Clinical Aspects of Multiple Sclerosis Essentials and Current Updates

Multiple Sclerosis (MS) is an inflammatory autoimmune disease affecting the brain and spinal cord. Despite significant advances in treatment modalities the prognosis of this patient population is still poor. New Updates on Clinical Aspects of Multiple Sclerosis reviews the clinical guidelines for diagnosis and treatment management for both pediatric and adult patients with Multiple sclerosis (MS). Multiple chapters present the various subtypes of MS in a case-based format, providing readers with the presentation of differential diagnosis. This book will also review the advancements in methods of assessing demyelinating plaques including, 7T MRI, DTI, PET, and MR spectroscopy. Multi-contributed, this book will become the essential guide for anyone in the field of MS

• Explores the practical applications of optical coherence tomography (OCT) and OCT angiography (OCTA) in assessing MS.
• Delves into utilizing advanced imaging modalities and corresponding radiological findings for the diagnosis and monitoring.
• Includes cutting-edge technologies: 7 Tesla (7T) magnetic resonance imaging (MRI), diffusion tensor imaging (DTI), positron emission tomography (PET), and magnetic resonance spectroscopy (MR spectroscopy).

• Language: English
• Publisher: Academic Press
• Release date: Jan 13, 2024
• ISBN: 9780323953429

Book preview

Chapter 1: Introduction to multiple sclerosis

Subtypes, pathogenesis, and diagnostic criteria

Shitiz Sriwastava ¹ , ² , ³ , Erum Khan ⁴ , Sarah Peterson ² , ⁵ , Samiksha Srivastava ⁶ , and Robert P. Lisak ⁷       ¹ Division of Multiple Sclerosis and Neuroimmunology, Department of Neurology, McGovern Medical School (UT Health), University of Texas Health Science Center at Houston, Houston, TX, United States      ² Department of Neurology, West Virginia University, Morgantown, WV, United States      ³ West Virginia Clinical Translational Science, Morgantown, WV, United States      ⁴ Department of Neurology, University of Alabama at Birmingham, Birmingham, AL, United States      ⁵ Department of Neurology, University of Cincinnati Medical Center, Cincinnati, OH, United States      ⁶ Department of Occupational Medicine, UTTyler Health Science Center, Tyler, TX, United States      ⁷ Department of Neurology, Wayne State University, Detroit, MI, United States

Abstract

Multiple sclerosis (MS) is an immune-mediated disease of the central nervous system characterized by demyelinating lesions in the brain and spinal cord including demyelination and cell loss in cortical gray and deep gray matter nuclei. It is one of the most common causes of central nervous system (CNS) inflammation and is seen more often among young women. The etiology of MS is unknown, and the pathogenesis is multifactorial, associated with both genetic and environmental factors. MS involves both loss of myelin and neuro-axonal damage caused by T-cell, B-cell, antibodies, and other immune factors mediated. These processes lead initially most often to a relapsing-remitting form of the disease. Relapsing forms, also called relapsing-remitting MS, are clinically considered a distinct stage of MS and present with neurological symptoms that may last a few days or weeks followed by remission. We know that even in this early stage, many patients have permanent damage in the CNS even if all symptoms and signs seem to resolve. In many patients, there are clinical residual findings, particularly with repeated attacks. Additionally, this relapsing pattern often is followed by a more severe irreversible stage of MS with neurological and cognitive deficits, with or without superimposed clinical or subclinical MRI-defined activity. A subset of patients may present with a progressive form of the disease from the beginning with no or subsequent rare relapses and/or occasional MRI activity and variable rates of progression. We also know patients have lesions demonstrable by MRI (radiologically isolated syndrome; RIS) before initial symptoms (called clinically isolated syndrome, CIS).

