REVIEW ARTICLE


Epidemiology and
C O N T I N UU M A UD I O
I NT E R V I E W A V AI L A B L E
ONLINE
Pathophysiology of
Multiple Sclerosis
By Melanie Ward, MD; Myla D. Goldman, MD, MSc, FAAN

CITE AS:
CONTINUUM (MINNEAP MINN)
2022;28(4, MULTIPLE SCLEROSIS
ABSTRACT
AND RELATED DISORDERS):988–1005.
PURPOSE OF REVIEW: This article provides an overview of genetic,
Address correspondence to environmental, and lifestyle risk factors affecting the disease course of
Dr Melanie Ward, One Medical multiple sclerosis (MS) and reviews the pathophysiologic characteristics of
Center Dr, Ste 1310, Morgantown,
WV 26506, mward9@hsc.wvu.edu.
both relapsing and progressive MS.

RELATIONSHIP DISCLOSURE: RECENT FINDINGS: The prevalence of MS has increased in recent decades,
Dr Ward has received personal
compensation in the range of and costs of care for patients with MS have risen dramatically. Black,
$500 to $4999 for serving as a Asian, and Hispanic individuals may be at risk for more severe MS-related
consultant for Bristol-Myers disability. Multiple genetic MS risk factors have been identified. Factors
Squibb Company, Celgene
Corporation, EMD Serono, such as low vitamin D levels and a history of Epstein-Barr virus, smoking,
Genentech, Inc, and Novartis AG. and obesity, especially during childhood, also influence MS risk.
The institution of Dr Ward has
received research support from
Traditionally thought to be a T-cell–mediated disease, recent research has
Genentech, Inc. Dr Goldman has highlighted the additional roles of B cells and microglia in both relapsing
received personal compensation and progressive MS.
in the range of $500 to $4999 for
serving as a consultant for
Greenwich Biosciences, Inc, SUMMARY: Complex interactions between genetic, environmental, and
Merck & Co, Inc, and Novartis AG lifestyle factors affect the risk for MS as well as the disease course. People
and as a data safety monitoring
board member for BrainStorm of color have historically been underrepresented in both MS clinical trials
Cell Limited; has received and literature, but current research is attempting to better clarify unique
personal compensation in the
considerations in these groups. MS pathology consists of the focal
range of $5000 to $9999 for
serving as a consultant for inflammatory lesions that have been well characterized in relapsing MS, as
Biogen, EMD Serono, Inc, well as a more widespread neurodegenerative component that is posited
Genentec, Inc, Immunic
Therapeutics, and Sanofi; and
to drive progressive disease. Recent advances in characterization of both
has received personal the inflammatory and neurodegenerative aspects of MS pathophysiology
compensation in the range of have yielded potential targets for future therapeutic options.
$10,000 to $49,999 for serving as
a consultant for Adamas
Pharmaceuticals, Inc.

UNLABELED USE OF INTRODUCTION

M
PRODUCTS/INVESTIGATIONAL
USE DISCLOSURE:
Drs Ward and Goldman discuss
the unlabeled/investigational
use of rituximab, Bruton tyrosine
kinase inhibitors, and vitamin D
supplementation for the
treatment of multiple sclerosis.
© 2022 American Academy
of Neurology.
ultiple sclerosis (MS) is an autoimmune demyelinating disease
of the central nervous system (CNS) with both inflammatory
and neurodegenerative components and is the most common
nontraumatic disabling neurologic condition in young adults.1,2
Although initial disease descriptions date to hundreds of
years ago, therapeutic options were limited until the past several decades.
Unprecedented advances in understanding pathogenesis and treatment of MS
have occurred in recent years, and this article reviews both historical descriptions
of MS as well as current understanding of disease expression and pathophysiology.

988 AUGUST 2022

Copyright © American Academy of Neurology. Unauthorized reproduction of this article is prohibited.

Particular attention is paid to populations that have been traditionally KEY POINTS
underrepresented in MS literature.
● The prevalence of
multiple sclerosis (MS) is
HISTORICAL PERSPECTIVE increasing, potentially
because of changes to
Early descriptions of possible MS date to the Middle Ages. Lidwina of Schiedam,
diagnostic criteria that allow
Holland, was born in 1380, and at age 16, she had a fall with subsequent gait for earlier diagnosis, more
impairment. She later developed facial pain possibly representative of trigeminal widespread use of MRI, and
neuralgia, progressive visual impairment, weakness, dysphagia, and difficulty population aging.
walking with few periods of remission. At the time, Lidwina’s affliction was
● Female predominance in
thought to come from God, and she was ultimately canonized in 1890.3 Diary MS has persisted over time,
entries from Augustus d’Este, grandson of King George III of England, are also with a female to male ratio
considered to be one of the first reported MS cases. In the 1800s, he maintained of approximately three to
detailed records of his struggles with initial relapsing symptoms, including one.
possible optic neuritis at age 28. Attempts at treatment included blood-letting,
dietary changes, and massage. After several focal, remitting events, he developed
a more progressive course that resulted in paralysis, marked spasticity, and death
by age 54.4
Jean-Martin Charcot detailed comprehensive clinical and pathophysiologic
descriptions of MS in the 1860s, and his reports included autopsy findings from
one of his own employees who developed progressive motor dysfunction.3 More
than 120 years after Charcot’s initial pathologic descriptions, the first
disease-modifying therapy (DMT) for MS was approved.3

