Abstract

This paper provides a review and summary of current knowledge and literature of the autoimmune disease multiple sclerosis (MS). This paper seeks to define MS and provide statistics about its prevalence, information about its suspected origins and causes, diagnostic information and common symptoms, classifications and subtypes of MS, and current treatments and future directions. MS is a chronic inflammatory illness that is not completely understood. Researchers have found both genetic and environmental causes that cause lesions within the central nervous system (CNS), leading to a variety of initial presentations. To further complicate diagnosis and treatment, there are 4 main subtypes of MS, not including clinically isolated syndromes that often serve as prodromal MS. Treatment options vary by subtype and severity of MS, but there is no cure currently.

Keywords:

multiple sclerosis

Multiple Sclerosis

Multiple sclerosis (MS) is the most prevalent chronic inflammatory disease of the central nervous system (CNS) and it is currently incurable (Reich, Lucchinetti, & Calabresia, 2018). An estimated 2-3 million people have multiple sclerosis worldwide (Reich, Lucchinetti, & Calabresia, 2018; Otaneda, Thompson, Fox, & Cohen, 2017; Thompson, Baranzini, Geurts, Hemmer, & Ciccarelli, 2018a). An estimated 400,000 people in the US have MS (Reich, Lucchinetti, & Calabresia, 2018). Peak onset of MS occurs at age 30 (Raffel, Wakerley, & Nicholas, 2016). MS is the most common cause of disability among young adults (Raffel, Wakerley, & Nicholas, 2016). Like most autoimmune diseases, MS is 2-3 times more common in women (Raffel, Wakerley, & Nicholas, 2016; (Reich, Lucchinetti, & Calabresia, 2018). MS is characterized by fully or partially reversible episodes of neurologic disability, usually lasting days or weeks (Reich, Lucchinetti, & Calabresia, 2018). While much of MS is misunderstood, in general, MS is an autoimmune disease that affects the integrity of myelin sheaths in the nervous system, a structure necessary for protecting axons. It is best recognized in white matter as areas of demyelination, inflammation, and glial reaction (Reich, Lucchinetti, & Calabresia, 2018). As the myelin sheath becomes disrupted, saltatory conduction and conduction velocity along nerves is reduced (Raffel, Wakerley, & Nicholas, 2016). Ultimately, the brain is unable to communicate with various parts of the nervous system, leading to diffuse effects over time. In some instances, cells can be repaired through remyelination, a process that is more likely in younger patients (Reich, Lucchinetti, & Calabresia, 2018).

Origin and Causes

The causes of MS are not completely understood, but researchers have hypotheses about the origins of the illness based on commonalities between patients. The most commonly cited causes are genetic and environmental (Raffel, Wakerley, & Nicholas, 2016; Michel, 2018; (Reich, Lucchinetti, & Calabresia, 2018). Environmental factors implicated in the development of MS are presence of Epstein-Barr virus infection, low levels of vitamin D, smoking cigarettes, obesity (Reich, Lucchinetti, & Calabresia, 2018; Thompson et al., 2018a), salt, and gut microbiota (Michel, 2018). First, there is strong evidence that the origins of MS are genetic in nature. The concordance rate between monozygotic twins is estimated to be between 25-76%, meaning that the origins of MS are not completely genetic in nature (Michel, 2018; (Reich, Lucchinetti, & Calabresia, 2018). The HLA region of chromosome 6 has been implicated in the development of most autoimmune diseases, including MS (Thompson et al., 2018a). The HLA locus accounts for 20-30% of the genetic susceptibility to MS (Thompson et al., 2018a). Genomewide association studies have identified 200 gene variants that raise the risk of developing MS, most notable the HLA DRB1*1501 haplotype – its presence increases the risk of developing MS by a factor of 3 (Reich, Lucchinetti, & Calabresia, 2018; Thompson et al., 2018a). Other genes discovered by genomewide association tests outside the HLA locus are IL2RA and IL7RA (Thompson et al., 2018a). Most alleles associated with the risk of developing MS are immune-pathway genes, providing further evidence that autoimmunity is culpable in the development of MS (Reich, Lucchinetti, & Calabresia, 2018). Another partially genetic risk factor may have to do with race. In general, risk for MS decreases as distance from the equator increases (Michel, 2018). MS is scarce in Chinese, Japanese, and American Indian populations (Michel, 2018). It has a high incidence in Palestinian and Sardinian populations (Michel, 2018). Within America, MS has a higher incidence among African Americans than Hispanic Americans and Asian Americans (Michel, 2018). This genetic risk factor appears to be partially activated by geography. People who move to another country after age 15 have the same risk factor as their country of origin, rather than their country of arrival. Likewise, those who move before the age of 15 have the same risk factor as their country of arrival (Thompson et al., 2018a). This suggests that something during the age of adolescence may activate likelihood of MS, even though most onset of MS is much later in life (Michel, 2018).

