CHAPTER 1: Multiple Sclerosis: Epidemiology, Genetics, Symptoms, and Unmet Needs

Multiple sclerosis (MS) is a chronic inflammatory demyelinating disease that affects the central nervous system (CNS)¹  and is thought to be autoimmune in nature. It is characterized by the appearance of areas of demyelination in the white and gray substances of the CNS,²  infiltration of inflammatory cells in the parenchyma, glial reaction, and axonal damage.^3,4  All these processes occur from the early stages of the disease with the consequent accumulation of disability.

Although the underlying cause of MS still remains unknown, there is increasing evidence that immune dysregulation may play a role in genetically susceptible individuals. Some risk factors related to immune dysregulation have been identified, such as infections (Epstein–Barr virus, varicella/zoster, and HHV-6), environmental factors (latitude, vitamin D), and epigenetic factors (post-genomic rearrangements or somatic mutations). The sum of one or more risk factors on a genetic susceptibility leads to the loss of homeostasis between the inflammatory response and self-tolerance, tilting the balance towards autoimmunity directed against the CNS.³ 

Between 1831 and 1842, Robert Carswell and Jean Cruveilhier presented their collections of autopsy material of MS patients in London and Paris, respectively. They described in vivo the brain lesions on plates for the first time. Cruveilhier was the first to relate these lesions to clinical findings and called it the medullar disease with paraplegia. Despite some preliminary clinical descriptions, made by Friedrich Theodor von Frerichs (1849), his pupil Valentiner (1856), Carl Rokitansky (1857) and Eduard Rindfleisch (1863), it was not until 1865 when Jean-Martin Charcot made the first detailed description of the disease.⁵  This description included plaque-like lesions disseminated in time and space with a predominant myelin involvement, mainly in the optic nerve, the periventricular region, and spinal cord, which were correlated with clinical manifestations alternating periods of exacerbation and remission. He explained the most characteristic clinical signs of the disease: oculomotor disorders, ataxia and dysarthria. In this way, MS was recognized for the first time as an entity distinct from other diseases.

The term “sclérose en plaques disseminées” was coined by Edmé Félix Alfred Vulpian in 1866.⁶  Later, his friend and collaborator Charcot reduced the term to “sclérose en plaques,” and the term “multiple sclerosis” was introduced in the medical literature by Edward Seguin in 1878,⁵  but it was not until McAlpine, Compston, and Lumsden's classic publication in 1955 that the term gained international usage.

In Diseases of the Nervous System, a book published in 1933, the author Russell Brain reported data on the incidence and course of MS, together with precise explanations on the underlying pathophysiology, some of which continue to be valid today. Since then, a series of clinical criteria have been used and updated periodically to make the diagnosis of the disease.⁷  Magnetic resonance imaging (MRI) techniques and cerebrospinal fluid (CSF) analysis have been incorporated into the diagnostic algorithms. This has allowed an improvement in the criteria sensitivity and specificity, resulting in the current McDonald criteria 2017.⁴ 

Age at onset of MS can vary from childhood to adult life, and the average is between 20 and 40 years. MS is the first cause of non-traumatic disability in young patients, which has a great impact on the quality of life, a high health cost, and important social repercussions.⁸  MS is estimated to affect some 700 000 people in Europe and 2.3 million across the world. Longitudinal studies have revealed an increase in MS prevalence in recent years, but this does not necessarily carry an increased risk of MS. The increase in prevalence is related to a higher life expectancy in MS patients (as in the general population) over the last decades as a result of the improvement in healthcare, better disability rehabilitation, and access to health resources. The continuous review of McDonald's criteria has allowed earlier diagnosis, which also increases the incidence of MS. An increase in Europe and North America of 0.064 per 100 000 each year has been reported.⁹  MS patients have a 7-year shorter life expectancy and two to three times higher mortality compared with the general population.¹⁰ 

MS is universally found to be more prevalent in women than men, and the MS prevalence ratio of women to men has increased markedly during the last 60 years.^9,11  According to a Canadian study published in 2006, the sex ratio increased from 2 : 1 in 1936–1940 to 3.2 : 1 in 1976–1980.¹²  Similar data supporting this increase have been published by other groups in Germany, France, and Norway.^9,11,13  An analysis carried out in Europe and the United States indicated that the sex ratio not only changes over time but has also been shown to be negatively correlated with latitude.⁹ 

There is unequivocal evidence to support genetic susceptibility as an important factor involved in the occurrence of MS. In the general population, the MS risk is about 0.1–0.25%¹³  and increases up 2–5% in individuals with an affected family member in proportion to the number of shared genes. The published study with the largest number of patients in this regard involved 15 000 Canadian patients with MS and their families.¹⁴  It has been demonstrated that first-degree relatives (parents, children, and siblings) of an affected individual have a risk of approximately 2–5%, which can increase up to 30% if both parents are affected or up to 27% in monozygotic twins. The concordance between dizygotic twins is 3.5%, and up to 14% of asymptomatic monozygotic twins have MRI lesions compatible with demyelination. Second-degree relatives (aunts and uncles) have a risk of about 1–2%, and third-degree relatives (cousins) have a risk of less than 1%. The risk of MS decreases with age, and after 43 years it does not exceed 0.5%. A variation in MS risk has also been observed according to geographic area, being 2.4% in high prevalence areas and 0.1% in low prevalence areas.¹⁴ 

It has been suggested that the origin of the disease is the result of genetic mutations in the Scandinavian population during the first millennium, which were spread through the offspring by the Vikings during invasions and migrations to the rest of the known world.¹⁵  This hypothesis can explain the highest prevalence rates for MS in the Scandinavian peninsula and the countries settled by their descendants, such as Canada, Australia, New Zealand, and the United States¹⁶  as well as the greater prevalence among the mestizo population compared with the native population in the Americas.

