Joseph Jankovic MD, in Bradley and Daroff's Neurology in Clinical Practice, 2022 MS is a heterogeneous disease and is characterized by neurological deficits disseminated in time and space. It is
a major cause of disability in the adult population in North America. Women are predominantly affected, in a ratio of 2 : 1. The disease is characterized by a varying array of neurological deficits. There are four main disease types, classified on the basis of the clinical disease course: relapsing-remitting (RR), secondary progressive (SP), primary progressive (PP), and progressive relapsing (PR). RR disease affects 65% of patients and is characterized by onset of neurological deficits that
remit over a period of weeks to months. After 15 years, most RR patients go on to have an SP form of disease in which neurological deficits become fixed and accumulate. PP patients accumulate permanent neurological deficits from theonset of disease, whereas patients with PR disease have a combination of progressive and stepwise deficits. Disease onset generally occurs in the early 20s for RR disease and in the mid-30s for PP disease, although
childhood-onset MS is becoming increasingly recognized. MS is a complex polygenic disease. Monozygotic twins carry a concordance rate of 27%, whereas dizygotic twins of the same sex display a 2.3% concordance rate. The incidence for first-degree relatives of MS patients is 2% to 5%, whereas the incidence for the general population is under 0.1%. Genetic linkage studies have been performed, and several regions of interest have been found, but the most
robust association remains with the HLA region. There is an increased incidence of MS in patients with the HLA-DR2 (DR1501) haplotype (Haines et al., 1998; Sawcer and Goodfellow, 1998; Stewart et al., 1981). More recently, a large genome-wide study identified single nucleotide polymorphism of IL-2R and IL-7R alleles as risk alleles for MS (Hafler et al., 2007). A report in 2013, now identifies 110 established MS risk
variants at 103 discrete loci outside of the MHC (International MS Genetics et al., 2013). MS remains most prevalent among people of Northern European descent. There is a lower prevalence in other populations, such as Arabic and Mediterranean people, but among those with disease, there is a higher incidence of other disease-associated haplotypes such as DR4 and DR6. Although genetic factors play an important role in pathogenesis,
migration and other studies have demonstrated that environment also plays a critical role. Epidemiological studies have shown that residence in certain geographical areas and migration to these areas before the age of 15 increases the incidence of MS. In addition, there is a diminishing north-to-south gradient in MS prevalence in the Northern Hemisphere, with an opposite trend in the Southern Hemisphere. This led to the hypothesis and demonstration of an inverse association between sunlight
exposure and MS (van der Mei et al., 2003). An extension of this hypothesis has led to exploration of the role of vitamin D in MS, since vitamin D is metabolized in the skin by ultra-violet (UV) irradiation. A prospective study in army recruits found that 25-hydroxyvitamin D levels in the highest quintile (above 99.1 nmol/L) were associated with a lower risk of MS (odds ratio [OR], 0.38) (Munger et al., 2006).
Treatment of animal models of MS with vitamin D ameliorates disease, and several studies have shown that the active form of vitamin D, calcitriol, can down-regulate proinflammatory dendritic cells (DC) and reduce TH1 lymphocyte responses while promoting anti-inflammatory TH2 lymphocyte responses (Adorini et al., 2004; Griffin et al., 2001; Penna and Adorini, 2000; Penna et al., 2007). Multiple SclerosisFrank J. Dowd, Neil S. Norton, in xPharm: The Comprehensive Pharmacology Reference, 2007 ClassificationMultiple Sclerosis (MS) has a highly variable clinical presentation, with some affected minimally while others may progress rapidly to total disability. Inflammation of the white matter of the central nervous system occurs during an MS attack. As the demyelination occurs, there is a disturbance in the ability of the nerves to conduct impulses. Plaques appear as hardened scars at sites where myelin is lost Miller (2000). MS is commonly classified into four major categories: Relapsing-Remitting Multiple Sclerosis (RRMS). RRMS, the most common form of this condition, occurs more often in women than men. With RRMS the attacks usually begin with prominent visual and sensory symptoms. There are unpredictable MS attacks in which new symptoms appear or the existing symptoms from prior attacks become more severe. The attacks can last from days to months. Following the attacks the disease may be inactive for months or years. While during remission the symptoms are present because of damage to the nerves, they are usually less severe Trojano et al (2003). Secondary Progressive Multiple Sclerosis (SPMS). SPMS begins as RRM S. At some point during the next 15 years nearly 50% of the RRMS patients worsen to a progressive form of the disorder. In this secondary progressive phase there is a slow and continuous decrease in overall function. Many SPMS patients may or may not have relapses and remissions during this stage Miller (2000). Primary Progressive Multiple Sclerosis (PPMS). PPMS is diagnosed in only 10% of all patients with M S. It is characterized by a lack of distinct MS attacks. Thus, while affected individuals never have the acute MS attacks there is a slow onset and increasingly worsening of symptoms. In PPMS, there is an accumulation of neurological deficits and disabilities that may level off or progress over months and years Ebers (2004), Thompson (2004). Benign Multiple