Another commonly theorized cause of MS is the Epstein-Barr virus. Over 99% of patients with MS have anti-EBV antibodies and signs of reactivation of the virus, indicating that this infection is a significant risk factor, if not a cause of the illness (Michel, 2018). Another hypothesized mechanism in the development of MS is vitamin D. Vitamin D is related to the modulation of the immune system and is often obtained through ultraviolet B radiation and vitamin D-rich fish. Coincidentally, prevalence of MS increases as distance from the equator increases and those who eat vitamin D-rich fish have a lower prevalence of MS (Michel, 2018).

Risk of MS is also correlated with cumulative exposure to tobacco products. Those who smoke are more likely to develop MS compared to those who have never smoked, and MS patients who continue to smoke develop secondary-progressive MS and become disabled more quickly (Michel, 2018). Incidence of obesity in childhood and adolescence is also associated with an increased risk of developing MS (Michel, 2018). Those who are obese also have lower levels of circulating vitamin D (Michel, 2018; Thompson et al., 2018a).

Mice models sometimes give researchers clues as to how diseases operate in humans. In mine, increased salt intake significantly increased the frequency of IL-17, a cytokine that is implicated in MS. Additionally, mice who had large salt intakes developed a more severe form of mouse MS called experimental autoimmune encephalomyelitis (EAE) (Michel, 2018). Lastly, it is possible that dietary factors such as vitamin D could modify gut microbiota and, subsequently, autoimmunity (Michel, 2018).

Although the pathophysiology of MS is not completely understood, there is good evidence to suggest that the adaptive immune system is implicated (Thompson et al., 2018a). T cells and B cells are probably recruited by antigens or autoantigens that are only expressed in the CNS, causing the T cells and B cells to inflame the CNS (Thompson et al., 2018a). Once activated, microglial cells possibly contribute to the pathology of the disease by secreting proinflammatory cytokines, chemokines, free radicals, and extra glutamate (Thompson et al., 2018a).

Symptoms and Diagnosis

The presenting symptoms of patients ultimately diagnosed with MS can vary widely. This is because the outward symptoms are related to where in the CNS the inflammation is occurring. Fatigue, generalized weakness, diffuse paresthesia, clumsiness, dizziness, and visual disturbance are common presenting complaints for patients with MS (Raffel, Wakerley, & Nicholas, 2016). About 50% present with weakness or numbness in one or more limbs, and another 25% present with optic neuritis (Raffel, Wakerley, & Nicholas, 2016; Brownlee, Hardy, Fazekas, & Miller, 2017; (Reich, Lucchinetti, & Calabresia, 2018). By examining the location of the lesion and inflammation, outward symptoms begin to make more sense. For example, brainstem dysfunction can result in vertigo, while inflammation of the cerebellum can appear as gait disturbance (Raffel, Wakerley, & Nicholas, 2016). Damage to the spinal cord can have diffuse symptoms, including bladder control problems, weakness of the legs, and sensory issues (Raffel, Wakerley, & Nicholas, 2016). As axonal loss increases and lesions cover more surface area, seizures can begin to occur (Raffel, Wakerley, & Nicholas, 2016). Within the body, the symptoms of MS are axonal or neuronal loss, demyelination, and astrocytic gliosis (Thompson et al., 2018a). The most important to outward symptoms is axonal or neuronal loss, also known as neurodegeneration, because it is most related to permanent clinical disability (Thompson et al., 2018a).

