**1. Introduction**

Multiple sclerosis (MS) is a demyelinating disorder with an underlying neuroinflammatory disease process affecting approximately 2.5 million people worldwide [1]. Traditionally, the disease has a greater prevalence in locations which are geographically north of the equator. In a study from 2015, North America and Europe had an average prevalence of greater than 100/100,000 individuals, whereas East Asia and Sub-Saharan Africa had rates of 2/100,000 individuals [2].

### **1.1 Environmental and genetic risk factors**

To better understand this disparity, an umbrella systemic review looked at the possible environmental risk factors involved in the development of multiple sclerosis [3]. An analysis of 44 potential risk factors was filtered down to 3 which were found to be profoundly significant: anti-Epstein-Barr Virus Nuclear Antigen IgG seropositivity, infectious mononucleosis, and smoking [3]. The hypothesis

behind anti-EBVNA IgG suggests that late adolescence exposure to EBV leads to infectious mononucleosis with significantly elevated IgG titers when compared to individuals who were exposed at a younger age [4, 5]. These titers in turn correlate to an increased risk of developing multiple sclerosis. One study done on this, "highhygiene" population found that individuals of the same age who were not infected with EBV had a 10-fold lower risk of developing multiple sclerosis when compared to their EBV infected counterparts [4]. The pathology linking EBV titers to the initiation of multiple sclerosis are not yet clear, however it may increase the risk for an autoimmune type response as was seen with Systemic Lupus Erythematous and EBV [4, 6].

Several studies have shown a direct correlation between cigarette smoking and incidence of multiple sclerosis [4, 7–10]. There is some variability in the literature between gender and age groups. One study suggests cigarette smoking at a younger age (<26.4 years) is associated with a 50% increased risk that was alleviated in individuals who were older [8]. A Canadian study comparing gender and smoking history and found that 71.5% males diagnosed with multiple sclerosis had previously smoked compared to 63.6% of females [10]. Smoking has previously been defined in several pathologies including cancer, asthma, atherosclerosis and heart disease, but within multiple sclerosis, the mechanism is still not understood.

Genetic risk factors have come to the forefront of current research as some have been linked with modulation of the immune response. Initial studies linked loci of the Major Histocompatibility Complex (MHC) and Human Leukocyte Antigen (HLA) as contributing risk in the development and progression of multiple sclerosis [4, 11–14]. In particular, HLA-*DRB1 and DQB1* gene loci were thought to play a role in developing the inherent autoimmunity associated with the disease [11, 14–16].

### **1.2 Diagnosis of multiple sclerosis**

In 2001, the McDonald criteria were created to streamline the diagnosis of multiple sclerosis even with its heterogeneous clinical presentation. The initial criteria introduced the utility of magnetic resonance imaging (MRI) and integration of multiple clinical symptoms while removing "clinically definite" and "possible multiple sclerosis" as alternatives [17]. Since 2001, 3 additional revisions have been made to the initial McDonald criteria: 2005, 2010 and 2017 [18–21]. Diagnosis of multiple sclerosis is now approached based on dissemination of time (temporal) and space. Dissemination in space is defined by either clinical presentation or MRI. Clinically, an individual must have symptoms which are distinct to different anatomical locations of the central nervous system. Usually, individuals present with optic neuritis or ocular symptoms and later acquire gait disturbances or peripheral weakness [18, 22]. On MRI, dissemination in space requires T2 evident lesions located in at least two distinct zones such as periventricular, infratentorial, juxtacortical or within the spinal cord [18, 22]. Dissemination in time requires the presence of a gadolinium-enhancing lesion on MRI, indicating an acute or active lesion, along with a non-enhancing lesion [18, 22]. The presence of a new lesion alone can meet the criteria if it is performed on a follow up scan. Essentially, dissemination in time seeks to distinguish multiple sclerosis symptomatology both typical and atypical from other neurological disorders which may share certain characteristics. As of McDonald 2010, CSF analysis is not required in order to make a definitive diagnosis [19–22]. Analysis of CSF typically presents with mildly elevated white blood cell count, protein, and IgG oligoclonal bands which are not typically seen in serum analysis [22]. IgG oligoclonal bands can be found in 90% of multiple sclerosis patients, but it may have a greater role in distinguishing individuals with clinically isolated syndrome (CIS) [20]. Some studies demonstrated that CSF

