There is currently no single diagnostic test for MS due to its aetiology is not completely understood. On the strength of the development in radiological scans, especially MRI, as well as the advancement in the new disease-modifying drugs; after a few revisions, the current “McDonald Criteria (2010)” is improved allowing MS to be diagnosed earlier. These criteria are based on the dissemination in space (DIS) and time (DIS) by MRI and clinical data DIS can be demonstrated by a presence of at least 1 T2 hiperintensive lesion in 2 out of 4 typical locations: Periventricular, subcortical, infratentorial and/or in the spinal cord.
Lesions in gadolinium-enhancing are not included in the current DIS critics. Regarding to second revision of criteria based on DIT, it may be characterised by a presence of a new T2 hiperintensive lesion or a gadolinium-enhancing lesion in the next MRI scan or by a presence of both gadolinium-enhancing and non- enhancing lesions in the first MRI scan. The time of which MRI scan was taken is not critical for both case.
Nowadays, its characteristic phenomena are based on the clinical outcomes (patient’s story), supported by helpful tests such as neuroimaging (MRI), in some cases by cerebrospinal fluid (CSF) as well as visual evoked potentials (VEP) analysis alongside McDonald criteria that are used for the clinician to get an MS diagnosis of the individual. Evoked potential tests can be useful as they can show functional disorders on afferent or efferent pathways that are not clinically examined. As similar, analysis of CSF could be very helpful to provide diagnose.
Also, disability status of a patient with MS is scored by expanded disability status scale (EDSS) which is outcome measurement scale developed by Kurtzke. Scale allows measuring the maximal function of each patient based on neurological examination. The scale consists of 10 steps and is prepared to have a space of 0.5 units between both steps. Steps from 1.0 to 4.5 refer to MS patients who are able to walk by themselves. These steps arise due to the disability measurements that occur in the eight functional systems (FS).
Hemogram (total blood cell count), sedimentation blood test, C reactive protein (CRP) test, thyroid-liver-kidney function test, vitamin D level measurements are among the other tests used for differential diagnosis of MS. Patient’s smoke intake, the case of EBV infection can also be provided.
Epidemiology Of MS
Multiple sclerosis is known to be one of the most common neurodegenerative disorders. Unfortunately, in many countries, this neurologic disease is mostly occurred in young adults without causing trauma. Globally, population of MS is approximated as 2.3 million in 2013. The disease is scattered globally: its prevalence ranges from less than five cases per 100,000 people in tropical regions or Asia and, hence, between 100-200 cases in 100,000 individuals in mild areas, especially in the region of Northern European which is highly populated (Figure 1).
Data coming from study collaboration of World Health Organization (WHO) and Multiple Sclerosis International Federation (MSIF) indicate that there is a peak in the prevalence of MS since 2008. The increase in MS prevalence reported between 2008 and 2013 can be attributed partly to survival (both MS and the general population is more prevalent) and increased incidence of MS in some countries, it can reflect in improvements in diagnosis (MRI techniques, increased numbers of neurologists). MS reporting may also link to the publications of epidemiological surveys.
It is known that patients with MS over than 65 years are more inclined to have PPMS (29 per cent), SPMS (26 per cent) rather than younger equivalents of whom have RRMS (57 per cent). This can be the result of that repairs, remyelination and other physiological functions become less efficient as the disease progresses. However, it should be noted that not every RRMS develop SPMS following disease courses or by aging. Although aging is a critical factor for MS, the disease is not only presented in older elders. Typically, young adults between the ages of 20 and 50 appear at the peak of the age of 30, and childhood or old age occasionally arises.
Female gender has been considered as a potential influencer of MS, more often RRMS. Its frequency is higher in women than men (2:1 ratio). These differences demonstrate that genetic and hormonal triggers take part in in sensitisation, especially in the identification of genes on X and Y chromosomes. In support of this hypothesis, MS has been observed to be relatively stagnant during pregnancy, but with increasing frequency after birth. In the case of primary progressive MS, the subtype of a disease, seen in elderly individuals, the ratio of female to male has been found 1:1.
Current Understanding Of The Disease Mechanism
Demyelination is a crucial pathological process which effects neuron fate. It is termed as the destruction of myelin sheath with preservation of axis cylinder continuity. The distinguishing feature of the disease is the occurrence of sclerotic plaque displays the last phase of course characterised by inflammation, de- or re myelination as well as axonal degeneration.
Even though the idea is squeezed, the arrangement and relationship of these different components continue to be completely unresolved. Myelin is produced by adult oligodendrocytes, each of them interacts with the short segments to axons 20-40 in the white matter pathways of the CNS. MS is considered as one of the autoimmune diseases which inflammatory demyelination occurs in CNS with a variety of clinical presentations.