Sclerosis (BMS). BMS, which is often observed with RRMS presents as a very mild form of the disorder. It is often referred to as benign or mild relapsing M S. Individuals with BMS have very few attacks. When attacks occur they are very mild, do not worsen over time, display an excellent recovery, and have no permanent disability. Individuals with BMS usually function normally since the condition has little or no impact on their ability to work. Read full chapter URL: https://www.sciencedirect.com/science/article/pii/B9780080552323606646 Multiple Sclerosis and Other Inflammatory Demyelinating Diseases of the Central Nervous SystemJoseph Jankovic MD, in Bradley and Daroff's Neurology in Clinical Practice, 2022 Clinical Phenotypes (RRMS, SPMS, PPMS)Approximately 80%–90% of MS cases begin as a relapsing disease characterized by acute neurological events referable to focal inflammatory lesions. MS relapses are defined as the acute or subacute onset of clinical dysfunction, usually reaching its peak in days to several weeks, followed by a remission during which the symptoms and signs usually resolve partially or completely. The minimum duration for a relapse has been arbitrarily established at 24 hours. Clinical symptoms of shorter duration are less likely to represent what is considered a true relapse (i.e., new lesion formation or extension of previous lesion size). Worsening of previous clinical dysfunction can occur concurrently with fever, infection, physical activity, or metabolic upset and last for hours to a day or more and is referred to aspseudo-relapse. Summaries of many studies provide an average figure of 0.4–0.6 relapses per year in patients in the relapsing-remitting phase of the illness, though this varies widely across individuals. In general, relapses are more frequent during the first years of the disease and tend to wane in later years, at which point it is more common for worsening to occur via a progressive course. A standardization of terms used to describe the pattern and course of the illness was introduced in 1996 (Lublin and Reingold, 1996) andrevised in 2013. The current classification identifies three main clinical course phenotypes: 1.RRMS: Clearly defined relapses with full recovery or with sequelae and residual deficit on recovery. The periods between disease relapses are characterized by a lack of disease progression. 2.SPMS: Initial relapsing-remitting disease course followed by progression with or without occasional relapses, minor remissions, and plateaus. 3.PPMS: Disease progression from onset, with occasional plateaus and temporary minor improvements allowed. The 2013 revisions to the clinical courses advise sub-categorizing the clinical course by whether there is evidence of activity and, in progressive forms of the illness, whether there is evidence of ongoing progression. Both characterizations should be qualified by a time frame. Activity is defined as either the occurrence of an acute relapse or new MRI changes defined as a new or, unequivocally, an enlarging T2 lesion or a gadolinium-enhancing lesion. Thus a patient with RRMS who has had a relapse or new MRI lesion over the past year would be characterized asRRMS with activity. Patients with PPMS or SPMS are further sub-categorized asprogressing ornot progressing over a defined period of time. Thus a progressive patient might be active or inactive and progressive or not progressing over the defined period of time (Lublin et al., 2014). PPMS remains a distinct clinical phenotype, although it is recognized that disease activity as seen on MRI can occur even in the absence of a history of relapses. Besides being able to more accurately describe a patient’s course, the new categorizations differ from previous in that progressive relapsing MS would be categorized as progressive with disease activity instead of being a separate disease classification (Fig. 80.13,A, B). Multiple SclerosisPatrick A. Lewis, Jennifer E. Spillane, in The Molecular and Clinical Pathology of Neurodegenerative Disease, 2019 7.2.2 Clinical Course and SubtypesMultiple sclerosis can be divided into a number of different subtypes that may overlap. Patients with multiple sclerosis will usually present with a single episode of neurological dysfunction that typically involves the spinal cord, brainstem, or optic nerves. The term “clinically isolated syndrome” is used to describe this first episode. Most patients with a clinically isolated syndrome, who have multiple magnetic resonance imaging lesions, will subsequently go on to develop a subsequent clinical episode, which heralds the onset of clinically definite multiple sclerosis. The most common form of multiple sclerosis is characterized by recurrent relapses—so-called relapsing remitting multiple sclerosis. A relapse is an episode of neurological dysfunction with symptoms typically evolving over days or weeks before plateauing and then remitting with a variable degree of recovery. Secondary progressive multiple sclerosis refers to a group of patients who initially had relapsing remitting multiple sclerosis but then develop progressive accumulation of disability [21]. There may be superimposed relapses during the progressive phase. The proportion of patients developing secondary progressive multiple sclerosis increases with disease duration. Primary progressive is a rarer form of multiple sclerosis, accounting for 10%–15% of cases and characterized by progressive accumulation of disability from the time of disease onset [22]. Primary progressive multiple sclerosis is more likely to affect men and tends to have a later age of onset than relapsing remitting multiple sclerosis [23]. Progressive relapsing multiple sclerosis is the term used to describe people