Although MS is a relatively common CNS disease, treatment modalities for MS are not always easily accessible and the available ones being expensive, MS often poses a significant financial burden on the patients and their families. Being a chronic disease, it also leads to problems with daily functioning and loss or lack of employment, overburdening the caregiver. These problems could be overcome with a better understanding of the disease, its risk factors, pathology, and diagnostic and therapeutic approaches. There are studies that have led to improvement in the management of MS, and there are ongoing studies that need to be applied clinically and therapeutically to see any additional significant advances in the future.

Keywords

Clinically isolated syndrome; DMT; McDonald 2017 criteria; Multiple sclerosis; Radiologically isolated syndrome

Abbreviations

ADEM    acute disseminated encephalomyelitis

APC    antigen processing cells

B-cell    B lymphocytes

BBB    blood–brain barrier

CADASIL    cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy

CD    clusters of differentiation

CIS    clinically isolated syndrome

CNPase    2,3-cyclic nucleotide 3-phosphodiesterase

CNS    central nervous system

DIS    dissemination in space

DIT    dissemination in time

DMT    disease-modifying therapy

EAE    experimental autoimmune encephalomyelitis

EBV    Epstein–Barr virus

ECTRIMS    European Committee for Treatment and Research in Multiple Sclerosis

FDA    Food and Drug Administration

FLAIR    fluid-attenuated inversion recovery

fMRI    functional magnetic resonance imaging

GFAP    glial acidic fibrillary protein

GM    gray matter

GWAS    genome-wide association studies

HLA-DRB1    human leukocyte antigen class II histocompatibility, D-related beta-chain

HLA    human leukocyte antigens

IL    interleukin

LFB    Luxol fast blue

LOMS    late-onset multiple sclerosis

MAG    myelin-associated glycoprotein

MAGNIMS    magnetic resonance imaging in multiple sclerosis

MBP    myelin basic protein

miRNA (miR)    microribonucleic acid

MOG    myelin oligodendrocyte glycoprotein

MOGAD    myelin oligodendrocyte glycoprotein antibody-associated disease

MRI    magnetic resonance imaging

MS    multiple sclerosis

NADPH    nicotinamide adenine dinucleotide phosphate

NF-L    neurofilament light

NMO    neuromyelitis optica

NMSS    National Multiple Sclerosis Society

Nox2    NADPH oxidase 2

OCT    optical coherence tomography

PBMC    peripheral blood mononuclear cells

PLP    proteolipid protein

PPMS    primary progressive multiple sclerosis

RIS    radiologically isolated syndrome

RRMS    relapsing-remitting multiple sclerosis

SDMT    symbol digit modalities test

SEL    social-emotional learning

SNPs    single nucleotide polymorphisms

SPMS    secondary progressive multiple sclerosis

T-cell    T lymphocytes

TEMV    Theiler's encephalomyelitis virus

Th    T-helper cells

US    United States

VEP    visual evoked potentials

VLOMS    very late-onset multiple sclerosis

Introduction

Multiple sclerosis: knowledge and inference

Multiple sclerosis (MS) is a chronic, inflammatory (relapsing-remitting or secondary and primary progressive subtypes) immune-mediated and likely autoimmune disorder with a wide spectrum of myelin as well as axonal and neuronal damage affecting the central nervous system. Bladder/bowel dysfunction, cognition, and gait are the most common domains affected by progressive decline leading to disability. Some of these may even constitute the initial presentation separated in time and space [1]. MS is estimated to affect 900,000 people in the United States, making it the leading cause of nontraumatic neurological disability in young adults (age 18–40 years). Females in particular are three times more likely to be affected than men. Overall, patients with MS can suffer from physical disability, cognitive impairment, decreased quality of life, and reduced life expectancy by 7–14 years [2,3].

MS has been extensively studied with advances in our understanding of this heterogenous disease documented in the literature over the past 15 years. Progress in treatment, insights into the initiating mechanisms of MS in the immune system, diagnosis, and classification have been notable. There is now a wide array of approved disease-modifying therapies (DMTs) approved by the US Food and Drug Administration (FDA) as well as similar agencies in other countries [4]. The cost of these MS DMT impacts the access to these therapies and is exacerbated by inequities in health care delivery [5]. The estimated healthcare cost of MS-related DMT in the United States ranges from US $57,202 to $92,719 per year [6,7].