There is a clear relationship between latitude and prevalence of MS¹⁷  since a latitudinal gradient has been demonstrated, with the prevalence of MS increasing as one moves farther from the equator. The most extensive survey on MS worldwide was published as the Atlas of MS 2013 and was conducted by The MS International Federation.¹⁸  Data on prevalence were available from more than 50 countries through official and unofficial sources. According to this report, the prevalence of MS varies between the different regions from above 100–200 cases per 100 000 population in high latitudes to below 5 cases per 100 000 in the regions near the tropics (Figure 1.1). Subsequent publications have been reporting new data of prevalence in different countries. The highest prevalence of MS is found in the Canadian population, with 291 per 100 000 population, followed by San Marino (250), Sweden (189), Hungary (176), Cyprus (175), United Kingdom (164), Czech Republic (160), Norway (160), Denmark (154), and Germany (149). The lowest prevalence has been reported in sub-Saharan Africa (2.1), Eastern Asia (2.2), and the equator region (3).^18–24  The reason for this latitude gradient is not yet fully understood but is probably related to genetic factors, hygiene of populations, and environmental factors such as the contribution of vitamin D, which will be discussed in detail later. However, this gradient is changing as more studies of geographical areas where prevalence was considered low are been published. In Latin America, for example, an increase in prevalence has been observed due to factors related to improvement in diagnosis, accessibility to MRI and to different healthcare resources.¹⁹ 

As a result, great interest has been generated in searching MS-related genes to explain the latitude gradient. The strongest and most consistent genetic determinant identified in MS is the major histocompatibility complex (MHC), which is located on chromosome 6p-21-23 and includes the Human Leukocyte Antigen (HLA) genes. The MHC type I region includes the genes HLA-A, HLA-B, HLA-C, HLA-E, HLA-F, and HLA-G and the type II region includes the genes HLA-DM, HLA-DO, HLA- DP, HLA-DQ, and HLA-DR. These molecules participate in the antigenic presentation to CD4+ (MHC type II) and CD8+ (MHC type I) lymphocytes. The genetic variability of this region is the highest in humans, with a large number of polymorphisms that allow them to serve as antigens of differentiation between different individuals.

The first studies that demonstrated an increased frequency of some types of HLA (HLA-B7, HLA-A3, and HLA-A9) in multiple sclerosis were published in 1972.²⁵  Subsequent publications continued to document an increase in the expression of some alleles of the HLA-DRB1, HLA-DRA, HLA-DQA1, HLA-DQB1, HLA-DMB, and TCRB genes as well as an increased frequency of combinations of alleles (haplotypes) in patients with MS compared to healthy controls in different populations.^26–28  The alleles most frequently found in MS are HLA-DRB1*15:01, HLA-DRB1*13:03, HLA-DRB1*03:01, HLA-DRB1*08:01, HLA-DQA1*01:02, and HLA-DQB1*03:02,²⁹  and the haplotype most strongly related to MS is DRB*1501-DQA1*0102-DQB1*0602, defined serologically as DR15 and abbreviated as HLA-DR2 or HLA-DRB1. The presence of HLA-DR2 significantly increases the risk of MS, especially in populations where this haplotype is more frequent, as in Caucasians of northern European descent³⁰  and to a lesser extent in southern regions of Europe and in the Brazilian population from Rio de Janeiro to Sao Paolo.³¹  There has also been reported a greater concordance of these associations between monozygotic twins compared with dizygotic twins.³²  On the other hand, the allele HLA-DRB1*15:03 has been related to susceptibility to MS in the African-American population³³  and in the mulatto population of Brazil but not in the black population.³⁴  An association between the HLA-DRB1*17 allele and the susceptibility to MS in the Swedish and Canadian populations has also been found.^35,36 

The risk of MS among the Latin American community is generally low to medium, but the frequencies are increasing. The mestizos are the most representative ethnic population in Latin America and are the product of centuries of interracial mixing between Native Americans (or Amerindians), European whites, and African blacks. Epidemiological studies show an extremely low prevalence of MS among non-mixed Amerindians.³³  This has been attributed to Mongolian ancestral protective genetics and possibly to environmental factors. The mestizos and the biracial community of Latin America with African ancestry have more susceptibility to MS, apparently due to the historical introduction of the European HLA-DR2 haplotype. Latin populations with a predominant European background (Argentina or Puerto Rico) seem to have a higher frequency of this haplotype.¹⁹ 

The populations of Sardinia and Sicily have a prevalence of MS and other autoimmune diseases similar to those of the northern European countries despite their geographical location and the low frequency of the HLA-DR2 haplotype. In these populations, as well as in populations of the Canary Islands and Turkey, there is a stronger association with other haplotypes such as DR4 and DR3.^37,38  Figure 1.2 summarizes the relationship between HLA-DR1 allele frequency, MS prevalence, and latitude with data obtained from the Atlas of MS 2013 ¹⁸  and more recent publications in the different countries.^{20–24,31,39–67} 

In 2007, the first genome-wide association study (GWAS) using DNA microarray technology was completed. In that study, carried out by the international MS genetics consortium (IMSGC), the common single nucleotide polymorphisms (SPN) were identified and tested for disease association in 931 family trios (consisting of a person with MS and both parents) and 2431 healthy controls from the UK and USA. For replication purposes, another 609 trios (2322 case subjects) and 789 control subjects were genotyped from another source. The final analysis involved 12 360 subjects. Forty-nine single nucleotide polymorphisms (SNPs) were found associated with MS, most in the HLA genes. However, new genes outside the MHC related to MS were also described, such as IL2RA (CD25 chr 10p15), IL7R (CD127 chr 5p13), EVI5 (ectopic viral integration site 5 chr 1p22), and KIAA0350 (CLEC16A chr 16p13).⁶⁸  Alleles of IL2RA and IL7RA genes have been associated with regulatory T cells, which are dysfunctional in MS. IL-2 is a cytokine related to the development of several autoimmune diseases, since it participates as an inductor of the differentiation⁶⁹  and proliferation⁷⁰  of autoreactive T cells. The IL-2-related proliferation process of T lymphocytes is carried out through the interaction of the cytokine with the α subunit of the interleukin-2 receptor (IL-2RA or CD25) on the surface of monocytes and lymphocytes. CD25 has also been described as a surface marker of regulatory T lymphocytes.⁷¹  CD127 interacts with the cytokine IL-7, an essential process for the proliferation of B and T cells.

