndrome and obesity, infection with the Epstein-Barr virus, low levels of vitamin D, and cigarette smoking [6-11] are considered to be risk factors for MS onset and progression. These factors account for a large proportion of cases of MS incidence, and thus provide a promising foundation for MS prevention. The aim of this review was to gather information for stress and MS pathogenesis and discuss recent evidences about the link among the impact of oxidative stress, obesity, T2DM and metabolic syndrome on MS risk and pathogenesis.  We searched for studies, reports, reviews, and editorials in the PubMed database, of the last 5 years. The related articles were related to the risk factor’s influence in MS prevalence. Older references served as auxiliary sources for comparison purposes.

Epidemiology of Multiple Sclerosis

MS affects mainly young people with onset usually at the age of 20–50 and a mean age of onset of 30, although the disease may develop also in childhood and after the age of 60, and is 3 times more common in females than in males [12]. MS Atlas estimated a global median prevalence of 35 cases and a median incidence of 4 cases per 100,000 people, with a total of 2.3 million people which have been affected by MS worldwide [13], albeit prevalence and incidence rates vary with geography and ethnicity [1] and are unevenly distributed throughout the world [12]. Women between 20 and 40 years affected the most by the disease. MS is the leading cause of neurological disability among young adults [14,15]. Half of the patients, will need wheeled mobility device 25 years after diagnosis, due to this disability [16]. MS is classified into four independent types: Relapsing–remitting MS (RRMS), Primary–progressive MS (PPMS), Secondary–progressive MS (SPMS), and Progressive–relapsing MS (PRMS), even though the clinical course of the disease is highly variable. RRMS is the most prevalent form and accounts for approximately 80-85% of all cases [12], and affects women about twice as often as men, a ratio that is increasing due to a disproportional increase in incidence of MS in women [14].  MS exhibits sex differences in both the immune response and neuro degeneration, affecting disease susceptibility and progression, respectively. Female gender is an independent risk factor for the development of clinically definite MS after optic neuritis [9] and women with MS have more inflammatory lesions in MRI compared to men, as well as earlier onset of disease. Women are more susceptible to MS. Men, on the other hand, exhibit increased rate of disability progression over females, have worse prognosis, progress more rapidly and have more cerebellar involvement [9,17], indicating a gender effect on disease mechanisms [9,18,19]. The etiology of the female preponderance is not yet clarified. Male relapse-onset patients accumulate disability faster than female patients. In contrast, the rate of disability accumulation between male and female patients with primary progressive MS is similar [20].  In the last decades, female/male ratio in MS has augmented, and is geographically distributed around the world from 2:1 to 3:1 [21]. Rojas et al showed a modest increase of the female/male ratio (from 1.8 to 2.7) over time among patients affected by MS in Argentina, but did not show differences considering MS subtype [22]. Late pregnancy ameliorates disease, exhibit over 70% reduction in MS relapses during the third trimester of pregnancy [18]. MS is not inherited from parents to their offspring’s. However, MS frequent instances within families, shows that MS etiology is highly affected by genetics [3].