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*Enkephalin Therapy Improves Relapsing-Remitting Multiple Sclerosis*

oligoclonal bands increase the specificity of MR imaging in adults with CIS and pediatrics with radiologically isolated syndrome (RIS) [23, 24]. Beyond the diagnosis of multiple sclerosis, CSF analysis may help distinguish other immune mediated

The disease course of multiple sclerosis is usually defined into four clinical subtypes: clinically isolated syndrome (CIS), relapsing-remitting multiple sclerosis, secondary progressive multiple sclerosis, and primary progressive multiple sclerosis. A majority of patients have a disease course defined by stages of relapses and remission which may later translate into the secondary progressive form [25]. Clinically, relapses are defined as distinct episodes of neurological dysfunction which can present as a wide array of symptoms including sensory defects of the limbs, visual loss, motor defects, gait disturbances, vertigo, heat sensitivity (Uhthoff phenomenon), Lhermitte sign and fatigue [22, 26]. However, multiple sclerosis can present atypically in younger individuals, making it difficult to diagnosis properly. The initial episodes are followed by periods of remission where the patient will fully or partially regain normal function and be deemed neurologically stable [27]. In the long term, as some individuals transition from the relapsingremitting form to secondary progressive, relapses no longer occur, yet patients will experience worsening neurological function [27]. After 10 years of disease, 50% of individuals with relapsing-remitting multiple sclerosis will convert to secondaryprogressive, whereas after 25 years of the disorder, more than 90% of the individu-

Prior to establishing criteria for dissemination in time and space, individuals may present with clinically isolated syndrome (CIS) or radiologically isolated syndrome (RIS). Clinically isolated syndrome is defined as a clinical episode resembling a multiple sclerosis attack, after which there is full or partial recovery of neurological function [14, 20, 27]. Studies have shown that individuals with CIS may have an increased rate of conversion to multiple sclerosis especially with the presence of CSF oligoclonal bands and gadolinium enhancing lesions on MRI [14, 18, 20]. Incidental findings of cerebral and spinal cord plaques without a clinical phenotype are defined as radiologically isolated syndrome (RIS). In a 5-year study of 451 patients with RIS, 34% of individuals developed a clinical event for which 9.6% were defined as primary progressive multiple sclerosis [28]. Interestingly, this study was able to strongly correlate the presence of cervical or thoracic spinal cord lesions with the first clinical event [28]. With this increase risk of progression to multiple sclerosis, the utility of disease-modifying therapies and longitudinal monitoring of CIS and RIS has become a priority for clinicians.

The direct cause of multiple sclerosis still eludes the scientific community; however, several hypotheses have emerged which have been utilized to develop disease-modifying therapies (DMTs) and alter the course of disease. Traditionally, multiple sclerosis has been considered a demyelinating disease of the white matter tracts leading to peripheral symptomatology with an underlying autoimmune cause. Recently, demyelination located in the cerebral cortex and deep gray matter has emerged as a marker of progressing neurological disability [13, 29, 30]. Damage seen to the CNS with infiltration of immune cells suggests the role of peripheral immune response leading to damage of the blood brain barrier prior to established demyelination. Peripheral inflammation in this case may be a result of a foreign

*DOI: http://dx.doi.org/10.5772/intechopen.91010*

neurological and non-neurological pathologies.

**1.3 Clinical presentation of multiple sclerosis**

als have secondary progressive multiple sclerosis [14].

**1.4 Inflammation in multiple sclerosis**

oligoclonal bands increase the specificity of MR imaging in adults with CIS and pediatrics with radiologically isolated syndrome (RIS) [23, 24]. Beyond the diagnosis of multiple sclerosis, CSF analysis may help distinguish other immune mediated neurological and non-neurological pathologies.