Some authorities thought that the disease process is the result of the increase of autoreactive lymphocyte migration throughout the blood brain barrier (BBB). The transition results in imperfections that allow these cells to develop an immune response. Lymphocytes of MS patients are ineffective in suppressing effector cells. These cells cannot effectively cause to decrease in stimulation due to overexpression of β-arrestin 1, an essential promoter of naïve and activated CD4 (cluster of differentiation 4) + T cell survival.
When the local regulatory mechanisms broke down within the brain, this causes the inflammation controlled by perivascular CD8 (cluster of differentiation 8) + cell, triggers plaque accumulation in different parts of CNS. Studies have shown that the main role attributed to experimental allergic encephalomyelitis T-helper 1 (Th1) (interferon-γ secretory) cells is misrepresented. Inflammation is mediated by T cells which produces interleukin-17 under the control of interleukin-23. Interleukin 17 and 22 allow T-helper 17 (Th17) cells to penetrate the brain-brain barrier, where Th17 cells can kill neurons.
An alternative hypothesis is that the first dysfunction occurs in the CNS and is not immunologic or inflammatory. Following the initial damage, CNS antigens infiltrate into lymph nodes and this activates T and other immune cells, eventually they can pass through nervous system. Thus, regardless of the origin of the MS pathology, immune cell subpopulations are activated and migrate to the CNS. This is the distinctive features of the MS pathology: demyelination, oligodendrocyte destruction and damage in axons.
For activation of T cell, there should be an antigen occupation. (Figure 2.). A pathogen is captured and decomposed by antigen presenting cells (APCs). Subsequently, APCs move towards to lymph nodes that has the pathogenic antigen associated with the major histocompatibility complex (MHC) on the surface of cells. Naive T cells within its receptors recognises the composition of antigen / MHC which is known as a first signal. A second is needed to activate, proliferate and differentiate T cells to effector cells.
B cells also have a critical role in the progression of MS disease considering that current monoclonal antibodies targeting the B cell antigen, known as CD20 (cluster of differentiation 20), are effective therapies in MS. Oligoclonal bands which is responsible from the production of immunoglobulins in cerebrospinal fluid are commonly observed in MS patients. Many follicle-like structures are likely to place on the meninges of many MS patients. It is believed that B cells produce of antibodies targeting CNS, like the ones in the Ranvier node, are associated with several functions in cells such as antigen production and assist T cells.
Influencers Linked to MS
Even though the cause of MS is still unknown, it seems clear that there is immune- mediated mechanism characterised by lesion of demyelination and gliosis in multiple locations within CNS white matter. It is believed that both genetics and environmental factors play roles in the pathogenesis of MS considering it is a complex disease. Newly concepts also concluded that immune dysregulation can be added to those relative factors. Current data are gathered from animal model studies and from genome-wide association studies (GWAS) and meta-analysis of different ethnic origins.
Considering MS holds heterogeneity; it would be wrong to evaluate disease progression through a single gene. Several gene polymorphisms have been identified through MS disease. Here, it is presented the most commonly found associated genes according to results of large cohort studies.
The human leukocyte antigen (HLA) gene subset located on the 6p21.3 chromosome is the most potential loci of sensitivity for the MS for over 30 years. It is gently identifiable both by candidate gene relation as well as by whole-genome linkage applications. Primary signal comes from MHC, HLA class II, DR beta 1 (HLA-DRB1) gene.
*1501 risk haplotype is predicted as the strongest MS risk factor in some ethnic groups, and its expression can be increased 1.6 times following stimulation with 1,25-dihydroxy vitamin D . Larger data set come from genome projects have identified new MS- related loci within HLA.
One of the recent additional genes that relate to MS is interleukin seven receptor alpha (IL7RA) which is also known as CD127 (cluster of differentiation 127). It is located on chromosome 5p13 and plays an important role in V(D)J recombination which is occurred in lymphocyte development/ cell survival and formation of the immune response. rs6897932 polymorphism which is located on exon 6 of IL7RA was eighth most strongly associated with MS in several studies.
The other most related gene to MS is considered as interleukin two receptor alpha (IL2RA). IL2RA considered in several disease pathogeneses like diabetes. Gene particularly takes part in process responsible for differentiation of T helper cell, which is found to be related to the MS development. The IL2RA gene has been illustrated suitability in MS progression. It was also found that a polymorphism locates in IL2 promoter region was enhanced MS risk, but GWAS has shown that IL2 polymorphisms do not hold statistically significance for MS.
Environmental Risk Factors
Studies indicated the effect of sunlight exposure and ultraviolet B (UVB) radiation on MS disease had been made since the beginning of 20th century. Case-control studies conducted regarding the information how individuals spend their time in open spaces and use indoors or outdoors as workspaces have provided results in support of this occasion. The study, carried out on Tasmanian, indicated that the frequency of MS who had chance to sun bathing for an average of two or three hours per day between the ages of six and 15 had declined considerably.