Pathogenesis of Multiple Sclerosis

MS pathology is characterized by plaques or lesions, indicative for the loss of myelin sheaths and oligodendrocytes. Demyelinating areas are found in the white and grey matter of the brain and spinal cord. Myelin sheaths are important for saltatory signal propagation and neuronal trophic support [23]. Sheaths are generated by oligodendrocytes, and consists of 70% lipids and 30% proteins and is the target of immune and OS attacks in MS [24]. In early MS, axons and neurons are mainly preserved. However, as disease progress, neuronal axons loss gradually and patients became disable. Brain atrophy appears and is followed by ventricular enlargement. Astrocytes form multiple sclerotic glial scars in white matter lesions. Remyelination occurs from new oligodendrocytes generated from precursor cells and results to the replacement of the lost myelin sheaths. However it can only partially repair demyelinated neurons in the adult CNS. The efficiency of this spontaneous regeneration is limited, which leads to incomplete remyelination and residual clinical symptoms [25].  Demyelination is also found in the grey matter of the cortex, nuclei and spinal cord [16]. MS is designated by the presence of infiltrating immune cells, irreversible demyelination, axonal degeneration and neuronal death in the CNS [26]. The pathological hallmarks of the disease are the plaques of inflammatory demyelination involving in the structures of the CNS. Demyelination is due to the damage to the myelin sheath surrounding nerves in the brain and spinal cord, which affects the function of the nerves involved [16]. Axonal degeneration, appeared even in early phases of the disease, affect patient’s future neurological disability [4]. CNS functions, treatment response and alterations in brain’s morphology exhibit essential heterogeneity. Heterogeneity’s mechanisms are not yet clear. However, different etiological risk factors and pathomechanisms are most likely to induce heterogeneity. Complex genetic trait with more than 100 quantitative trait loci and numerous environmental risk factors are implicated in MS’s etiology [14]. There are no genetic, experimental or pathological investigations that clearly suggest a single causative factor and thus a therapeutic target in MS. On the other hand, multiple manifestations occur resulting to the observed MS phenotype [27]. Neuro inflammation and probably autoimmunity and play a key role in the onset and the progression of the disease. The pathogenesis of MS lesion development is complex and involves the activation of the immune system. There are several mechanisms, including autoimmune inflammation, de-and remyelination, secondary and primary neuro degeneration. The process of progressive dysfunction, axonal and neuronal loss, astrogliosis and metabolic alterations remains to be elucidated [16]. The relative representation of these mechanisms in different patients most likely underlies the diverse phenotypic presentations of the disease [14].  Dysregulation of various different cell types of the adaptive immune system appears to contribute to lesion formation and progression. Pathogenesis is not completely understood, although is likely to involve inflammation against myelin and other proteins, mediated by T-cells, with a possible role of B-cells [3]. Macrophages internalized and degrade normal myelin sheath leading to the appearance of acute demyelinating lesions [28], in the presence of infiltrating T cells. As observed, in white matter lesions of patients with MS, macrophages usually contain myelin debris [29]. Once an active demyelination is established, peripheral immune cells (such as lymphocytes, recruited monocytes) and their central counterparts (astrocytes and microglia) contribute to progressive tissue damage in MS [28]. The CNS access is controlled by an endothelial blood brain barrier (BBB). Therefore, circulating immune cells entrance in strictly controlled, although only a minimal entry of immune cells can occur through the choroid plexus, under physiological conditions. Activated T-cells release cytokines, which under conditions, are able to reach capillaries located in the brain parenchyma, start to express adhesion molecules, and activate the BBB [14]. Migration of T-cells through the BBB, activation of T-cells and mast cells, demyelination, gliosis (proliferation and activation of glial cells [microglia, oligodendrocytes and astrocytes] in response to damage in the CNS [16]), axonal/neuronal degeneration occurs [26]. Microglia affects oligodendrocytes and neurons through inflammatory cytokines, phagocytosis, antigen presentation and ROS/RNS. Furthermore, immune cells including mast cells directly damage axons and neurons in MS [26]. The myelin basic protein released from demyelination also activates the immune cells to release neurotoxic and proinflammatory mediators that cause axonal or neuro degeneration in MS [26]. Inflammation is closely linked with oxidative stress and ROS-mediated tissue injury [10,28]. OS plays a key role in the pathogenesis of MS. In blood and in cerebrospinal fluid of MS patients during the active phase of the disease, it has been detected increased levels of oxidative stress indicators and/or decreased levels of antioxidant enzymes and antioxidant molecules. This indicates increased levels of ROS, which may have resulted in the depletion of cellular antioxidants [30]. The mechanisms which lead to oxidative damage and neuronal degenerations, is different in every stage of the disease. Inflammation and microglia activation due to oxidative stress cause the degeneration in early stages of MS. As disease progress mitochondrial injury and iron accumulation in the brain and liberation in demyelinating areas, are of great importance [31]. Inhibiting ROS production with NADPH oxidase inhibitors, lipoic acid or catalase can reduce the oxidative stress’s impacts and decrease myelin phagocytosis by macrophages. Oligodendrocytes contain large amount of polyunsaturated fatty acids which react with ROS, triggering lipid peroxidation. Furthermore, oligodendrocytes contain high intracellular concentrations of iron and reduced levels of antioxidant enzymes and free radical scavengers and consequently reduced antioxidant capacity. Thereby oligodendrocytes are strongly prone to oxidative injury. These findings indicates that pathophysiological mechanisms leading to lesion formation in MS, are ROS induced [30], mediated by macrophage and microglia, resulting to neuronal and oligodendrocyte injury in MS [32]. Nowadays regiments fails to stop MS progression and neuronal loss, remarkably. However, are of great effectiveness in reducing inflammation [33].