who have progressive disability from the onset but also superimposed relapses [24]. Read full chapter URL: https://www.sciencedirect.com/science/article/pii/B9780128110690000070 Inflammatory and Metabolic DiseaseAndreas Adam CBE, MB, BS(Hons), PhD, PhD (hon caus), DSc (hon caus), FRCP, FRCR, FRCS, FFRRCSI(Hon), FRANZCR(Hon), FACR(Hon), FMedSci, in Grainger & Allison's Diagnostic Radiology, 2021 Multiple SclerosisMS is a progressive inflammatory, demyelinating and neurodegenerative autoimmune disease of the CNS characterised pathologically by perivascular infiltrates of mononuclear inflammatory cells, demyelination, axonal loss and gliosis, with the formation of focal and diffuse lesions. These lesions mainly affect the optic nerves, brainstem, spinal cord and cerebellar and periventricular white matter, although cortical and subcortical grey matter damage is also prominent. This disease leads to chronic progressive and irreversible disability in most patients. MS affects more than 2.3 million people worldwide; most often starts between 20 and 40 years of age; affects approximately two/three females per male; and is the leading cause of non-traumatic disability in young adults in Europe and North America. Half of all patients will need assistance with mobility within 20 years of diagnosis, and 50% of patients will eventually develop substantial cognitive deficits. As a consequence, MS is associated with a tremendous loss of health-related quality of life, work productivity and unemployment. The global median prevalence of MS is 33 per 100,000 people, with a great variance between different countries. North America and Europe have the highest prevalence (>100 per 100,000), while and Asia and sub-Saharan Africa have the lowest. Although the precise cause of MS remains unknown and its pathogenesis is only partly understood, complex genetic traits as well as environmental and infectious factors, such as Epstein–Barr virus infection, vitamin D levels, smoking and latitude determine the susceptibility to develop the disease. The clinical course of MS can follow different patterns over time, but is usually characterised by acute episodes of worsening (relapses, bouts), gradual progressive deterioration of neurological function or a combination of both these features (relapsing MS). Relapsing MS accounts for 85% of all MS. This clinical form typically presents as an acute clinically isolated syndrome (CIS) attributable to a monofocal or multifocal CNS demyelinating lesion. The presenting lesion usually affects the optic nerve (optic neuritis [ON]), spinal cord (acute transverse myelitis), brainstem (typically an internuclear ophthalmoparesis) and cerebellum (clumsiness and gait ataxia). Over the following years, patients usually experience episodes of acute worsening of neurological function, followed by variably complete recovery (RR course). Clinical and subclinical activity is frequent in this form. After several years of the RR course, more than 50% of untreated patients will develop progressive disability with or without occasional relapses, minor remissions and plateaus (SP course). As long as the aetiology of MS remains unknown, causal therapy and effective prevention are not possible. Different disease-modifying treatments (DMTs) can alter the course of the disease, particularly in the RR form, by reducing the number and severity of relapses and the accumulation of lesions as seen on MRI, and by influencing the impact of the disease on disability. Patients with the SP form of MS, continuing relapses of activity and pronounced progression of disability may also benefit from immunomodulatory or immunosuppressive therapy. Multiple SclerosisAmir-Hadi Maghzi, ... Alireza Minagar, in Neuroinflammation, 2011 Publisher SummaryMultiple sclerosis (MS) is an immune-mediated neurodegenerative disease of the central nervous system (CNS), which largely affects young adults with certain genetic backgrounds, often following exposure to several as yet unidentified environmental antigen(s). Based on the clinical disease pattern, four types of MS are recognized: relapsing–remitting MS (RRMS), secondary progressive MS (SPMS), primary progressive MS (PPMS), and progressive relapsing MS (PRMS). Interestingly, it appears that these four different forms of MS have dissimilar underlying neuropathologies, which, in turn, indicates that MS may represent a heterogeneous group of related diseases. The most common form of MS, RRMS, begins with a single unifocal or multifocal demyelinating attack (known as clinically isolated syndrome [CIS]), with a complete or partial resolution of the attack. This form of MS with its dominant neuroinflammatory sequelae is clinically recognized by relapses and development of new lesions on magnetic resonance imaging (MRI) studied by CNS neuroimaging. The clinical course of RRMS is characterized by clear disease relapses with development of new neurologic deficits or worsening of older symptoms that last more than 24 hours; each relapse is typically separated from the last attack by at least 1 month of stability. Patients with relapse of MS, either with treatment with corticosteroids or spontaneously, may return to their baseline neurologic status or may recover partially, with residual neurologic deficits. Read full chapter URL: https://www.sciencedirect.com/science/article/pii/B9780123849137000010 Multiple SclerosisAmanda L. Hernandez, ... David A. Hafler, in The Autoimmune Diseases (Fifth Edition), 2014 Multiple sclerosis (MS) is a multifocal inflammatory autoimmune disease that grossly affects the CNS white matter resulting in progressive neurodegeneration in genetically susceptible hosts. In the past half-century great strides have been made in understanding