One meta-analysis also indicated that as MS patients become more impaired physically, they also had poor subjective evaluation as to how their disease was progressing (Mazanciex, Souchay, Casez, & Moulin, 2019). These authors hypothesize a quadratic relationship between impairment and subjective evaluations wherein MS patients who are not very impaired and those who are very impaired underestimate their level of impairment, and those who are moderately impaired overestimate their level of impairment.

The McDonald criteria are used for diagnosis of MS (Raffel, Wakerley, & Nicholas, 2016). When a patient presents with symptoms that are typical of MS, the first step is usually an MRI (Brownlee et al., 2017; Reich, Lucchinetti, & Calabresia, 2018). Abnormal MRIs are present in nearly all diagnosed cases of MS and about 80% of patients with a clinically isolated syndrome that later develops into MS (Brownlee et al., 2017). To be diagnosed, there must be evidence of nervous system damage that is disseminated in both time and space (Raffel, Wakerley, & Nicholas, 2016; (Brownlee et al., 2017). Dissemination in time refers to evidence that lesions have occurred on different dates, and dissemination in space refers to lesions on at least two different parts of the CNS (Raffel, Wakerley, & Nicholas, 2016). Addiitionally, the diagnosing physician must determine there is no better alternative explanation for the patient’s presentation – this includes ruling out alternative diagnoses (Brownlee et al., 2017). Clinical history, examination by a physician, and MRI are essential to diagnosis (Raffel, Wakerley, & Nicholas, 2016). MRIs are used to identify active lesions and loss of brain volume (Raffel, Wakerley, & Nicholas, 2016) or neurodegeneration of the spinal cord (Reich, Lucchinetti, & Calabresia, 2018). Some studies have shown loss of brain volume prior to visible outward symptoms (Reich, Lucchinetti, & Calabresia, 2018). MRI can also be used to investigate alternative diagnoses (Thompson et al., 2018a), such as a longitudinally extensive spinal cord lesion (Brownlee et al., 2017). CSF examination is used to identify the presence of oligoclonal immunoglobim G (igG) bands (Raffel, Wakerley, & Nicholas, 2016; (Brownlee et al., 2017) or a raised white cell count (Brownlee et al., 2017). Oligoclonal bands are a unique antibody that is produced within the CNS (Reich, Lucchinetti, & Calabresia, 2018). Blood tests are often used to rule out other diseases (Raffel, Wakerley, & Nicholas, 2016).

A recent panel applied 2017 revisions to the McDonald criteria (Thompson et al., 2018b). Previous studies have shown that a clinically isolated syndrome in an adult patient accompanied by oligoclonal bands is predictive of a second attack (Thompson et al., 2018b). The panel also recommended including symptomatic and asymptomatic MRI lesions to better determine if the lesions meet the criteria for dissemination of space and dissemination of time (Thompson et al., 2018b). This new criterion will make it easier to diagnose primary progressive MS. The panel also recommended that cortical lesions, in addition to juxacortical lesions, be able to fulfill the MRI criteria for dissemination in space (Thompson et al., 2018b). Although this new recommendation makes it theoretically easier for MS to be diagnosed, it doesn’t have a lot of practical utility currently. Standard MRIs do not currently have the ability to detect cortical lesions or properly identify the cause of those lesions as MS.

The rate of misdiagnosis of MS may be as high as 10% (Brownlee et al., 2017). The most common ailments mistaken for MS were small vessel cerebrovascular disease, migraine, fibromyalgia, and functional neurological disorders (Brownlee et al., 2017).

There is increased awareness in the presentation of childhood MS (Thompson et al., 2018a). Interestingly, almost 5% of paitents with MS developed their first symptoms in childhood (Brownlee et al., 2017). In children younger than 12, initial symptoms appear as encephalopathy, multifocal neurological deficits, and seizures (Brownlee et al., 2017). Children older than 12 tend to have presentations that look alike to a clinically isolated syndrome (Brownlee et al., 2017).

After MS has been diagnosed, older age, male sex, higher disability at diagnosis, and greater brain atrophy are predictive of disability accumulation (Thompson et al., 2018a).