Oxidative Stress and Brain

Cells respond to danger in an evolutionarily conserved mechanism that aims to preserve homeostasis, and prevent from damage [34]. Chemical, physical or biological stimuli that threat cells and exceed the cellular homeostasis capacity, trigger the cell danger response (CDR). Insufficient resources and functional capacity results in various alterations in cellular responses. Initially, metabolic intermediates like ATP and ADP, Krebs cycle intermediates, oxygen and ROS are released. After the danger passed, pathways with anti-inflammatory and regenerative activities are activated to invert danger response and to treat. A persistent cell danger response, even if the stimulus has gone, could result to the development of chronic diseases, including Alzheimer’s and Parkinson’s disease, diabetes, kidney, liver and heart disease etc. and autoimmune disorders like MS, rheumatoid arthritis, lupus [34]. The CDR includes the OS response [35]. Stress as a homeostatic condition, is implicated in the pathogenesis of numerous disorders, such as cardiovascular, autoimmune, and neurodegenerative diseases [36]. There is a relationship between stress and oxidative damage caused by the ROS and Reactive Nitrogen Species (RNS). Under some circumstances, the balance between ROS/RNS generation and elimination is disturbed, the buffering capacity of the endogenous antioxidants is surpassed, leading to enhanced ROS/RNS level called "oxidative stress" [35]. This results to the oxidation of lipids in the plasma membrane, proteins in cytosol and nucleus, and nucleic acids [37]. As a consequence, oxidation of endogenous subcellular components causes alterations in their functions, leading to the development of biological stress. Pathological hallmarks and alterations in neurodegenerative disorders, are area-specific and affect certain types of neuronal cells. Radi (2014) outline similar pathological processes suggesting a common pathway that leads to neuro degeneration. However, clinical signs and symptoms and neuronal vulnerability may differ [38]. Factors such as normal ageing process, dementia, trauma, stroke, hypertension, depression, diabetes, tumours, infections, toxins and drugs can initiate neuro inflammation in the CNS. Neuro inflammation in the CNS is characterized by increased production of chemokines and cytokines, altered integrity of the BBB, influx of leukocytes as well as the activation of microglia and astroglia [39]. Aging is also associated with increased systemic inflammation, increased BBB permeability, impaired glial cell signalling and chronic pro inflammatory reactions in the CNS cells. Inflammatory mediators released, includes inteleukin-1beta (IL-1β), IL-6 and tumour necrosis factor-alpha (TNF-α). In addition, astrocytes and microglia function as inflammatory cells and release many neuroinflammatory cytokines and chemokines within the aging CNS [26] Mitochondrial dysfunction contribute significantly to neuronal and axonal damage and loss [33]. Several mechanisms, such as energy failure, induction of apoptosis and enhanced production of ROS can induce the tissue damage. Mitochondrial damage evoke liberation of apoptosis induced factor or cytochrome C and thus induced pro-apoptotic events [32]. Dysregulation of mitochondrial function implicated in adult onset neurodegenerative disorders such as Alzheimer’s disease (AD), Amyotrophic Lateral Sclerosis (ALS), Parkinson’s disease (PD) and Huntington’s disease (HD). Mitochondrial dysfunction in collaboration with oxidative damage due to oxidative stress and the induced neuro inflammation are believed to cause the tissue damage in MS [32]. Brain is prone to oxidative stress due to its high demand for oxygen and a limited capability of obtaining antioxidants [40]. The brain weighs about 2% of the total body mass, nevertheless it