Younger patients experience a higher frequency of the inflammatory phase of disease, as opposed to patients having onset above 50 years of age, who tend to have a more progressive course or those with secondary progression [8]. The differences in biological mechanisms (age, gender, ethnicity, socioeconomic status, serum levels of vitamin D, interactions between genetic and environmental factors, and infectious diseases particularly Epstein–Barr virus [EBV]) likely affect relapse frequency/location as well as irreversible disability, disease progression, and overall disease severity [9].

The disease trajectories have been documented and well studied with early severe disability seen in less than 20% of patients and milder late disability seen in a majority after 10–15 years [10]. Some negative prognostic factors that have been reported include male sex, older age at onset, symptom localization at first presentation, number and pattern of attacks, incomplete recovery from first relapse, and progressive symptoms from disease onset.

The definitions used to describe the clinical course of multiple sclerosis, first established in 1996, have since been updated in 2013 by the European Committee for Treatment and Research in MS and the US National Multiple Sclerosis Society. This has played a pivotal role in standardizing terminology and descriptions for clinical states of patients. It has allowed the facilitation of communication between clinicians and people with MS, support of studies describing the natural history of MS, reduced heterogeneity in populations recruited for clinical trials, and assisted application of results in clinical practice [10–18].

Clarification on aspects of the disease, made possible through such standardizations, has led to the discovery of specific disease courses and subtypes that do not fit in the already established niches. The new terms thus formed have the potential to enter the classification system, and their characteristics may contribute to the betterment of the criteria. This demonstrates the dynamic nature of MS in Neurological sciences, which we intend to explore and remark about.

Multiple sclerosis: epidemiology

Heterogeneity is also reflected in the prevalence and incidence of MS. MS has a global prevalence of over 2.5 million people and incidence rates have been reported to be as high as 10 new cases per 100,000 people [19,20].

In the last few decades, several studies exploring the state- and country-wide prevalence of MS have been published. Studies reported prevalence to be highest in Olmsted County [21–29], Minnesota (ASR:191.2 per 100,000) [24] and lowest in Lubbock, Texas (ASR:39.9 per 100,000) [27]. Studies reported estimated prevalence in Canada to be 240 per 100,000 ranging from 56.4 per 100,000 [30–40] in Newfoundland to 298 per 100,000 [41], in Saskatoon [38]. Six studies in countries of central and south Americas estimated prevalence to range from 17.2 per 100,000 [42–47] in Argentine Patagonia to 5.24 per 100,000 in Panama [45–50].

The British Isles and the Italian peninsula areas are currently the most studied in Europe. Estimation of prevalence ranged from 96 to 100 per 100,000 with the highest estimates originating from Scotland and Northern Ireland. However, national-level standardized estimates were few with large geographical disparities, thereby demonstrating nonuniform patterns of prevalence being statistically higher in northern regions [48]. In continents such as Africa and Australia, the prevalence was found to be lowest in Africa and highest in Australia, that is, 0.22 per 100,000 in South African blacks and 125 per 100,000 in Australian born.

Several reviews and studies of MS prevalence in Canada and Argentine Patagonia found no striking latitudinal or longitudinal gradient, though opposing this stands a meta-analysis study from 59 countries, which demonstrated a statistically significant latitudinal gradient [45–51].

These discrepancies can be acknowledged by considering the variations in methodologies used, quality of medical care, and differential population susceptibility to MS. Due to this, it is advisable to not rely on geography alone for predicting the prevalence or risk of MS. Furthermore, the overall increase in MS regardless of age has also been documented worldwide including in Canada, Norway, New Zealand, and the United States [30,33,37,39,49,52–54]. Increasing incidence rates have also been seen in Lithuania, Germany, the Netherlands, and Austria.