the genetic risk, immunomodulation, and immune dysregulation that is responsible for establishing MS, as well as in the development of various disease modifying therapies that have succeeded in controlling disease evolution and survival. While MS immunopathology has long been attributed to the Th2 subset of T cells, recent work has identified novel genetic susceptibility loci in addition to establishing a putative role for the regulatory T cell and Th27 T cell subsets, among a potential role for CD8+ T cell and B cell subsets. Nevertheless the identification of an antigen or infectious agent responsible for driving the ongoing inflammatory and humoral response in MS remains to be elucidated. This chapter examines the paradigms currently being utilized for deciphering MS, highlights current disease modifying therapies, and defines compelling future directions for MS-based research. Read full chapter URL: https://www.sciencedirect.com/science/article/pii/B9780123849298000526 Multiple SclerosisJulia Schaeffer, ... Stefano Pluchino, in Neurobiology of Brain Disorders, 2015 IntroductionGeneral DefinitionMultiple sclerosis (MS) is a chronic inflammatory demyelination disease of the human central nervous system (CNS) that affects young adults and over subsequent decades transforms into a progressive neurodegenerative disorder associated with major clinical disabilities.1 The main pathological lesions of MS are multiple sclerotic plaques displaying demyelination of white and gray matter in the brain and spinal cord.2 Within these focal lesions the myelin sheaths and the oligodendrocytes are destroyed after myelin protein components are recognized by cells of the immune system.3 This inflammatory reaction includes the activation of myelin-specific CD4+ autoreactive T cells and their differentiation into a proinflammatory T-helper-1 (Th2)-like phenotype, and also CD8+ T cells, B cells secreting myelin-directed antibodies and cytokines, and other factors of the immune system.4,5 During the initial state of the inflammatory response, activated lymphocytes recruited from the periphery to the CNS cross the blood–cerebrospinal fluid (CSF) barrier and the blood–brain barrier (BBB).6,7 The presence of activated immune cells, as well as immunoglobulins and cytokines in the CSF of MS patients compared with control donors, suggests the participation of the immune system in MS pathogenesis.6,7 The resulting pathological features in the CNS are the (chronic) demyelinated plaques, which consist of a well-demarcated hypocellular area characterized by the loss of myelin, relative preservation of axons, and formation of astrocytic scars. Lesions can be observed in the optic nerves, the periventricular white matter, brainstem, cerebellum, and spinal cord white matter, and can also involve gray matter.1,2 Within MS lesions, myelin, oligodendrocytes, and axons are destroyed, and axonal dysfunction is likely to result from nerve conduction disorders following demyelination. The concept of MS as an autoimmune disease is confirmed by experimental autoimmune encephalomyelitis (EAE), the most widely used animal model of MS. EAE is typically induced in animals either by injection of an emulsion containing a fragment of a myelin membrane protein or a homogenate of spinal cord tissue, or by injection of myelin antigen-specific T cells. Following disease induction, activated T cells cross the BBB and initiate a disease course similar to that observed in MS (inflammation, demyelination, and axonal degeneration).4 Genetic susceptibility to MS is associated with several genes of the major histocompatibility complex (MHC) regions, for example the HLA-DRB1 gene on chromosome 6p21; most of them are likely to have immune response functions.6 In MS pathogenesis, demyelination results in a progressive loss of structure and function of neurons, namely neurodegeneration, due to impaired propagation of action potentials across the demyelinated axons. No explanation has yet been given for the temporal relationship between inflammation, demyelination, and axonal degeneration, which could be a key point in understanding MS pathogenesis. It is still unclear whether inflammatory reactions cause neurodegeneration through demyelination, or whether MS is a primary neurodegenerative disease with secondary inflammation and demyelination. The accumulation of demyelinated lesions may lead to the neurological features of MS and explain the heterogeneity of the disease. During early stages of MS, spontaneous remyelination – the process by which oligodendrocyte progenitor cells (OPCs) re-ensheath demyelinated axons – helps to restore axonal conduction. However, over time, remyelination fails to compensate for the progression of inflammation-driven demyelination and consequent axonal damage/dysfunction leads to permanent, irreversible neurological decline.2,8 Different Forms of Multiple SclerosisThe current classification of MS clinical forms distinguishes at least four clinical patterns. •Relapsing remitting multiple sclerosis (RRMS) is the most common form (about 85% of cases) and is characterized by discrete attacks (relapses) over days or weeks, described as episodes of acute worsening of neurological functions. These are followed by complete or partial recovery periods (remissions) over months or years, supposedly without any disease progression. •Secondary progressive multiple sclerosis (SPMS) is characterized by gradual neurological decline with occasional minor recoveries. Most cases of RRMS (50% within 10 years of the initial diagnosis) evolve into SPMS (Table 30.1 and Fig. 30.1). TABLE 30.1. Clinical Forms of Multiple Sclerosis