consumes 20% of the total basal oxygen uses by mitochondria [27]. Antioxidative defense mechanisms minimize the oxidative stress in under normal conditions [31].xidative stress is of great importance for tissue lesioning in brain aging, as in chronic inflammatory, vascular and neurodegenerative disorders of the CNS [31]. Free radicals are unstable, short-lived and highly reactive atoms or molecules and can affect important classes of biological molecules, via peroxidation and nitration process [40]. Production of ROS and nitric oxide mainly by microglia cells and macrophages, induces the expression of enzymes necessary for their production [31]. Due to the cellular redox-buffering capacity and their reactivity and instability, ROS are not able to migrate far from their production site. Because of their high reactivity, the half-life of [OH]• in cells, is limited only to 10⁻⁹ s, indicative that [OH]•  will oxidize biomolecules in proximity [41]. As a result, direct oxidation of lipids, proteins and DNA occurs, thus interfering with the function of these molecules and propagating their degradation [31]. Successively biological macromolecules such as polyunsaturated fatty acids in membrane lipids, essential proteins and DNA/RNA, oxidized as a result of ROS reactivity [31]. The products of these reactions are oxidized nucleotides, proteins and lipids and can become markers of OS [40] and can potentially be used as diagnostic biomarkers [42]. 4-hydroxynonenal, is one of the major oxidized polyunsaturated fatty acids end-product and is widely accepted as an indicator of lipid peroxidation and oxidative stress. Recently, Kemp et al proved is found adjacently to myelin and its levels raised while myelin basic protein’s levels decline [10].  It is well established, as brain tissue examination revealed, that antioxidant defensive mechanisms impair and/or decrease, along with increased ROS and RNS, in neurodegenerative diseases. Antioxidant defense mechanism includes superoxide dismutase, catalase, glutathione/glutathione peroxidase, ????-tocopherol, and uric acid [43]. Superoxide dismutase (SOD1 and SOD2) enzyme localised within cerebellar neurons, are up-regulated nonetheless catalase and glutathione peroxidase perform deficiently. That evidences shows that cerebellar grey matter lesioning in MS has oxidative origin [10]. Chiurchiu examined MS plagues and detected an increased free radical activity along with depleted levels of antioxidant molecules such as GSH, a-tocopherol, and uric acid [43]. Recent research demonstrated an association among immune-inflammatory oxidative stress and nitrosative stress biomarkers as predictors of disease progression in MS as assessed with EDSS score and specific target symptoms [24]. CNS is vulnerable to lipid peroxidation due to its high oxygen consumption and its enrichment in polyunsaturated fatty acids [30]. Mitochondrial dysfunction is an important contributor in the neurodegenerative aspects of MS [44,45], whereby ATP production is reduced in demyelinating segments of upper motor neuron axons and impacts on ions homeostasis, induces Ca²⁺-mediated axonal degeneration, and contributes to progressive neurological disability in MS patients [46]. Mitochondrial DNA mutations leading to mitochondrial dysfunction extensively described in the cortex and white matter of MS patients, are induced by ROS inhibition of the efficiency of oxidative phosphorylation and further increase the production of ROS, and thus leading to a vicious circle [27]. Excessive production of ROS in the brain, causes neuronal and glial cells oxidative injury and impairs neuronal performance and communication. Apoptosis’s morphological alterations are induced. Chromatin is condensed, DNA fragment and caspases are activated. Cell death and significant loss is evident neurodegenerative diseases [38].