Subsequently, several GWAS were published in different countries and populations (The Netherlands, Switzerland, Australia, Germany, Spain, and Sardinia), confirming the previous findings and describing new associations between SNPs of genes outside the MHC and MS, such as TNFRSF1A (chr 12p13), IRF8 (chr 16q24), CD6 (chr 11q12 ), GPC5 (chr 13q31), and IL2A (chr 4 26q27).^72–79  The TNFRSF1A gene codes for the tumor necrosis factor receptor alpha (TNF-α), which exerts a regulatory effect on inflammation, having anti-apoptotic properties, by stimulating NFKB. The IRF8 and CD6 molecules are involved in the myeloid and lymphoid differentiation, respectively, and the GPC5 in a heparan sulfate proteoglycan. Two meta-analyses of all GWAS were published in 2011 and 2012, assembling data of 5545 and 2619 patients, respectively. These analyses confirmed the previous associations and added new genes (EOMES, MLADA, THADA).^80,81 

A new generation of GWAS was implemented in 2011 with the possibility of analyzing 10–15 times more patients and allowing the discovery of a greater number of genes.^81–84  In 2011 and 2013, the IMSGC published two studies carried out with 9972 and 14 498 patients, respectively, in the US, Europe, and Australia. From these two studies the list of genes related to MS was expanded by more than 100.^82,85  The last GWAS meta-analysis was published in 2017 with data from 47 341 MS patients and 68 248 healthy controls and from which MS association data were obtained for 200 SNPs outside the MHC, 1 variant on the X chromosome, and 32 associations with variants of the MHC.⁸⁶  Figure 1.3 shows a summary of the main genes discovered in order of appearance.

On the island of Malta, the prevalence of MS is remarkably low compared with that of neighboring Sicily. Initially, it was thought that a low frequency of the HLA-DR2 haplotype was related to the low susceptibility of the Maltese population, but in a study published in 2008 it was demonstrated that the HLA-DRB1*15 allele is also significantly present in MS patients on Malta. The apparent inhibition of MS risk in the Maltese has been related to the presence of an apparently strong protective factor, the HLA-DR11 haplotype.⁶⁴  The HLA-B*44:02 is frequently expressed in people of Northern European ancestry, but carriers have a 46% reduction in the risk of developing MS. Other haplotypes described as protective factors are HLA-A*02:01, HLA-B*38:01, and HLA-B*55:01.²⁹  Ancestral communities such as the Sami in Laponia,⁸⁷  the Uzbeks in Central Asia (Uzbekistan and Afghanistan), the Kirguis in Kirguistan, the Siberians, and African black natives have a low prevalence of MS, and Bedouin ethnicity appears to be protective.^88,89  The frequency of the DR2 haplotype is significantly reduced among Sami people compared with non-Sami Norwegian controls, contributing to the low prevalence of MS in the Sami.⁸⁹ 

According to an Australian study, the CD58 gene (chr 1p13), whose product binds to CD2 to facilitate the entry of immune cells into the CNS, and the DBC1 gene have been found to be up-regulated during remission.⁹⁰  The CD58 gene has also been linked to the inhibition of endothelial adhesion and the decrease in the penetration of inflammatory cells in the CNS.

Data obtained from migratory dynamic studies^32,91  have confirmed that individuals under 15 years who emigrate from high-risk to low-risk zones are significantly less likely to develop MS than those who migrate at an older age, suggesting that the environmental component plays a very important role in the risk of MS. More than 40 environmental factors have been tested in relation to the risk of MS in numerous studies,⁹²  including infections, vaccines, toxic agents, weather agents and serum markers.

A systematic review of meta-analyses published in 2015 assessed the statistical weight of each of the environmental risk factors according to the number of patients and the methodology they used and found that the only three factors that meet the requirements to be unequivocally considered MS risk factors are: seropositivity in antibodies against EBV type IgG, infectious mononucleosis, and smoking. The other factors require further investigation to differentiate simple association with genuine pathogenesis.⁹² 

There is a large body of evidence implicating Epstein–Barr virus (EBV) infection in the pathogenesis of MS, although its exact role is incompletely understood. Approximately 95% of the world's population is thought to have been infected by EBV at some point in their lives. Why only some of those people develop MS is an unresolved question. On the other hand, a meta-analysis of multiple studies with different EBV test methodologies confirmed 100% of MS patients as seropositive when two different methods were used.⁹³  The hygiene hypothesis suggests that contact with the virus at a young age reduces the risk of MS. This contact is almost 90% at 4 years in tropical countries and almost null in individuals from developed countries before adolescence.⁹⁴  It is not clear whether the infection is directly related to the pathophysiology of the MS or is only a reflection of the gradient in hygiene and health inequalities among children. An individual who suffers a primary infection from EBV that results in infectious mononucleosis has a 2–3 times higher risk of MS than one who presents an asymptomatic contagion.⁹⁵ 