Source: Lublin and Reingold. Neurology. 1996;46(4):907–911.9  FIGURE 30.1. Schematic description of the clinical evolution of relapsing–remitting into secondary progressive multiple sclerosis over the decades. The graph shows neurological disability, brain atrophy, frequency of inflammatory events [T1 lesions with gadolinium (GD) contrast enhancement showing blood–brain barrier breakdown] and global level of tissue damage (T2 lesions). •Primary progressive multiple sclerosis (PPMS) affects about 15% of patients with MS. This clinical pattern of disease is characterized by a steady functional worsening from the onset of symptoms, without identifiable relapses or remissions. •Progressive relapsing multiple sclerosis (PRMS) is also characterized by steadily worsening symptoms from the onset, although with clear acute relapses with or without recovery observed. Heterogeneity of clinical features within these patterns increases the difficulty in understanding the pathogenic mechanisms responsible for the onset of the disease.9 Therapeutic agents that have been proposed so far primarily target the immune system and help to slow the progressive deteriorating effects of the disease, but do not cure it or reverse the damage. EpidemiologyMS usually affects young adults, between 20 and 40 years old, with a later onset of disease for PPMS than for RRMS.10 MS displays different incidence depending on gender, age, geographic distribution, and ethnic origin. Women are more susceptible to MS, the ratio women to men approaching 2:1 to 3:1, which suggests the possible involvement of sex hormones in susceptibility to MS.11 However, the clinical pattern of PPMS does not show a female predominance.10 Pediatric MS accounts for 3–4% of cases and corresponds to symptom onset before age 18. The initial disease course of MS in children and adolescents is similar to that of adults affected by RRMS, with similar symptoms including cognitive deficits. Despite the variability in studies, it seems that pediatric MS patients reach the progressive stage of the disease later than patients with adult-onset MS (within 20 years from onset). Limited data are available regarding the immunopathogenesis of MS with childhood onset. However, pediatric MS patients display an increased activation of the innate immune system, at a higher level than observed in adult MS patients, whose pathophysiology is more dominated by the activation of the adaptive immune response. Magnetic resonance imaging (MRI) of pediatric MS cases shows fewer T2-weighted lesions and a higher frequency of large diffuse MS lesions than in adult MS cases. The first acute episode in MS at an early age has to be distinguished from a single neurological event, such as acute disseminated encephalomyelitis symptoms, which include those of optic neuritis.12 MS affects approximately 300,000 people in the USA and about 1 million worldwide,13 raising critical socioeconomic, health, and care issues. Population- and family-based studies have observed a north to south gradient in disease prevalence in the northern hemisphere and the opposite in the southern (Fig. 30.2). The prevalence of MS per 100,000 population is higher than 60 in Europe and North America,14 whereas the risk of developing MS in Asia and Africa is low. The geographic distribution of MS may be explained by environmental factors such as sunlight exposure or climate, as well as genetic susceptibility among populations. Migration studies have shown that the risk of developing MS is low if an individual migrated from a region with a high prevalence rate to one with a low prevalence rate before age 15, whereas it did not change after the age of 15, supporting the hypothesis that individuals born in low-risk areas benefit form long-lasting protection without transmission to their children. It has been suggested that ultraviolet light exposure may negatively influence disease development through its suppressive effects on the immune system, or through its involvement in the biosynthesis of vitamin D, one metabolite of which may have a role in inflammation.11 Other behavioral or lifestyle factors such as industrialization, urban living, pollution, smoking habits, or diets may explain the disease distribution and the increasing worldwide prevalence over recent decades.7 FIGURE 30.2. Prevalence of multiple sclerosis (MS) per 100,000 population in 2008. Source: Data from World Health Organization; 2008. Atlas Multiple Sclerosis Resources in the World 2008.14 Figure produced using Servier Medical Art.Read full chapter URL: https://www.sciencedirect.com/science/article/pii/B9780123982704000306 Multiple SclerosisMaria K. Houtchens, Samia J. Khoury, in Women and Health (Second Edition), 2013 Overview of Multiple SclerosisDefinitionMultiple sclerosis (MS) is a complex inflammatory and demyelinating disorder of the central nervous system (CNS) resulting in initially intermittent, and subsequently, often progressive neurological impairment. MS produces characteristic lesions which may affect the brain, the spinal cord, and the optic nerve. It is the leading cause of neurological disability among young adults. The destruction of myelin is thought to be orchestrated by autoreactive T-lymphocytes, but humoral and antibody-mediated immunity also play important roles in the pathogenesis. The loss of the myelin sheath results in decreased axonal transmission and eventually in axonal disruption.1,2 Clinical manifestations are varied, and can involve any functional neurological system depending on the affected area of the CNS. Diagnostic definitions of MS have undergone significant changes over the last decade, and now rely on both clinical and radiographic criteria of disease dissemination in time and space with improved diagnostic sensitivity and specificity. This has enabled early