PREVALENCE
The prevalence of MS in the adult population in the United States was estimated
at 309 per 100,000 population in 2010, and the extrapolated prevalence in 2017
was 337 to 362 per 100,000 population.1 This translates to more than 900,000
individuals living with MS in the United States.1 In contrast, estimated
prevalence in 1990 was 58 per 100,000, with an estimated 300,000 total US
patients.1 Female predominance, with a female to male ratio of approximately
three to one has held steady in this time period1 and persists across racial
populations.5,6 Several factors may contribute to increased MS prevalence,
including widespread access to MRI, changes to diagnostic criteria allowing for
diagnosis earlier in disease presentation, and population aging accompanied by
longer survival.1

PATHOPHYSIOLOGY OF MULTIPLE SCLEROSIS

Normally, CNS autoreactive immune cells are deleted during development
through central tolerance in the thymus (T cells) or bone marrow (B cells).
Although some may escape this mechanism and be released into the circulation,
peripheral tolerance mechanisms typically prevent them from causing disease.
Mechanisms by which peripheral tolerance can fail include impaired regulatory T
cell (Treg) function or resistance of autoreactive cells to suppression. A complex
interplay between genetic and environmental risk factors may influence function
and activation of these autoreactive cells and lead to disease pathogenesis.
Primary T cell subsets implicated in MS include CD8+ T cells and CD4+ T helper
(TH) 1 and TH17 cells.7 Autoreactive T cells also produce cytokines that may
contribute to MS pathogenesis including interferon gamma, interleukin (IL)-17,
and granulocyte-macrophage colony-stimulating factor.8 Efficacy of some MS

CONTINUUMJOURNAL.COM 989

Copyright © American Academy of Neurology. Unauthorized reproduction of this article is prohibited.

MS EPIDEMIOLOGY AND PATHOPHYSIOLOGY

DMTs may at least partially relate to shifting T cell differentiation from TH1 and
TH17 to TH2 phenotypes, which have a less inflammatory profile.7
Although MS was historically thought to be a primarily T cell–driven disease,
the role of B cells in MS pathophysiology has been increasingly recognized and
characterized in recent years. CSF-specific oligoclonal IgG bands are antibodies
produced by B cells and have long been included in MS diagnostic criteria,9 and
peripheral B cells play a variety of roles in the pathophysiology of MS. In MS, B
cells produce proinflammatory cytokines including lymphotoxin-α, IL-6, TNF-α,
and granulocyte-macrophage colony-stimulating factor. In turn, B-cell depletion
can attenuate proinflammatory activity of CD4+ and CD8+ T cells.9,10 Normally,
B cells can also generate anti-inflammatory cytokines including IL-10, IL-35, and
transforming growth factor β1, but the production of these in patients with MS
may be impaired.9 Interestingly, higher levels of IL-10–producing B cells were
previously found in patients with MS with concurrent helminth infections, and
this correlated with lower MS disease activity.11

FIGURE 1-1
Microglial involvement in neurodegeneration in multiple sclerosis (MS). Microglia and
macrophages release many cytokines, including tumor necrosis factor (TNF)-α, and interleukin
(IL)-1β, which may contribute to neurodegeneration via cytokine-induced cell death, inhibition
of astrocytic glutamate reuptake, and the induction of dysfunctional RNA-binding proteins.
Microglia and macrophages can also release glutamate, potentially contributing to glutamate
excitotoxicity and neurodegeneration. Lastly, microglia and macrophages release reactive
oxygen species/reactive nitrogen species, which may contribute to neurodegeneration by
inducing oxidative stress and mitochondrial injury. Microglia can also express anti-inflammatory
phenotypes, which may contribute to remyelination, and much remains to be determined
regarding the definitive pathophysiologic mechanisms underlying neurodegeneration in MS.
Modified from Kamma E, et al, J Neuroinflamm.17 © 2022 The Authors.

990 AUGUST 2022

Copyright © American Academy of Neurology. Unauthorized reproduction of this article is prohibited.