Likewise, there are statistically significant data from large studies that link serum antibody titers against the nuclear protein 1 of EBV (EBNA1) with the risk of MS.^96–98  Although the data about the EBV infection related to a higher risk of conversion from the first demyelinating episode (clinically isolated syndrome, CIS) to MS are contradictory,^99,100  in established MS, the serum level of IgG antibodies to EBNA1 correlates with the number of gadolinium-enhanced lesions in MRI and with the total number of T2 MRI brain lesions.^101,102  In addition to elevated levels of EBNA1 antibodies in the serum, patients with MS also have elevated levels of IgG antibodies to EBNA1 in the CSF, suggesting a high EBV-specific intrathecal immune response related to MS, in particular at the onset of the disease.^103,104 

EBV-specific CD4⁺ and CD8⁺ lymphocytes are enriched in the serum and CSF of patients with MS compared with healthy controls.^105–107  However, the presence of EBV in MS lesions in the CNS has been controversial^108–111  and this is probably due to the lack of unification in pathological techniques. Recently, a study was published with the largest number of CNS samples (101 patients and more than 1000 tissue samples), in which the presence of the virus was documented in 90% of B cells, microglia, and astrocytes of patients with MS and only in a small proportion of healthy controls.¹¹²  EBV infection also interacts with other risk factors in MS: women with DRB1*15 and higher anti-EBNA-1 levels had a nine-fold increased risk of MS compared to those with lower EBNA-1 levels and DRB1*15 presence.¹¹³ 

The human cytomegalovirus (CMV) belongs to the herpes virus family and has been widely studied as a possible etiological agent in MS. It is present in 60–100% of the world population as a latent infection. In post-mortem studies of demyelinating lesions of patients with MS, the presence of CMV-specific CD8⁺ cells has been documented.¹¹⁴  Additionally, anti-CMV IgG titers in CSF are higher in patients with MS than in healthy controls.¹¹⁵  However, unlike EBV, CMV appears to have a protective role in MS, and two meta-analyses concluded that the seropositivity for CMV confers a decrease in the risk of developing MS.^116,117  It has also been described that high titers of anti-CMV antibodies in MS patients correlate negatively with relapses and T2 lesion load in MRI¹¹⁸  and that the expansion of a CMV-induced NK cell type carries a lower risk of progression in MS.¹¹⁹ 

Parasitic infections seem to be another environmental factor, with a theoretically protective role against MS. Infection by some species of helminths and other parasites such as Trypanosoma cruzi and Paracoccidioides have been related to a decrease in the appearance of relapses and radiological activity, as well as to an increase in the differentiation of IL-10-producing regulatory lymphocytes (CD4⁺CD25⁺FoXP3⁺IL-10⁺).¹²⁰  However, there is not enough evidence to infer that parasitism, despite its attractive role in the hygiene hypothesis, can have an essential impact on the epidemiology of MS.¹⁹ 

Multiple studies have shown the relationship between smoking and the increased risk of MS.^121–125  The increased risk is estimated at 40%, with a dose-response effect from 20% for moderate smokers to 60% for heavy smokers.⁹⁴  Obesity at early ages of life and increased salt intake have also been risk factors related to MS in several studies.^126–128 

Several investigations have suggested that low exposure to ultraviolet light and the consequent decrease in vitamin D skin synthesis, measured as 25-hydroxy-vitamin D [25 (OH) D], is an important environmental risk factor implicated in the onset of demyelination at an early age,¹²⁹  and it has even been proposed that the month of birth, the maternal exposure to ultraviolet light and 25(OH)D levels during pregnancy have an effect on MS risk.¹³⁰ 

It has been reported that a decreased risk of MS in individuals with high levels of 25(OH)D compared to those who have low levels and different cut-off points have been proposed to establish an increased risk of MS.^92,131,132  The concentration of vitamin D fluctuates with the seasons and the implication of this variation in MS risk has not yet been established. According to these findings, sun exposure has also been positively correlated with a low risk of MS,^133,134  and the prevalence of MS is inversely proportional to the solar radiation of a determined population¹³⁵  being a risk factor 20 times more important than latitude according to a Scandinavian study.¹³⁶  However, it is a fact that solar radiation depends mainly on latitude, and this could partially explain the geographical gradient of MS incidence in relation to vitamin D. In MS patients, low levels of vitamin D have been correlated with an increased risk of relapses and long-term disability.¹³⁷ 

A prospective longitudinal study showed that women who take a dietary supplement of vitamin D with a content greater than 400 IU/d have a 40% lower risk of developing MS¹³⁸  as well as those individuals who regularly consumed cod liver oil, an important source of vitamin D, during childhood.^139,140  However, a recent meta-analysis of similar studies found no evidence of the therapeutic benefit of vitamin D as an add-on treatment in MS.¹⁴¹ 

MS is a disease in which there is an accumulation of demyelinating lesions and axonal loss in the CNS that generates progressive neurological disability. It is clinically heterogeneous, which leads to the definition of different forms of presentation.

The relapsing–remitting form of MS (RRMS) is the most frequent (90% of patients) and is characterized by episodes of a focal neurological deficit (relapses) of greater or lesser magnitude that alternate with periods of neurological remission or stability. Patients may accumulate secondary disability, depending on the number, severity, and level of recovery after each relapse.

Following this course, within 20–25 years, 60–70% of RRMS patients transform into secondary progressive multiple sclerosis (SPMS), which is characterized by progressive neurological decline (mediated by the cumulative damage of the relapses and the underlying degenerative component of the disease). Age markedly influences the phenotype before progression. RRMS patients who are younger at onset are more likely to display a predominantly inflammatory course, although the number of relapses does not affect the age at onset of progression.¹⁴²  In general, SPMS is diagnosed retrospectively, since there are no clinical and imaging criteria for establishing the transition from RRMS.