disease detection and treatment initiation. EpidemiologyAutoimmune diseases in general, and MS in particular, affect more females than males, with a cumulative female-to-male ratio of 1.77 to 1.00 in MS.3 Based on the US Census Bureau population statistics in 1996 of 264,775,000 people, the prevalence of MS in the US was 58.3/100,000 people (64.2% female) and the incidence was 3.2/100,000 people. Currently, 10,000 new cases of MS are diagnosed each year in the US.4 Approximately 2.5 million people worldwide, including 400,000 in the US, are affected by the disease.5 The highest incidence of MS is observed at the extremes of latitude in the Northern and Southern hemispheres, even in racially homogeneous populations. (For further discussion, please refer to sections on ‘Genetic and Environmental Determinants’.) The mortality statistics for MS are difficult to ascertain due to poor data reporting in death certificates and no centralized reporting structure. The last decade saw a relative paucity of newly published data on this important subject, both in the US and in the European Union. The US Department of Health and Human Services report on the 1992 mortality statistics documented a mortality rate of 0.7/100,000 people, with MS deaths of 1,187 women (89% white/10% black) and 713 men (90% white/9% black).6 The mean age at death of MS patients was 58.1 years compared to 70.5 years for all causes of death, with the life expectancy for MS patients being 82.5% of normal.6 Updated mortality data are particularly needed in light of the new advances in treatment. Some data suggests that mortality rates are improving. An analysis of MS mortality data from 1963–1990 in England and Wales revealed a steady and consistent improvement in mortality compared to the general population, with a decrease from 556 to 360 deaths among those aged ≤ 59 years.7 However, this was balanced by an increase from 275 to 440 deaths for MS patients aged 60 and older. There was also an increase in the MS mortality percentage from 33.1% in 1963 to 55.0% in 1990; however, the total number of deaths remained essentially stable (831 deaths in 1963 and 800 deaths in 1990) due to a decrease in the total number of MS patients reported for that time period. However, more recent studies demonstrated an increase in the incidence and prevalence of MS worldwide, related, in part, to improved early diagnostics. It is not yet known whether these results indicate a true increase in the frequency of MS worldwide.7,112 Current estimates suggest that over half of the deaths in MS patients are due to direct effects of the disease. Most studies report that the median age of MS onset is 23.5 to 39 years depending on the type of MS, with relapsing patients getting diagnosed at a younger age.8,9 Please refer to the section ‘Clinical Parameters’ for further discussion about MS diagnostic categories. The annual cost of MS, including personal services, alterations to home and vehicle, purchase of special equipment, and earnings loss was nearly $35,000 per patient, translating into a national annual cost of $9.7 billion in 1994 dollars.10 The average total cost for individuals with chronic progressive MS was $50,000/year, and for relapsing-remitting disease was $30,500/year. Mean lifetime cost per case was $2.5 million in 1994. Genetic DeterminantsEvidence supports a genetic predisposition to MS which can be best described as a ‘complex susceptibility’. Monozygotic twin studies estimate the genetic risk to be 25–30% with a rapid drop off in dizygotic twins to 3 to 5%, indicating significant influence of environmental and physiological factors.11 There are several candidate genes for MS, including human leukocyte antigen (HLA), T-cell receptor, myelin basic protein (MBP), immunoglobulin, complement, tumor necrosis factor (TNF), and mitochondrial genes. HLA-DRB1 is widely accepted as a susceptibility locus for MS in both genome-wide linkage studies in familial MS and in sporadic cases.12 The results of 3 entire genomic scans have been reported.13–15 In recent years, additional MS susceptibility loci outside of the MHC have been described. Specifically, the loci coding for interleukin-7 (IL-7) receptor and IL-2 receptor are strongly linked with MS susceptibility.16 Signaling through the IL-7 and IL-2 receptors is critical for the differentiation of CD4− CD8−thymocytes and has a role in survival of CD4+ CD8+cells after positive selection. This may be important not only in MS predisposition, but also in disease course and outcome. The Apolipoprotein E (APOE) gene has been associated with MS disease severity in some studies, with the e3 and e4 alleles conveying greater disease severity, and the e2 allele lesser disease severity, in women with familial MS.17 In terms of genetic heritage, MS is very rare in Japan, China, and African blacks.18 It has never been reported in ethnically pure Eskimos, Inuits, North and South Amerindians, Australian aborigines, New Zealand Maoris, Pacific Islanders, or Lapps. Worldwide, the most common thread for the development of MS is in women of Scandinavian and northern European ancestry. This is also discussed in some detail in the section on ‘Epidemiology’. Environmental DeterminantsThe world geographic distribution of multiple sclerosis may provide clues to environmental determinants (Table 52.1).18 The incidence, prevalence, and mortality rates of MS vary with latitude. MS is rare in tropical and subtropical areas. Within temperate zones, disease rates increase with increasing latitude in both the Northern and Southern Hemispheres. A North–South prevalence gradient has been detected in Europe, the US, Japan, Australia, and New Zealand. In both Europe and the US, the prevalence of MS reflects