(Table 1) Impact of Metabolic syndrome on Multiple Sclerosis.

Table 1: Depiction of usually risk factors of Multiple Sclerosis, effects as studied in the at least years.

Over the past years, we have met a substantial increase in autoimmune disease. The influence of environment contributes in the rising prevalence of autoimmune diseases. MS has been associated with several environmental factors, such as diet and obesity, Epstein-Barr virus (EBV) infection, ultraviolet radiation, low vitamin D levels, smoking [7,8]. Smoking rises MS’s risk in about 50%, in comparison with never smokers. The risk is directly proportional to the smoking duration and intensity [6]. A wide variety of other environmental factor have also been suggested as triggers for MS, but their role is disputed [12]. Vascular comorbidities such as obesity, type 2 diabetes and dyslipidemia are consider to be risk factors for MS’s onset and progression, denoting the impact of cardiovascular physiology in pathophysiological mechanism in MS [4]. Obesity is defined as a Body Mass Index (BMI) >30kg/m^-2. Due to inflammation in metabolic tissues or to a chronic low-grade sterile inflammation, obesity is thought to be a chronic proinflammatory disease state. There are no clinical signs of inflammation, however there are increased levels of proinflammatory factors [4]. It has been implicated as a proactive factor in several chronic autoimmune inflammatory disorders [47]. Over the past years, obesity’s prevalence is increased by modern lifestyle and has become epidemic due to changes in life-style and dietary habits, which promotes consumption of large amount of fat, sugar and salt. Consequently, energy intake is more than expenditure and fat accumulates in the body [4], while the prevalence of immune-mediated diseases has been also increased [48]. Urbanized lifestyle accompanied with psychological stress, sleep disturbances, lack of physical activity and changes in dietary habits, and is considered to be a risk factor for weight increase [49]. Obesity is the principal lifestyle modifiable risk factor associated with an increased risk of developing type 2 diabetes [50] and also is a risk factor for the onset of neuro inflammation. Obesity seems to be a major contributing environmental factor to the onset and progression of autoimmune diseases [51]. Recently, obesity was associated with MS onset and interacts with genetic and environmental factors to increase MS susceptibility [52]. Since the discovery of the remarkable secretory properties of adipose tissue recently, the possible association between MS and obesity and underlying mechanisms, has become more intriguing [51]. Adipokines, are produced from fat tissue, and are involved in the regulation of several physiological functions, such as immune response. Low-grade inflammatory reactions are constantly present in the adipose tissue in an obese person. Adipocytes also release many pro inflammatory mediators including adipokines. Thus, obesity is a predisposition to neuro inflammation and neurodegenerative diseases [26]. Adipose tissue (AT) is involved in metabolic, hormonal and immune processes and is very important in the organism’s homeostasis. AT consists of adipocytes, with endocrine function and other cells types, including fibroblasts, endothelial cells and innate (macrophages, neutrophils, eosinophils and mast cells) and adaptive (various subtypes of T and B cells) immune cells [4]. Adipokines such as adiponectin, leptin and resistin, secreted from adipocytes and play an important role in inflammatory regulation, insulin resistance and satiety. Proinflammatory cytokines, such a tumour necrosis factor (TNF)-α, monocyte chemoattractant protein (MCP)-1 and interleukin (IL)-6, are up regulated and secreted by adipocytes. On the other hand, there is a decline in anti-inflammatory adipokine’s secretion. In consequence, adipose tissue inflammation is established, and leads to the onset and progression of metabolic disorders related to obesity [4]. Inflammation, either is local or systemic, induces immune cells infiltration into the adipose tissue. In result, production of pro-inflammatory factors is increased which are secreted into systemic circulation. This evidence signify the correlation between obesity and metabolic disorders [4]. Pro-inflammatory molecules predominate over anti-inflammatory molecules, and combined with the incapacity to eliminate inflammatory stimuli, pro-inflammatory cytokines and ROS are produced. This results to the establishment of oxidative stress, leukocytes oriented at the site of inflammation, causing tissue injury [4]. Over nutrition and obesity and are related to adipose tissue dysfunction and immune system over activation, resulting to adipocytes hypertrophy, hyperplasia and differentiation, and also in recruitment and activation of immune cells, such as macrophages, and release of pro-inflammatory cytokines. CNS and brain are susceptible to the effects of systemic inflammation