Clinically isolated syndrome (CIS) is a recently added category, although the term has been used for years. It refers to the first typical focal event of the disease, accompanied, in many cases, by the evidence of a possible demyelinating disease (positive MRI with typical abnormalities of the CSF) but has yet to fulfill criteria of dissemination in time. Clinical trials in MS have shown that CIS coupled with brain MRI lesions carry a high risk for a second relapse and therefore for MS conversion.¹  For that reason, the current clinical criteria allow some patients with CIS and radiological evidence of dissemination to be diagnosed with MS.¹⁴³ 

There is a clinical form in which the accumulation of neurological disability occurs from the onset of the disease without the presence of clinically evident relapses. It has been called primary progressive multiple sclerosis (PPMS) and represents between 10 and 15% of patients with MS. It frequently manifests as a slowly progressive asymmetric spastic paraparesis or symptoms of cerebellar dysfunction. According to the North American Research Committee on Multiple Sclerosis (NARCOMS) survey, the age at onset and diagnosis of PPMS is greater than that of relapsing forms: 36 and 44 years old, respectively.¹⁴⁴  Although their course is progressive, PPMS patients are not free from acute exacerbations or worsening consistent with relapses. The natural history of disability progression in PPMS seems identical to SPMS when compared from the beginning of the progressive phase. These data indicate that progressive forms, regardless of their start, have a similar progress.¹⁴⁵  Age and bilateral motor symptoms at onset are the most important predictors of disability accumulation in PPMS throughout its course.¹⁴⁶ 

MS phenotypes can be categorized as active or progressive. According to the description by Lublin et al. in 2014, clinical activity is defined as the occurrence of new relapses frame and imaging activity is defined as the occurrence of contrast-enhancing T1 hyperintense lesions or new or unequivocally enlarging T2 hyperintense lesions in a determined time.¹⁴⁷ 

In addition to the concept of activity, it is important to define progression since it would mark the beginning of the secondary progressive form in an RRMS patient or a suboptimal response to treatment in a patient with an established progressive form. Clinical progression is defined as a progressive increase of neurological dysfunction/disability, objectively documented, without unequivocal recovery.¹⁴⁷  The appearance of clinical progression does not necessarily imply a continuous course: stationary periods of greater or lesser duration throughout the disease are possible. The term “confirmed progression” describes an increase in neurological dysfunction confirmed throughout a defined time interval (3, 6, or 12 months). The most common definition of progression used in clinical trials is the worsening of more than one point on Kurtzke's scale of neurological disability (EDSS) confirmed for more than 6 months.

The diagnosis of MS must include the clinical form and the presence or absence of activity or progression. It is recommended that the assessments for disease activity and progression be conducted at least annually by clinical and MRI examinations.¹⁴⁷  This periodic evaluation is necessary, especially because of the availability of highly effective therapies that can be used when the response is suboptimal.

The increasing availability of MRI in medicine has led to an increase in incidental abnormal findings suggestive of multiple sclerosis. The detection of demyelinating lesions in individuals with no neurological symptoms and whose presence is not explained by other pathologies (vascular, toxic, neuro-infections, etc.) has been called isolated radiological syndrome (RIS). Approximately one-third of these patients will develop MS within a 5-year follow-up period.¹⁴⁸ 

The study with the largest number of individuals with RIS revealed that the main risk factors associated with conversion to MS are younger age (<37 years), male gender, high lesion load in MRI, family history of MS, positive CSF (intrathecal synthesis of IgG), and the presence of at least one asymptomatic spinal cord lesion.¹⁴⁹  Therefore, RIS is considered as a possible pre-symptomatic form of MS, and it might be expected that treatment with disease modifying therapy (DMT) at this stage might protect some individuals against the development of MS. However, there is no consensus on the possible therapy for RIS.¹⁴³ 

In most cases, relapses are confined to only one functional system; less frequently they can be multifocal. The symptoms of a relapse depend on the location of damage in the CNS and the structures most frequently affected are the optic nerves, spinal cord, brainstem, and cerebellum. According to data published in the Atlas of MS 2013, the most common symptoms at onset are sensitive (40%), motor (39%), visual (30%), and cerebellar (24%), and the least common are pain (15%) and cognitive complaints (10%).¹⁸  Multifocal syndromes due to simultaneous involvement of two or more regions of the CNS occur in up to 25% of patients. There is a tendency to recurrence in the same anatomical location.

Certain circumstances such as anesthesia, fever, surgical interventions, stress, infections or other intercurrent diseases can temporarily worsen a pre-existing neurological deficit, causing what is known as a pseudo-exacerbation or pseudo-relapse. The most frequent types of clinical relapses and their characteristics are as follows.

Optic neuritis (ON) is one of the most frequent symptoms of presentation in MS, in approximately 20% of cases, and affects about half of MS patients at some point in the course of their disease.¹⁵⁰  ON is characterized by a subacute decrease of visual acuity (VA), evolving over hours to days. This is typically unilateral, although less frequently both eyes can be affected simultaneously.

Patients may complain of blurred vision or loss as well as a blind or blurry spot within the visual field and a scotoma can be evident on formal visual field testing. Visual field defects include diffuse visual loss (48%), altitudinal defects (15%), central or cecocentral scotomata (8.3%), arcuate or double arcuate (4.5%) and hemianopic defects (4.2%).¹⁵¹  In 90% of cases ON is associated with eye pain, which can precede the loss of vision. On visual examination, low-contrast vision and color desaturation (dyschromatopsia) are affected. The dyschromatopsia is especially for red color and may not be proportional to the level of visual impairment.

In two-thirds of cases, the optic disc is normal on funduscopic examination and in the other third of patients papilledema can be found. If the ON is unilateral, a relative afferent pupillary defect may be evident in the affected eye (Marcus Gunn sign). Recovery is progressive, at least 90% of the visual acuity after 6 months, and depends largely on the severity of visual loss. The low-contrast test and some complementary tests, such as visual evoked potentials (VEP), continue to be pathological despite full recovery of visual acuity.