the degree of Scandinavian and northern European heritage in resident populations.19 The incidence rises as one moves away from the equator. This is especially true in the northern hemisphere. However, prevalence varies widely even in populations living at the same latitude. The strongest correlate of latitude is the duration and intensity of sunlight. Exposure to sunlight is, for many people, the major source of vitamin D. The hypothesis that vitamin D deficiency could increase MS risk may provide a reasonable explanation for the latitude gradient and change in risk among migrants. Several studies have attempted to validate this hypothesis using measures of sun exposure, vitamin D intake, or measures of vitamin D in the serum. A recent study from Norway reported that the time spent outdoors in summer, frequent fish consumption, and use of cod-liver oil were all associated with a reduced risk of MS.20 The only longitudinal study on dietary vitamins and MS risk in the US included 200,000 nurses and reported decreased MS risk with increasing vitamin D intake.21 A large study of US military recruits demonstrated 62% decreased risk of MS in caucasian individuals with the highest serum levels of the hydroxylated form of vitamin D (25(OH)D) above 99.2 nmol/l compared to those with lower levels (less than 63.2 nmol/l).22 Cigarette smoking appears to be associated with increased risk of MS, as well with an increase in neurological disability progression.23 Table 52.1. World Geographic Distribution of Multiple Sclerosis
Studies in the US confirmed that the MS risk decreases with migration southward, and that this change was most prominent when migration occurred before 10 years of age.24,25 Although an increased MS risk has been found with northward migration in the US, the relationship with age at migration is less clear.19 Migration between countries of different prevalences does not seem to result in a change in MS risk. Japanese and other Asians retain their relatively low susceptibility after immigrating to the US. However, US Asians seem to have higher rates of MS than do Asians in Japan.19 The issue of environmental determinants as a factor for the development of MS remains unresolved. Read full chapter URL: https://www.sciencedirect.com/science/article/pii/B9780123849786000522 Multiple SclerosisMICHAEL J. OLEK, SAMIA J. KHOURY, in Women and Health, 2000 I. Overview of Multiple SclerosisA. DefinitionMultiple sclerosis (MS) is a process of chronic demyelination in the central nervous system (CNS) resulting in progressive neurological impairment. The destruction of myelin is thought to be orchestrated by autoreactive T lymphocytes. The loss of the myelin sheath results in decreased axonal transmission and eventually in axonal loss [1,2]. Clinical manifestations surface if the destruction occurs in functionally relevant areas of the brain. While early definitions of MS relied solely on clinical criteria, technological advances have enabled neurologists to accurately diagnose the disease at an earlier juncture where new therapeutic agents may be more beneficial. B. EpidemiologyAutoimmune diseases in general and MS in particular affect more females than males. In a summary of 30 incidence/prevalence studies of MS there was a cumulative female-to-male ratio of 1.77 to 1.00 [3]. A total of 80 prevalence studies were conducted from 1965 to the present: 49 in Europe, 16 in the United States or Canada, and 15 in other countries. Based on the U.S. Census Bureau population statistic in 1996 of 264,775,000 people, the prevalence of MS in the United States was 58.3/100,000 people. The percentage of female patients was 64.2%. There were 28 incidence studies that met the strict criteria of Jacobson et al. [4], with 20 conducted in Europe, 5 in the United States or Canada, and 3 in other countries. Again, based on the 1996 population estimate, the incidence of MS in the United States in 1996 was 3.2/100,000 people. The mortality statistics for MS are difficult to ascertain due to poor data reporting and collecting. The U.S. Department of Health and Human Services report on the 1992 mortality statistics documented that 1900 U.S. citizens died of MS that year for a U.S. mortality rate of 0.7/100,000 people [5]. A breakdown of the numbers shows that 1187 women (89% white/10% black) and 713 men (90% white/9% black) died of MS in the U.S. in 1992. From these data, the mean age at death of MS patients was 58.1 years compared to 70.5 years for all causes of death. The life expectancy for MS patients was 82.5% of normal [5]. In another study, mortality from MS in England and Wales for the years 1963–1990 was reported [6]. Analysis revealed a steady and consistent improvement in mortality compared to the general population, with a decrease from 556 to 360 deaths up to age 59. This was balanced by an increase from 275 to 440 deaths for MS patients aged 60 and older. There was also an increase in the MS mortality percentage from 33.1% in 1963 to 55.0% in 1990; however, the total number of deaths remained essentially stable (831 deaths in 1963 and 800 deaths in 1990) due to a decrease in the total number of MS patients [6]. Most studies report that the median age at onset of MS is 23.5 years [7–9]. The peak age of onset for women is the early twenties, whereas for men it is the late twenties. The mean age of onset overall is 30 years. The relapsing–remitting group has a mean age of onset of 25–29 years, the relapsing–remitting progressive group has a mean age of onset of 25–29 years (with a mean age of conversion to the progressive type of 40–44 years), and the primary progressive group has a mean age of onset 35–39 years [10–12]. C. Genetic DeterminantsThere are several candidate genes for