Types of MS

There are three recognized forms of MS, although the differences in underlying pathophysiology have yet to be uncovered: relapsing-remitting, primary progressive, and secondary progressive (Thompson et al., 2018a). Early MS is usually characterized by acute episodes of neurological deficits known as relapses; their severity depends on the location of the lesions and the extent of the inflammation (Thompson et al., 2018a).

Most patients who are ultimately diagnosed with MS begin with a single episode known as a “clinically isolated syndrome” (Thompson et al., 2018a). Most patients who have a clinically isolated syndrome have an abnormal brain scan, and those with both an abnormal brain scan and a clinically isolated syndrome are very likely to have a second episode or relapse and meet the criteria for MS (Thompson et al., 2018a). Those who do not have a second episode typically see their neurological issue resolve with time (Thompson et al., 2018a). For those who have a clinically isolated syndrome, female sex, younger age, and non-optic neuritis complaints are low-impact prognostic factors, meaning they are less likely to develop full MS (Thompson et al., 2018a). The presence of oligoclonal bands is a medium prognostic factor, and the presence of ten or more brain lesions is a high-impact prognostic factor, virtually guaranteeing diagnosis of MS (Thompson et al., 2018a). Patients who have two or more relapses have relapsing-remitting MS (Thompson et al., 2018a).

About 90% of patients have relapsing-remitting type MS from the onset, most of whom the disease develops into secondary progression (Raffel, Wakerley, & Nicholas, 2016). For about 10-15% of patients, they are diagnosed with primary progressive MS from the outset (Raffel, Wakerley, & Nicholas, 2016; Reich, Lucchinetti, & Calabresi, 2018; Thompson et al., 2018a).

Some features are characteristic of one type of MS rather than another. For example, RRMS is associated with active demyelinating plaques that cause inflammation and injury to the blood-brain barrier. These plaques are much rarer in patients with progressive-type multiple sclerosis (Mahad, Trapp, & Lassmann, 2015). For those who have lived with progressive-type multiple sclerosis for at least 15 years, increasing disability from multiple interacting symptoms is common. Most disability is related to compounding difficulties from gait impairment, vision impairment, and decreased cognition (Otaneda, Thompson, Fox, & Cohen, 2017).

Women have a higher relapse rate than men during the course of the disease (Thompson et al., 2018a).

Treatment Options

In general, there are two types of treatment: treatments that treat the symptoms of MS, or treatments that try to modify the course of the disease by preventing relapses (Raffel, Wakerley, & Nicholas, 2016). One class of drugs, corticosteroids, help patients recover from relapses more quickly but do not actually affect the progression of the disease (Raffel, Wakerley, & Nicholas, 2016). Over a dozen drugs have regulatory approval for RRMS (Otaneda, Thompson, Fox, & Cohen, 2017; Reich, Lucchinetti, & Calabresi, 2018). Drugs that target progressive multiple sclerosis, either by preventing disease progression or even reversing it, have been slow to come (Otaneda, Thompson, Fox, & Cohen, 2017). There is currently no disease-modifying treatment for primary progressive MS (Raffel, Wakerley, & Nicholas, 2016).

There are two main obstacles to the treatment of progressive-type multiple sclerosis: first, the pathophysiology of progressive-type multiple sclerosis is not as well understood as the relapse-remitting type, and second, there is a lack of phase 2 trial studies that predicts success of repair-promoting strategies in phase 3 studies (Otaneda, Thompson, Fox, & Cohen, 2017). Three neuroprotective agents are currently being evaluated: amiloride, riluzole, and fluoxetine (Otaneda, Thompson, Fox, & Cohen, 2017).

There are several drugs that are currently marketed for the treatment of MS. Some are injectable, like interferon beta, glatiramer A, and natalizumab, while others are oral, such as fingolimod, teriflunomide, and dimethyl fumarate (Yu, Liu, & Hu, 2019). All of the above medications are intended to correct abnormal autoimmune responses and inhibit inflammation (Yu, Liu, & Hu, 2019).