Acute myelitis is the presenting symptom in about 40% of MS patients and usually presents sub-acutely. The spinal lesions related to MS are usually small and peripheral, located especially in the lateral or posterior region of the spinal cord, are asymmetrical and have a longitudinal extension less than two vertebral segments. The myelitis that occurs in MS is typically partial with the involvement of one or more, but not all, functional spinal tracts such as motor, sensory, and bowel or bladder tracts.¹⁵² 

The symptoms evolve over hours to days and are usually bilateral. Patients usually complain of a sensory abnormality with a horizontal level or a band-like constriction sensation around the abdomen or chest. There is a predominance of the sensory symptoms over the motors and of the deep sensitivity over the superficial one. Cervical location of myelitis can cause a Lhermitte phenomenon, which consists of an uncomfortable electric shock-like sensation extending down the cervical spine and radiating to the limbs, triggered by cervical flexion. It is common to find patchy areas of sensory alteration in the trunk, as well as the abolition of cutaneous-abdominal reflexes in dorsal myelitis. In the acute phase, sphincteric dysfunction is usually milder than in established MS.

The clinical syndromes produced by brainstem involvement are the first manifestation of MS in 10–20% of cases and include diplopia, oculomotor palsy, nystagmus, vertigo, facial hypoesthesia, neuropathic facial pain, facial weakness, myokymia, dysarthria, dysphagia, tongue weakness, postural and gait instability. Less frequent brainstem symptoms include hearing loss and severe bulbar signs.

Diplopia and oculomotor palsy are caused by the involvement of the intra-axial portion of the nerves or the cranial nerve (CN) nuclei responsible for ocular motility in the brainstem (III, IV, and VI CN) and the VI CN is the most frequently affected.

Internuclear ophthalmoplegia (INO) is a common disorder in MS and consists of a limitation for the abduction of the eye ipsilateral to the lesion with nystagmus in the contralateral eye and convergent movements not altered. The lesion of INO is located in the medial longitudinal fascicle and may be unilateral or bilateral. It may be asymptomatic, but occasionally it may generate a sensation of movement (oscillopsia) or, more rarely, diplopia.

One-and-a-half syndrome is also a common abnormality in MS, characterized by conjugate horizontal gaze palsy in one direction plus an INO, with the abduction of the eye contralateral to the lesion as only conserved movement.

In PPMS, symptoms at onset are predominantly motor, typically a slowly progressive spastic paraparesis (80% of patients), cerebellar dysfunction (60%), sensory symptoms, or sphincteric involvement. The diagnosis can be difficult and may go unrecognized by patients or physicians for some time, with multiple visits to different specialists such as orthopedic surgeons, rheumatologists, etc. Additionally, the differential diagnosis of spastic paraparesis includes a wide range of hereditary, degenerative, inflammatory, and toxic-metabolic disorders. Cognitive progressive syndromes, long motor pathway affectation, or visual symptoms are infrequent as initial manifestation of PPMS. The delay in diagnosis of PPMS leads to an accumulation of disability, and early-detection strategies are needed.

The disability accumulation after relapses and the disease progression generate different symptoms and signs in MS patients that differ according to the affected domains. The systems mainly affected are visual, pyramidal, sensory, and cerebellar, as well as the brainstem and the control of sphincter functions. Some manifestations of the established phase of MS are not a direct consequence of the pathological process of MS but are due to secondary changes such as the pain in immobile joints due to muscle spasticity.

NARCOMS¹⁵³  is a self-reported registry for MS, with over 37 500 patients who complete semi-annual surveys collecting information on perceived impairment in 11 domains commonly affected in MS: hand function, vision, fatigue, cognition, bowel/bladder function, sensory, spasticity, pain, depression, tremor/coordination, and mobility. In 2013, data from the NARCOMS registry were presented as a function of disease duration (up 30 years).

According to these data, most patients exhibited some degree of impairment in nearly all domains after disease onset. Certain symptoms such as sensory and fatigue were particularly prevalent from early in the disease within the first year after diagnosis: 85% and 81%, respectively. More than 50% of patients complained of some degree of cognitive impairment at onset. Motor symptoms such as mobility, hand function, and spasticity were progressively more common with longer disease duration. Other symptoms such as vision, cognition, pain, and depression had no significative cumulative change. The worsening impairment was more evident throughout the first decade for 11 domains and few changes between 15 and 30 years of follow-up were observed. In Figure 1.4, a summary of the prevalence of MS symptoms according NARCOMS is presented.

A recent study with 611 RRMS and 244 progressive MS (PMS) patients evaluated the frequency of MS symptoms. Among participants with RRMS the most frequent symptoms were paresthesia (77.1%), fatigue (74.1%), weakness (54.8%), problems with balance (51.6%), and memory problems (48.4). In PMS group gait problems (90.6%), balance problems (84.0%), fatigue (83.2%), paresthesia (80.3%), and spasticity (79.5%) were the most common. Epilepsy and dysarthria were the least common symptoms in both groups. In this study, the impact of MS symptoms on the quality of life (QoL) was also quantified. In RRMS patients, the biggest QoL losses are caused by balance problems, spasticity, and depression, while in PMS patients, the QoL is most affected by spasticity, paralysis, weakness, and pain.¹⁵⁴ 

As previously described, in the neurological examination of MS patients, sequelae of past ON can be found, such as decreased uni- or bilateral visual acuity, alteration in contrast perception, or pallor in the temporal region of the papilla. It is also common to find alterations in the conjugation of the horizontal gaze and palsy of oculomotor muscles of which the patient is not conscious as a sequel to brainstem relapses, and less frequently an evident diplopia.

Weakness is a constant symptom in advanced MS and affects up to 89% of MS patients at some point in the disease.¹⁵⁵  Paraparesis and lower monoparesis are more frequent patterns of weakness than hemiparesis. The weakness severity can vary from a slight difficulty in walking to a complete inability to walk, making necessary the use of support devices or a wheelchair. In some patients, weakness is evident only during physical activity.