MS including human leukocyte antigen (HLA), T-cell receptor, myelin basic protein (MBP), immunoglobulin, complement, tumor necrosis factor (TNF), and mitochondrial genes. The results of three entire genomic scans have been reported [13–15]. The HLA region was strongly positive in two of these studies. Only the HLA complex has been widely accepted as a susceptibility complex with the studies showing association and linkage with HLA-DR15, DQ6 haplotype. This haplotype, however, is neither sufficient nor necessary for the development of MS [16]. In terms of genetic heritage, MS is very rare in Japan, China, and Africa blacks [17]. It has never been reported in ethnically pure Eskimos, Inuits, North and South Amerindians, Australian aborigines, New Zealand Maoris, Pacific Islanders, or Lapps. Worldwide, the most common thread for the development of MS is in women of Scandinavian and northern European ancestry. In one study, the highest risks for developing MS were found in daughters of either female or male patients with MS (Table 54.1) [18]. For a female patient, a daughter had an age-adjusted lifetime risk of 4.96% of developing MS. The combined cumulative incidence for first-, second-, and third-degree relatives of MS index cases in this cohort, as well as in another study [19], approached 20%. These risks must be understood in the context of the incidence of MS in the general population, which is estimated at 3.2/100,000 people. Table 54.1. Familial Risks for the Development of Multiple Sclerosis
Modified according to [18]. D. Environmental DeterminantsThe world geographic distribution of multiple sclerosis may provide clues to environmental determinants (Table 54.2) [17]. The incidence, prevalence, and mortality rates of MS vary with latitude. MS is rare in tropical and subtropical areas. Within temperate zones, disease rates increase with increasing latitude in both the Northern and Southern Hemispheres. A North–South prevalence gradient has been detected in Europe, the United States, Japan, Australia, and New Zealand. In both Europe and the United States, the prevalence of MS reflects the degree of Scandinavian and northern European heritage in resident populations [16]. The prevalence rises as one moves away from the equator. However, prevalence varies widely even in populations living at the same latitude. Table 54.2. World Geographic Distribution of Multiple Sclerosis
Modified according to [17]. Studies in the United States confirmed that the MS risk decreased with migration southward and that this change was most prominent when migration occurred before 10 years of age [20,21]. Although an increased MS risk has been found with northward migration in the United States, the relationship with age at migration is less clear [16]. Migration between countries of different prevalences does not seem to result in a change in MS risk. Japanese and other Asians retain their relatively low susceptibility after immigrating to the United States. However, U.S. Asians seem to have higher rates of MS than do Asians in Japan [16]. The issue of environmental determinants as a factor for the development of MS remains unresolved. Geographic clusters in MS have been identified and studied. The most common cluster studies are those attempting to interpret an apparent excess of cases within a small geographic area. This is referred to as post hoc cluster analysis [22]. Nine post hoc clusters studies spanning the years 1937 to 1990 and involving 155 patients were identified [23–38]. These studies do not provide enough evidence to establish any proposed agent as a specific risk factor for MS. There are also reports of clustering among groups of workers in the general population. Four MS cases among seven veterinarians working on swayback disease, a nervous system disease in sheep [39,40], and an excess number of MS cases among workers at a zinc plant in upstate New York, have been reported [41,42]. A second type of analysis is space-time cluster analysis, an epidemiologic model used for investigating an infectious etiology. There have been six published studies [43–48] on space-time analysis in MS and only two have found significant clustering. The study in Norway [48] showed clustering between 13 and 20 years of age with a peak at age 18. The study in the Orkney and Shetland Islands [46] showed clustering at 21–23 years of age. Read full chapter URL: https://www.sciencedirect.com/science/article/pii/B9780122881459500632 Does MS cause loss of reflexes?Symptoms may include burning, numbness or tingling of the hands and feet or the arms and legs. Reflexes are reduced or absent, and the muscles of the face may become weak. Other symptoms may include difficulty in walking and respiratory problems.
What parts of the brain are affected by multiple sclerosis?MS affects nerves (and the myelin that covers them) in the two types of tissue that make up the brain and spinal cord: Grey matter. This tissue makes up the outer layer of your brain. You may also hear it called the cerebral cortex.
What part of the body is most often affected by poliomyelitis quizlet?Polio is a viral disease which may affect the spinal cord causing muscle weakness and paralysis. The polio virus enters the body through the mouth, usually from hands contaminated with the stool of an infected person.
Is Multiple Sclerosis considered a neurological disorder?Multiple Sclerosis (MS) is the most common disabling neurological disease of young adults with symptom onset generally occurring between the ages of 20 to 40 years.
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Which of the following sensitivities are experienced in many individuals with multiple sclerosis
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