The mortality rate due to MS has been shown to be negatively related to exposure to solar radiation, either residential or occupational. In another study, it was statistically supported that the possible risk of skin cancer related to sunlight found lower in individuals with MS, suggesting that exposure to sunlight may be a protective for MS. There was no correlation between other types of cancer and other neurodegenerative diseases in the study. The most important limitation of such studies is that exposure time to sunlight was severely reduced by MS patients who preferred to work indoors because of insomnia and physical disabilities, and this prevents secondary assessment.
It has been suggested that there are two common hypotheses in the aetiology of MS. Mostly acceptable one is poliomyelitis-hygiene hypothesis that states an interaction with the active substance throughout early childhood or infection protects from MS while late interaction causes the disease. As a second, Kurtzke’s prevalence hypothesis, another theory based on the epidemics of the Faroe Islands after the World War II, suggests that MS originated from a more common pathogen in regions with high MS frequency.
Varicella, rubella, varicella zoster and mumps viruses are biologically acceptable infectious agents as MS pathogens, but epidemiological and laboratory studies showed that Epstein-Barr virus (EBV) plays an important role for MS. EBV, an agent of the ubiquitous herpesvirus, spreads widely and can cause persistent asymptomatic infection. Studies have focused on EBV because expression of EBV antigens has found considerably higher levels in CSF.
When saliva exchange becomes more direct during adolescence, mononuclear infections closely related to MS are observed. Most episodes of MS epidemiology have resulted in paralysis with infection, thus they have parallel outcomes; in areas where MS is not frequent, younger people have the higher percentage in terms of infection with EBV, while, in regions where MS is more frequent, rate of EBV positivity cannot reach that high until puberty. In researchers’ findings, the population with EBV seropositive is higher than 90 per cent and this suggests that early contact with EBV is likely to have protective effect for MS.
This also smooths out the high incidence of MS with high socioeconomic status as well as the low frequency of MS in black people and individuals from Asia. It is believed that virus is the common agent that increases MS ratio in Australia from north to south. However, studies have shown that about 93 per cent of MS patients do not have intrathecal anti-EBV antibody synthesis. Therefore, the relationship of EBV to adult MS should be investigated, and its role in pathogenesis should continue to be examined.
Physical and emotional stresses have been considered as potential influencer for MS. One of the important issues to consider is the definition of the stress and the time of impose. In one study, any relationship was excluded except for impact between cranial trauma and MS. Results explaining effects of emotional stress in MS have found weak, however emotional stress effectors are likely to be informal factors. A Danish cohort study indicated the association between MS and child’s death was highly significant.
In this study, most of the result and selection cohorts from other case-control studies were avoided. Yet, it is not possible to rule out that the death of a child is merely a clue rather than an informal factor, and that this may be related to differences in behaviour or in the environment. A study reported that more MS patients were more stressed than controls, two years before the onset of illness. Another study concluded that MS patients had more serious life events than controls in the early period of disease. Nevertheless, studies show that stress is among MS enhancing factors that cannot be proven.
Smoking has been criticised as potential influencer for MS. In a study, evidences showed that smoking increases awareness of disease, it has been shown that the relative prevalence of MS in patients with smoking is higher than no-smokers. Studies showed that passive smoking increases the risk of MS in child and adults. It also affects the inflammatory results in MS. In a study of patients with CIS, occurrence of clinically definite MS was higher for smokers than for non-smokers. Smokers who had more lesions and partially lost their brain compared to non-smokers have been concluded in an imaging cross-sectional study.
Similar results have been obtained in another study which patients were taken under control approximately 2.8 years. However, the relationship between cigarette and MS disease is still unclear. In a study, smoking has not been found in association with either the risk of secondary progression or the risk of reaching EDSS 4.0 or EDSS 6.0.
Contrast to this, a study has shown a risky association between cigarette and secondary progressive course. In a recent cohort study among large population, cigarette smoking has increased the risk of secondary progression, however no peak in EDSS scores; in another study, cigarette went up the EDSS scores over a two-year follow-up period. For this reason, although smoking appears to affect the early progression of disease, studies are still performed to determine the effects smoking on early and late MS terms.
While there are many environmental factors that may be associated with MS, there is not enough evidence unrelated to most MS gradients. These include organic solvents, dental amalgam, physical trauma, dietary fat, dietary antioxidants, high education status and oestrogen, which can alter the immune response. Apart from these, it is also possible to mention other environmental factors that may be associated with MS: tetanus toxoid inoculation, antibiotic use and antihistamines and increased uric acid in the blood.