that impaired the BBB permeability, activated microglia, macrophages and lymphocytes, releasing pro-inflammatory cytokines and causing oligodendrocytes cell death. Consequently, neuronal degeneration is established, as a result of the inflammatory processes in the CNS. Therefore, obesity induced inflammation evokes a chronic low-grade of systemic inflammation, resulting to beta cells apoptosis and insulin resistance, establishment of oxidative stress, liver lipogenesis and steatohepatitis, endothelial dysfunction and activation of innate immune response. The inflammatory responses with the activation of immune system, contributes to a relationship between neuronal inflammation, endothelial dysfunction, autonomic dysfunction and demyelination mediated to the pathogenesis of MS. Obesity negatively influences MS progress and treatment response and thus increase disease severity, after the disease initiated. However, in early life, obesity is consider to be a factor that increase MS’s vulnerability and a causal risk factor for late MS development [48]. Obesity prior to adulthood is associated with increased risk of MS [53,54]. There is strong level of evidence, supporting an increased risk of MS (OR=2) in obese subjects [51].  Based on the North American Research Committee on Multiple Sclerosis [NARCOMS] registry, involving 8983 participants responded to a questionnaire, and based on their maximum reported weight in the surrounding years, it was found that nearly 50% of participants were overweight (2175) or obese (1652) at MS onset [55]. In a cohort study Munger [56], in American female population, showed a greater than twofold increased risk of MS, in obesity at the age of 18. At the age of 20, a large body size increases the MS risk to 96%. However, MS risk in association with body mass in adulthood was found of no significance. In a prospective cohort study, Munger, found that a higher BMI at ages 7-13 was associated with a 1.61–1.95-fold increased risk of MS among girls, although the associations were attenuated in boys [53]. In a Swedish, population-based case-control study using incident cases of MS, aged 16–70 years, in both male and female, subjects with BMI more than 27 kg/m² at age 20 had a double risk to develop MS in comparison with normal weight subjects [57]. Another study [54], identified a higher risk of pediatric MS and clinically isolated syndrome in extremely obese adolescent girls (BMI ≥35 kg/m²).

Vitamin D is fat-soluble vitamin, thus is highly distributed in adipose tissue. Consequently, obese individuals have lower circulating levels of vitamin D than non-obese [58], but they have higher serum levels of proinflammatory cytokines, particularly IL-6 and TNF-α. Both of them contributes to a risk increase of the disease [7]. Childhood and adolescent obesity doubles the risk of MS. Recent studies used separate-sample Mendelian randomization suggested that a higher BMI due to genetic predisposition was associated with increased susceptibility to MS, supporting a causal effect of BMI on susceptibility to MS. Inflammatory processes, a common feature of obesity and MS, seems to play a key role in that associations, although the mechanism remains unclear [59]. Adolescence obesity is associated with future risk of MS in females, whereas a high adult BMI at diagnosis had no influence. Obesity is also associated with increased risk of pediatric-onset MS. Therefore, adolescence seems to be the critical period in which weight affects the risk of MS in childhood, as a high BMI at 10 years of age was not associated with future disease risk [60].  Abdominal obesity is an important risk factor for coronary heart disease and T2DM. MS patient’s mortality rate, due to cardiovascular diseases, was 2.4 times higher than individuals without MS [61]. The higher risk of cardiovascular diseases in MS patients is not yet clear if is associated to a higher risk of obesity or in body’s composition changes, hypertension, dyslipidemia or T2DM [62]. T2DM is characterized by insulin resistance and impaired islet beta cell function and beta cell loss. As a result, pancreas become incapable to supply organism with sufficient insulin for its demands [11]. The onset of T2DM, is associated with various modifiable and non-modifiable risk factors [50]. Recent studies, comprised large nationwide T2DM population-based cohort study, suggest that T2DM contributes to a higher risk for developing MS, in both genders. The increased risk was higher in female patients with T2DM, aged 50 years or less. The association of T2DM and MS, was of moderate significance, and independent of other comorbidities related to MS or socio demographic characteristics [11]. MS and T2DM are both considered as autoimmune diseases; therefore, T2DM patients are more susceptible to the development of MS due to the interactions of immunity and environment. The metabolic syndrome is also known as syndrome X, the insulin resistance syndrome. It is characterized by