Some medications limit the access of T-cells to the CNS, which reduces new MS lesions (Reich, Lucchinetti, & Calabresia, 2018). Current medications include 5 types of interferon beta, 2 types of glatiramer acetate, natalizumab, alemtuzumab, daclizumab, orcrelizumab, mitoxantrone, fingolimod, dimethyl fumarate, and teriflunomide (Reich, Lucchinetti, & Calabresia, 2018). Additionally, dalfampridine is used for symptom management to improve walking speed (Reich, Lucchinetti, & Calabresia, 2018). One alternative treatment is that of autologous haemopoietic stem-cell transplantation (Reich, Lucchinetti, & Calabresia, 2018; Thompson et al., 2018a).

Only one disease-modifying medication, ocrelizumab, has been shown to slow disease progression in primary progressive-type MS (Thompson et al., 2018a). Other treatments include rituximab and cladribine (Thompson et al., 2018a).

Discussion

In summary, multiple sclerosis (MS) is a chronic inflammatory disease that is one of the leading causes of disability among young adults. Theorized causes of MS are genetic, including over 200 genes that increase risk, and environmental, including factors such as geographic latitude, vitamin D deficiency, obesity, tobacco use, salt, gut microbiota, and previous infection with the Epstein-Barr virus. Although its causes are not completely understood, MS is identified as an autoimmune disease in which the myelination of neurons is degraded, leading to a loss of nerve conduction over time. Depending on the location and the severity of the demyelination, or lesions, patients with MS can present with diverse symptoms, such as vision loss, gait and motor disturbance, numbness and tingly limbs, general weakness and fatigue, and loss of bladder control, among others. There are a few different forms of MS: clinically isolated syndromes, primary progressive MS, relapsing-remitting MS, secondary progressive MS, and progressive-relapsing MS. Lastly, there are some treatment options for MS, like those that alleviate the symptoms of MS, or those that change the course of the illness. There are several medications on the market to treat relapsing-remitting MS, but very few disease-modifying treatments to help patients with primary progressive MS. Nevertheless, there is hope for the future that this disease, its causes, its forms, and its treatments will all be better understood.

References

• Brownlee, W. J., Hardy, T. A., Fazekas, F., & Miller, D. H. (2017). Diagnosis of multiple sclerosis: Progress and challenges.
  
  Lancet, 389,
  
  1336-1346.
• Mahad, D. H., Trapp, B. D., & Lassmann, D. (2015). Pathological mechanisms in progressive multiple sclerosis.
  
  Lancet Neural, 14,
  
  183-193.
• Mazancieux, A., Souchay, C., Casez, O., & Moulin, C. J. A. (2019). Metacognition and self-awareness in Multiple Sclerosis.
  
  Cortex, 111,
  
  238-255.
• Michel, L. (2018). Environmental factors in the development of multiple sclerosis.
  
  Revue neurologique, 174,
  
  372-377,
  
  https://doi.org/10.1016/j.neurol.2018.03.010
  
  .
• Ontaneda, D., Thompson, A. J., Fox, R. J., & Cohen J. A. (2017). Progressive multiple sclerosis: Prospects for disease therapy, repair, and restoration of function.
  
  Lancet, 389,
  
  1357-1366.
• Raffel, J., Wakerley, B., & Nicholas, R. (2016). Multiple sclerosis.
  
  Medicine, 44
  
  (9), 537-541.
• Reich, D. S., Lucchinetti, C. F., & Calabresia, P. A. (2018). Multiple sclerosis.
  
  The New England Journal of Medicine, 378,
  
  169-180, 10.1056/NEJMra1401483.
• Thompson, A. J., Baranzini, S. E., Geurts, J., Hemmer, B., & Ciccarelli, O. (2018). Multiple sclerosis.
  
  Lancet, 391,
  
  1622-1636,
  
  http://dx.doi.org/10.1016/S0140-6736(18)30481-1
  
  .
• Thompson, A. J., Banwell, B. L., Barkhof, F., Carroll, W. M., Coetzee, T., Comi, G., … Cohen, J. A. (2018). Diagnosis of multiple sclerosis: 2017 revisions of the McDonald criteria.
  
  Lancet Neural, 17,
  
  162-173.
• Yu, S., Liu, M., & Hu, K. (2019). Natural products: Potential therapeutic agents in multiple sclerosis.
  
  International Immunopharmacology, 67
  
  , 87-97.