Weakness in MS is mainly due to lesions of the corticospinal tract and is usually accompanied by other signs of upper motor neuron syndrome, such as exaggerated myotatic reflexes (hyperreflexia), spasticity, or the presence of extensor plantar reflex (Babinski sign). It is common to observe repetitive and rhythmic muscle contractions called clonus. Occasionally, myotatic reflexes are found to be diminished or absent if lesions in the dorsal root entry area are present. Atrophy is infrequent, seen in very advanced stages and in relation to prolonged immobilization.

As the disease progresses, weakness is usually accompanied by spasticity, defined as muscle stiffness and spasms that occur in up to 90% of patients at some point.¹⁵⁶  Clinically, it is characterized by increased pyramidal tone, slowing down the muscle contraction-relaxation sequence and decreasing the range of voluntary movements. In the initial phases, spasticity may be an aid to gait by providing involuntary support of body weight in standing, but in the long term, it usually causes painful spasms and ultimately ankylosis in limb flexion, limitation of ambulation, and hygienic difficulties. Spasticity predominates in the lower extremities and is a determinant factor of disability.

Sensory symptoms are commonly experienced by MS patients (more than 90% of them) and reflect the involvement of the spinothalamic tracts, the dorsal-medial lemniscus column system or the dorsal root entrance region. They are often described as numbness, tingling, stinging, or tightness in the trunk (such as an abdominal band) or the extremities.

Neurological examination shows frequent alterations of deep sensation (vibration and positional hypoesthesia) with a predominant involvement of the lower limbs. The presence of a sensory level is more frequently unilateral than bilateral and is sometimes accompanied by allodynia. A posterior spinal cord injury in the region of entry of the posterior root at the cervical level and affecting the posterior cords can generate an infrequent but typical syndrome of MS, the useless hand syndrome, which consists of difficulty in the tactile recognition of objects, and sparing superficial sensation and motor function.

Pain is a frequent symptom in MS of multifactorial origin. In some cases, it is caused by an injury in the area of entry of the fifth cranial nerve (trigeminal neuralgia), the dorsal root entrance area (root pain), or directly by a spinal cord injury (painful dysesthesiae). Pain in MS usually has neuropathic features such as burning, electrical, or sharp sensations. The radicular pain may be unilateral or bilateral and there may be also a sensation of intense unilateral cervical itching. However, in most patients, pain is not a direct effect of the pathological process but is due to abnormal postures or to prolonged immobilization.

The cerebellum is a commonly affected structure in MS and cerebellar dysfunction contributes significantly to clinical disability. It usually manifests as: limb ataxia with dysmetria, decomposition of movement, final tremor, and hypotonia predominantly in the upper limbs; truncal ataxia with postural instability for sitting and standing; and gait ataxia with increased support base that is usually aggravated by proprioceptive sensory deficit. Severely affected patients may be unable to stand or move their arms in the presence of a violent intentional tremor. Dysarthria and scanty speech are also frequent symptoms, and patients with advanced disease can show an incomprehensible speech.¹⁵⁷ 

Involvement of the brainstem-cerebellum networks that are implicated in neural integration of gaze can lead to acquired pendular nystagmus, a disorder characterized by involuntary oscillating movements of the eyes and by the detection of pendular movements of the optic disc at fundoscopic examination. On the other hand, the disruption of the cerebellar-pontine networks leads to uncoordinated limb movements (limb ataxia) with or without tremor, nystagmus, postural (truncal ataxia) and gait (gait ataxia) instability, dysarthria, or scanty speech. Vertigo is usually accompanied by alteration in vestibular function or, less frequently, by hearing loss. Alterations of saccadic movements such as fixation instability (macro-saccadic oscillations), saccadic dysmetria, and abnormal pursuit movements also suggest cerebellar alteration.¹⁵⁷ 

The impairment of cognition correlates with the severity of hemispheric lesions and the degree of cortical and corpus callosum atrophy.¹⁵⁸  It is more common in advanced stages of the disease, although it can occur at any time. Studies show that 45–65% of patients with MS have cognitive dysfunction of a subcortical profile.^159,160  The most frequently altered neuropsychological functions are sustained attention, speed of information processing, abstract reasoning, executive functions, and long-term verbal and visual memory. The memory impairment is secondary to decreased attention and information retrieval rather than to problems in storage or encoding capacity. The involvement of cortical functions such as aphasia or negligence is exceptional. MS can lead to frank dementia, but this is rare and usually occurs in the context of extensive disease.¹⁶¹ 

Exceptionally, cognitive dysfunction is the first manifestation of MS, and these patients develop a progressive cognitive deterioration from the beginning of disease.

Fatigue is a very disabling symptom reported by 80–90% of patients with MS and is defined as the subjective sensation of lack of energy (physical or mental), disproportionate to physical activity or as resting asthenia that worsens with the passing of the hours of the day. Fatigue is associated with a negative impact in the quality of life by approximately 30% of patients. The pathophysiological mechanisms involved are unknown and there is a poor correlation between fatigue and the degree of disability.¹⁶² 

Patients with MS have an increased risk of psychiatric disorders. Depression occurs in up to 60% of patients and correlates with cognitive impairment.¹⁶³  It is considered that there is a relationship between genetic susceptibility to develop MS and hereditary susceptibility to suffer depression. The risk of suicide is also increased, especially when certain predisposing circumstances are associated such as social isolation, poor psychosocial support, alcoholism, or a family history of depression and suicide, among others.¹⁶³  Bipolar disorder and psychotic symptoms are less frequent and occur in the advanced stages of the disease.