glucose intolerance and insulin resistance (type 2 diabetes, impaired glucose tolerance, or impaired fasting glycaemia), central obesity, dyslipidemia and hypertension. Overall, metabolic syndrome is consider to be enough evidenced as a risk factor for cardiovascular diseases [63]. Increased insulin resistance is followed by higher circulating insulin levels and increased ferritin, which is a biomarker of inflammation [64]. Therefore, metabolic syndrome is consider to be a risk factor for T2DM and obesity and consequently a risk factor for the initiation of MS. Identification of metabolic syndrome helps identify individuals at risk for both diabetes and cardiovascular diseases. Metabolic syndrome’s prevalence in MS patients with EDSS score ≥3.0, was 30% with no gender differences, while obesity (BMI ≥ 30 kg/m²) was present in 18.5% and overweight (BMI 25.0–29.9 kg/m²) in 34.6% [61].

Differences in immune response and neuro degeneration between genders, affects MS susceptibility and progression, respectively. Women are at increased risk of MS while men may face a worse disease course [9,65]. Studies indicate a gender biased disease mechanism [9,18,19]. Immune differences among genders might be the key component to its etiology [66]. The present review identified recent studies linking MS to the risk factors associated with modern lifestyle and other environmental factors, contributing to the increased risk of MS. As long as environmental factors and lifestyle attends an ascending course, following with augmenting OS effect, MS’s prevalence will also be increased. According to the studies, MS exhibits a gender effect, while women had a higher risk of developing MS than men and men have worse prognosis. It might be due to sex differences in the immune and nervous system between the two genders, which may be affected by sex hormones, genetic differences, as well as by different environmental exposures [67], affecting disease susceptibility and progression respectively. It is well known that there are no investigations (genetic, experimental or pathological) that clearly suggest a single causative factor in MS, although autoimmunity and neuro inflammation play key roles. In the last decade, the key role of neuro inflammation in neuronal degeneration has been studied extensively. Evidence strongly shows that stress and neuro inflammation are crucial factors in the onset and progression of neuro degeneration and neuronal loss in neurodegenerative diseases [69]. Inflammation is closely linked with oxidative stress and nerve damage mediated by ROS. Therefore, oxidative stress seems to play a key role in the pathogenesis of not only MS, but in several disorders.  Oxidative stress results to the oxidization of biomolecules, leading to the establishment of biological stress. Factors such as increased production of chemokines and cytokines, increased BBB permeability, influx of leukocytes, microglia and astroglia activation and dysfunctional mitochondria are considered to be characteristics of neuro inflammation and with oxidative stress promote tissue damage in MS [69]. There are a large number of studies investigating the role of the potential risk factors for MS development. Cardiovascular health seems that may a pivotal role in the pathophysiological mechanism as vascular risk factors and typical vascular comorbidities like obesity, T2DM and dyslipidemia have been associated with MS [4]. Over the past years, obesity’s prevalence is increased and has become epidemic due to changes in life-style and dietary habits, resulting to an excessive accumulation of body fat [4], while the prevalence of immune-mediated diseases has been also increased [48]. Investigations demonstrate that obesity is the major environmental factor contributing to the onset and progression of autoimmune diseases and recently were associated with MS onset, contributing to MS susceptibility augmentation. Along with obesity, studies show that metabolic syndrome (type 2 diabetes, dyslipidemia, insulin resistance, and hypertension) is a risk factor for cardiovascular diseases and also risk factor for MS, due to the pathophysiology of the syndrome. Urbanized lifestyle is a contributor factor for weight increase in women [49] and may give an explanation to the increased incidence of MS among women. However, Poorolajal, shown that the risk of MS in people with type a personality behavior pattern, which are known to have more stress, nervousness and anxiety than people with type B personality was higher compared to type B personality, but this was no statistically significant. Patient’s behavior was assessed by a standard questionnaire and upon the total score were considered as type A otherwise as type B personality [67]. Habit and lifestyle changes, such as cigarette smoking, obesity, hormonal replacement therapy and later childbirth, over the past decades, especially in women, might be responsible factors for the observed differences in MS epidemiology [68].