With regard to age, the peak prevalence of MS has demonstrated an upward trend, now at 55–59 years [52–55]. Improvement in diagnostic tools and diagnostic criteria, advancement in imaging modalities, and improvement in MS survival with treatment are the likely factors contributing to this [56]. An example of this is diagnostic exclusion criteria like symptom onset after the age of 50 years being modified to accommodate late onset MS (LOMS) and very late onset MS (VLOMS), as LOMS accounts for 3.4%–4.8% of all MS diagnosis [57–62].

In part, these various changes can be attributed to increased equity of access to MRI across the board based on sex, geographic region, and socioeconomic status [63–66]. However, these incidence levels are not consistently reported for countries or regions altogether, hence it is difficult to confirm and claim them [63–68]. These changes have also been attributed to epigenetic factors that alter with the migration of populations with different ancestries [69]. MS is unequally distributed between ethnic groups, so much so that heterogeneity of parental ethnicity is also documented as a significant risk factor for MS [70]. The high risk of MS in immigrants has, in the past, influenced the remodeling of the worldwide epidemiological picture and may continue to do so in the future.

Multiple sclerosis: pathogenesis

The primary etiology of multiple sclerosis unknown including its pathogenesis. One way to go about exploring plausible etiologic possibilities is to work backward from the known final common pathways of MS pathology. Two of the most widely accepted models of these pathways involve the use of the jargon nomenclature inside out and outside in [71].

The outside-in model (see Fig. 1.1) involves an unknown factor triggering the autoimmune response peripherally (outside the CNS), which in turn instigates our immune system, particularly T cells, and monocyte/macrophages to begin to invade the CNS and demyelinate nerve fibers within the CNS creating the hallmark histological findings of MS [71]. Although the triggering event is debatable, the general consensus is that antigen-presenting cells like dendritic cells, monocytes/macrophages, microglia, and B cells activate naïve T cells and promote differentiation of CD4+ Th17 and Th1 cells through a cascade of cytokines such as IL-1, IL-6, and IL-23; IL-12, IL-17, and IFN-g.

Figure 1.1  Outside-in model of MS pathophysiology. The outside-in model of MS pathogenesis begins with the activation of myelin-specific T cells in response to a myelin peptide mimic epitope expressed on a pathogenic virus or other microbe exposure [1,2]. Activated autoreactive T cells then migrate into the CNS, are reactivated by CNS-resident APCs [3], and release cytokines leading to direct and indirect damage to myelin [4]. Additional myelin epitopes released by the primary T-cell response induce epitope spreading [5] leading to additional myelin destruction [6]. From Titus HE, Chen Y, Podojil JR, Robinson AP, Balabanov R, Popko B, Miller SD. Preclinical and Clinical Implications of Inside-Out versus Outside-In Paradigms in Multiple Sclerosis Etiopathogenesis. Front Cell Neurosci 2020;27(14):599717. https://doi.org/10.3389/fncel.2020.599717. PMID: 33192332; PMCID: PMC7654287 with permission.

The inside-out model (see Fig. 1.2) indicates primary damage of oligodendrocytes/myelin as the inception of MS. This then proceeds to drive an autoimmune attack, furthering the inflammatory demyelination in MS. This hypothesis compels us to work backward once again to find the specific trigger of the oligodendrocyte/myelin damage. This includes exploring possible environmental insults targeting oligodendrocytes such as a toxin, relative hypoxia, metabolic abnormality, genetic abnormality effecting oligodendrocytes or infection, presumably viral [71]. Several hypotheses, like the diphtheria epsilon toxin model, cuprizone intoxication model, and Theiler's encephalomyelitis virus (TEMV), support the possibility of such triggers. It should be noted that infectious triggers might work through molecular mimicry. Additionally, metabolic and traumatic disorders that may accumulate abnormal products (i.e., lipids and proteins) increase cellular turnover and in the process may trigger demyelination leading to inflammation in the CNS. Genetic polymorphisms or phenotypic predisposition, as seen in adrenoleukodystrophy and traumatic brain injury models, are also possible triggers [72,73]. In the inside-out model, the immune response is then triggered in immunogenetically susceptible individuals, influenced by epigenetic and other environmental factors.