Impairment of bowel and bladder control occurs in more than 75% of patients in advanced stages of the disease and correlates, in most cases, with the degree of motor involvement in the lower extremities. The most frequent alterations (>70%) are increased micturition frequency, urinary urgency, and incontinence secondary to hyperactivity of the detrusor muscle, which is present in about two-thirds of MS patients who undergo formal urodynamic testing.¹⁶⁴  The hyperactivity of the muscle is caused by a loss of inhibition of the detrusor reflex, which involves the contraction of the detrusor in coordination with the urethral sphincter relaxation.

It is also common to observe a delay or difficulty in emptying the bladder, urinary retention, increased post-voiding residue or overflow incontinence as a result of inappropriate detrusor muscle contraction or a detrusor-sphincter dyssynergia (20–25% of the patients). Detrusor overactivity and detrusor-sphincter dyssynergia often coexist in the same patient. The alteration of bowel function referred as constipation is also frequent and may be aggravated by the anticholinergic drugs used in the treatment of urinary disorders. Fecal incontinence and retention are infrequent.¹⁶⁴ 

Erectile dysfunction is a common symptom present in up to 75% of men¹⁶⁵  with MS and correlated with high degrees of paraparesis and sphincter disorders. In women, a decrease in libido and anorgasmia are also frequent. Depression, motor symptoms, severe spasticity, and perineal sensory disturbances can aggravate sexual problems.¹⁶² 

Gait disturbance is one of the main causes of disability and diminished quality of life in patients with MS. The cause is multifactorial, including paresis, spasticity, and proprioceptive alteration of the lower limbs, truncal ataxia and gait, and visual disorders. The most frequent patterns are spastic and cerebellar gait.

Dysphagia is present in up to 30% of patients with MS and is accompanied by other signs of brainstem dysfunction such as dysarthria or diplopia. In advanced stages, it can generate problems of nutrition or pulmonary infections requiring a multidisciplinary treatment.

Epilepsy affects up to 4% of MS patients and is thought to be due to cortical or juxta-cortical lesions. The most frequent seizures are focal, with or without secondary generalization.

Paroxysmal phenomena are episodes of sudden onset and very short duration consisting of repetitive neurological symptoms such as tonic or dystonic spasms, hemifacial spasm, facial myokymias, dysarthria or paroxysmal diplopia, Lhermitte phenomenon, sudden muscular atony, or kinesigenic choreoathetosis. The associated pathophysiological mechanisms are not known.

Uhthoff phenomenon is defined as the worsening of any focal symptom during processes in which body temperature rises, such as physical exercise or fever, secondary to a blockage of conduction in the optic nerve induced by heat when exceeding the safety threshold. This mechanism is not unique to the optic nerve, and patients with MS often complain of worsening of various neurological symptoms when there are increases in body temperature due to exercise, fever, or hot environments.

MS has been termed the disease of “the thousand faces” since it can affect any region of the CNS and produce a large number of symptoms and signs. However, there are symptoms that, due to their low frequency of presentation in MS, make it necessary to consider alternative diagnoses. Table 1.1 presents a summary of the typical and atypical symptoms of the disease.

Despite the available armamentarium of DMTs for MS, current agents are effective in reducing relapses and radiological activity but have a limited impact on the accumulation of disability and have not been shown to be effective in progressive forms of the disease. The existing agents are directed to reduce inflammation but lack efficacy for repairing the existing damage, restoring function, or inducing remyelination.

One difficulty in conducting studies in progressive forms of MS is the lack of a primary outcome of progression that can be reliably measured early in the disease. Monitoring disability progression over time is a need, which can require longer and more costly trials. Disability progression has been defined as an increase in the EDSS score of 0.5–1.0 point after 3 or 6 months. The EDSS often has problems of reliability and validity because interrater variation has been reported to be greater than a 1-point increase in about 40% of times. Therefore, the EDSS may be inaccurate at determining disease progression in RRMS patients after a short time period and new outcomes of disability progression are needed.

Loss of brain volume is greater in patients with MS than in healthy individuals and is independent of the clinical phenotypes of the disease.¹⁶⁶  Brain atrophy has generated great expectation as a measure of neurodegeneration, and its reduction is proposed as a therapeutic objective. Additionally, new techniques and MRI sequence advances such as magnetization transfer (MTR), diffusion tensor images (DTI), and magnetic resonance spectroscopy (MRS) may serve to quantify demyelination and remyelination processes. However, both brain atrophy measures and new MRI techniques are not available in clinical practice yet.

A substantial percentage of patients show a suboptimal and unpredictable response and continue to accumulate disability. There are no accurate markers of response to treatments that can be applied in daily clinical practice. Furthermore, the best measure of response to treatment in MS is still to be determined.

The absence of relapses is a good indicator of stability, but it does not consider the appearance of inflammation in areas of the CNS that do not manifest clinically. MRI has become very important in the follow-up of inflammatory activity, since new lesions are 5–10 times more frequent than relapses and, nowadays, radiological activity is considered a virtual surrogate marker of activity.¹⁶⁷  However, the best response data are obtained through a combination of clinical and radiological measures. Different response measurement schemes with combined variables have been proposed such as Río criteria,¹⁶⁸  modified Río criteria,¹⁶⁹  Canadian model,¹⁷⁰  German model,¹⁷¹  NEDA3,^172,173  and NEDA4 status,¹⁷⁴  but there is no general agreement on the best way to measure the response or what is the expected time to determine suboptimal response to each treatment.

A high efficacy is achieved with high levels of immunosuppression, increasing the risk of toxicity problems, of long-term adverse events as well as of potential effects on protective autoimmunity. An unmet need exists for new medications, with more specific treatment targets, that provide efficacy while avoiding risk for the adverse events associated with deep immunosuppression.

As previously described, a large number of symptoms may be experienced by MS patients and only a few medications are available to treat them. Effective symptom control without adverse effects is still a challenge.