Genetic, experimental, and pathological investigations conclusively suggest that there is no evidence for a single cause and thus therapeutic target of multiple sclerosis [27]. On the other hand, multiple steps orchestrate the clinically observed phenotype in susceptible individuals. There are many factors that influence MS susceptibility and progression, and substantial progress has been made in understanding the risk factors for MS. These give us the opportunity to make interventions that are likely to substantially reduce MS risk and to delay its progression in order to improve the outcomes of individuals with MS. Gender seems to play a key role in the onset of the disease, that has been underscored the need for investigating disease in both males and females in basic and clinical research. Disease mechanisms have a gender effect, indicated by the increased susceptibility of females over males, but increased rate of disability progression of males over females. Consequently, therapies discovered for one gender may have a different impact on clinical improvement on the other gender. The pathophysiological mechanisms responsible for MS pathogenesis and disentangle mechanisms underlying sex differences has to be elucidated. Thus, investigation of therapeutics based on these insights might be helpful to discover novel, more effective and targeted therapeutics. Understanding the mechanisms in which MS is initiated and identifying the immune mechanisms responsible for disease, is crucial and has many potential advantages. Inflammation is closely linked to Oxidative Stress. Both seem to be important factors in MS pathogenesis. Is generally accepted that ROS induce pathological mechanisms of MS lesion formation [30] and are mediated by macrophage and microglia, resulting to neuronal and oligodendrocyte injury in MS [32]. Obesity prevalence increased in the last decades, and has become epidemic, and thus may give an explanation for increased MS incidence. Obesity in adolescence is associated with a higher risk of MS. Taking these observations into account, there is a possibility to take measures taken against adolescent obesity may thus be a preventive strategy against MS.  Urbanized lifestyle is a risk factor for excess weight in women and may give an explanation to the increased incidence of MS among women. Vascular risk factors and vascular comorbidities such as obesity, type 2 diabetes and dyslipidemia have been associated with MS. These findings are indicating that cardiovascular health plays an important role in the pathophysiological mechanisms contributing to MS onset [4].

A better understanding of the pathophysiological mechanisms and fundamental principles responsible for neurodegenerative diseases is a major significance for treatment options. It is important to become more aware of MS modifiable risk factors, in order to advice MS patients in avoiding preventable comorbidities. That fact indicates the need for future research in modifiable risk factors impact in MS onset and progression. Further observational studies should provide more definitive evidence on MS susceptibility among individuals and a depth elucidation in which way modifiable and non-modifiable risk factors interferes with genetic background for the development of MS and is promising to shed light to new approaches to prevention and treatment. The findings may be useful to policymakers in preventing programs to reduce MS rate and its associated predisposing factors. It is challenging to develop novel drugs with anti-inflammatory activity in order to halt the disease progression and/or with neuro trophic activity to induce neuronal regeneration and remyelination to neuronal injury restitution. In addition, further investigation is needed, to understand the manner the potential risk factors affect the pathogenesis of MS, along with long-term prospective cohort-studies.

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