Figure 1.2  Inside-out model of MS pathophysiology. The inside-out model of MS pathogenesis begins with the release of myelin antigens from injured or destabilized myelin to the periphery [1] followed by the presentation of myelin epitopes to Ref. [2] and activation of autoreactive T cells [3]. Activated autoreactive T cells then migrate into the CNS, are reactivated by CNS-resident APCs [4], and release cytokines leading to direct and indirect damage to myelin [5]. Additional myelin epitopes released by the primary T-cell response induce epitope spreading [6], leading to additional myelin destruction [7]. From Titus HE, Chen Y, Podojil JR, Robinson AP, Balabanov R, Popko B, Miller SD. Preclinical and Clinical Implications of Inside-Out versus Outside-In Paradigms in Multiple Sclerosis Etiopathogenesis. Front Cell Neurosci. 2020;27(14):599717. https://doi.org/10.3389/fncel.2020.599717. PMID: 33192332; PMCID: PMC7654287; with permission.

Several ways to approach genetic involvement in MS have been documented, including focusing on genes already implicated in autoimmune or immune pathogenesis like HLA class I and II or genes implicated in family aggregation studies. The most significant signals reported in genome-wide association studies (GWASs) were mapped to the HLA-DRB1 class II gene [72].

Within families, siblings of patients with MS have a 2%–5% lifetime risk, while parents and children of MS patients have a 1% lifetime risk [73]. In one study, a mean difference of 8.87 years was found in age of onset between probands and affected siblings. In addition, the study found a higher concordance rate among sister pairs compared to brother pairs [74]. Other additional studies found a maternal parent of origin effect showing an increase in chances of MS transmission via unaffected mothers compared to unaffected fathers, as well as a 10 times higher risk for monozygotic twin pairs when compared to biological first-degree relatives [75,76]. However, as the majority of monozygotic twins have also been found to be discordant in all studies, and as the pattern of inheritance is non-Mandelian, it is important to consider the contribution of nongenetic risk factors and gene interactions between genes with minor single nucleotide polymorphisms (SNPs) [77]. See Chapter 3 for a more detailed discussion of genetics.

The pathological mechanisms that are effects of or associated with the predispositions mentioned earlier for underlying pathogenesis include lymphocytic inflammation, demyelination, variable axonal loss, and reactive gliosis (see Fig. 1.3) [78]. On the basis of histopathological reports, there are four types of lesions:

1. Blood–brain barrier (BBB) damage and profound inflammation characterizing active lesions

2. Slowly expanding chronic active lesions

3. Inactive lesions

4. Remyelinating plaques

Active lesions are most likely seen in relapsing-remitting MS in the acute phases of white matter lesions. Chronic active, slowly expanding lesions are observed with peripheral demyelination and axonal loss and are associated with a rim of activated microglia/macrophages. These tend to appear more frequently in progressive MS patients, and they can be used to identify patients with a rather aggressive disease course [79,80]. Inactive plaques are not very specific to any one subtype of MS.

The presence of remyelinating plaques depends upon several factors—they are seen more commonly in younger individuals and early in the disease course, as opposed to in older individuals or progressive MS phases.

Figure 1.3  The spectrum of brain lesions in a 34-year-old male patient with secondary progressive multiple sclerosis after 10 years of disease duration. (A) The global brain section shows extensive cortical demyelination (red), widespread white matter lesions (green), some of them with remyelination (yellow), and focal demyelinated lesions in the deep gray matter (blue). There is profound brain atrophy with dilatation of the lateral ventricles. (B) Within and around the lesions, there is extensive perivascular inflammation, mainly around large periventricular veins. (C) The lesions show a spectrum of activity including a few small active lesions (A) with dense macrophage infiltration and a slowly expanding lesion (SEL) with a rim of activated microglia and macrophages at the lesion edge and an inactive (IA) lesion center. (D) SELs show microglia activation in the peri-plaque white matter, a dense rim of activated microglia, macrophages at the expanding edge, and only a few macrophages in the IA lesion center. From Filippi M, Preziosa P, Langdon D, Lassmann H, Paul F, Rovira À, Schoonheim MM, Solari A, Stankoff B, Rocca MA. Identifying Progression in Multiple Sclerosis: New Perspectives. Ann Neurol. 2020;88(3):438–452. https://doi.org/10.1002/ana.25808. Epub 2020 Jul 6. PMID: 32506714; with permission.

Apart from the type of lesions, their location and progressive course also give insights into disease pathology. They may arise within deep gray matter (GM), the spinal cord, cerebral cortex, or cerebellar cortex—both in early disease as well as progressive MS in older patients that have suffered long disease duration. Demyelination, which extends inward from the brain pial surface and involves several gyri, characterizes the subpial lesions that are highly specific for MS and are relatively acellular other microglial activation (type 3 lesions). T and B cells surround and inhabit the leukocortical lesions abundantly and to a lesser degree intracortical lesions [81,82]. While in type 3 cortical lesions, there are some, not abundant infiltrating T and B cells, but in secondary progressive multiple sclerosis (SPMS) and in primary progressive multiple sclerosis (PPMS) and relapsing remitting multiple sclerosis (RRMS), the majority of the inflammation with B and T cells plasma cells and dendritic antigen-presenting cells, is in the overlying pia arachnoid. In SPMS, there are atypical germinal follicles. These inflammatory cells, rather than utilizing a focal entry method in the form of waves, compartmentalize within the meninges and large perivascular venular spaces during progressive stages [83]. Such compartmentalization is more likely present in slowly expanding white matter lesions (actually that is probably backward) while active cortical demyelination is associated with a greater degree of meningeal inflammation as well as inflammatory aggregates in the meninges.

Microglial activation, oxidative injury, and subsequent mitochondrial injury appear to play a prominent role in neurodegeneration. These processes can be partially understood by studying histopathology, but this has several limitations. One major limitation is the lack of longitudinal assessment from early relapsing to late progressive stages. This limitation is further increased when we consider the low number of autopsy cases and even fewer biopsies early in the course of the disease.

Biomarkers in MS also help in studying the disease course; the several protective and pathogenic signaling pathways they target can provide insights into disease mechanisms. These specific targets include several miRNAs such as protective miR-199a, pathogenic miR-320, miR-155, miR-142-3p, and miR-142, which are increased in MS lesions or peripheral blood mononuclear cells (PBMCs) [84–86]. Conversely, miR-219, miR-34a, miR-103, miR-182-5p, miR-124, and miR-15a/b are typically reduced in the PBMCs of MS patients. These miRNAs could affect cognitive status and oxidative dysfunction leading to depression and fatigue among MS patients. Another oxidative biomarker is nicotinamide adenine dinucleotide phosphate (NADPH) oxidase 2 (Nox2), an enzyme that catalyzes the reduction of oxygen to produce reactive oxygen species, which play a role in the pathogenesis of MS. In addition, reactive T cells reactive against the neuronal protein β-synuclein are likely involved in the disease process by invading and destroying GM and are present in high levels in the peripheral blood of MS patients [87]. However, a single agreed upon and widely available nonimaging biomarker for MS disease progression is still lacking. Serum levels of neurofilament light (NF-L) and perhaps of glial acidic fibrillary protein (GFAP) measured early in the disease has some prognostic use. When measured serially it seems to be useful to indicate active inflammatory disease with axonal damage in RRMS patients rather than a measure of slower degenerative