 Within the CNS, inflammatory B-cell infiltrates can be found in the meninges KEY POINTS
of patients with MS, and a higher burden of these infiltrates correlates with the
● Autoreactive T cells are
degree of cortical lesions and neurodegeneration as well as clinical disability.9,12 involved in MS pathogenesis
B cells may also act as a reservoir for Epstein-Barr virus (EBV), which is further and were traditionally felt
discussed in a subsequent section of this article. Other pathologic mechanisms to be the primary
involving B cells in MS include antigen presentation to T cells and secretion of disease-driving immune
subset. B cells have been
molecules that may be directly toxic to oligodendrocytes.9,13 B cell–depleting
increasingly recognized as
agents have emerged as effective DMTs and are now widely used in MS treatment. important in MS
Currently used agents are monoclonal antibodies to CD20, a protein expressed by pathophysiology as well,
several subtypes of B cells, and include rituximab, ocrelizumab, and ofatumumab. likely through multiple
mechanisms.
Ocrelizumab is also the only DMT currently approved by the US Food and Drug
Administration (FDA) for treatment of primary progressive MS (PPMS).9 ● Microglia are immune
Microglia are immune cells residing in the CNS and can shift between both cells residing in the central
pro- and anti-inflammatory phenotypes.2 Microglia have previously been nervous system and are
implicated in genetic leukoencephalopathies and neurodegenerative diseases and involved in both active and
chronic MS lesions. Several
are increasingly recognized in MS pathophysiology. Microglia contribute to both therapeutic agents
acute and chronic lesion formation in MS and, on the opposite spectrum, can also potentially targeting
facilitate remyelination and neuronal repair.2,14,15 In early active MS lesions, microglia are in
about 40% of phagocytic cells are proinflammatory microglia.15 Activated development.
microglia and CD8+ T cells lead to myelin destruction; recruitment of B cells,
● Compared with the acute
other T cells, and macrophages; axon damage; and disruption of the blood-brain inflammatory lesions that
barrier.16 Activated microglia are also found in the periphery of mixed active/ characterize relapsing MS,
inactive (also called chronic, slowly expanding, or smoldering) lesions, whereas chronic, inactive, and
cortical lesions and
inactive lesions demonstrate more axonal loss and less microglia.2,14 In
more widespread
progressive MS, activated microglia and macrophages may mediate neurodegeneration
neurodegeneration by several mechanisms including cytokine release, glutamate may predominate in
release resulting in excitotoxicity, and release of reactive oxygen/nitrogen species progressive MS.
resulting in oxidative injury (FIGURE 1-1).17 Consequently, interest has increased
in therapeutic agents potentially targeting microglia. Bruton tyrosine kinase is
expressed in B cells and in CNS microglia, and several therapeutic agents
targeting inhibition of Bruton tyrosine kinase are currently in clinical trials for
both relapsing and progressive MS.2
Relapsing MS is primarily characterized by acute inflammatory activity
associated with disruption of the blood-brain barrier, as evidenced by
gadolinium-enhancing lesions on MRI.16,18 Classic acute lesions begin with
infiltrates of inflammatory B, T, and plasma cells and macrophages surrounding
a central vein.19 As discussed, proinflammatory microglia are also present in
acute lesions.16 In addition to demyelination, axonal and neuronal injury also
occurs within acute lesions.19 As lesions evolve, remyelination occurs in varying
degrees and may be partially mediated by anti-inflammatory microglia.20
Previously felt to be a predominantly white matter disease, cortical and deep gray
matter involvement have now been well characterized in all subtypes of MS and
have been associated with disability progression.21-23
Although relapsing MS is primarily influenced by peripheral immune
responses targeting the CNS, progressive forms of MS may be more heavily
driven by intrinsic immune processes within the CNS behind an apparently
intact blood-brain barrier.16,24,25 Although active/enhancing lesions can occur in
progressive disease, studies indicate that slowly expanding, inactive, and
remyelinated shadow plaques, as well as cortical lesions, may be more
abundant.16 Other mechanisms contributing to neurodegeneration in progressive

CONTINUUMJOURNAL.COM 991

Copyright © American Academy of Neurology. Unauthorized reproduction of this article is prohibited.

MS EPIDEMIOLOGY AND PATHOPHYSIOLOGY

MS may include chronic microglial activation (even in normal-appearing white

matter), impaired ion homeostasis, mitochondrial injury, and meningeal
inflammation.16,24 Characteristics of meningeal involvement appear to differ
between PPMS and secondary progressive MS (SPMS). In SPMS lymphoid
follicles consisting of B and T lymphocytes, macrophages, and plasma cells are
frequently found in the meninges and perivascular spaces, whereas meningeal
inflammation in PPMS is more diffuse without the presence of follicles.17,24
Compared with relapsing MS, spinal cord lesion load has been demonstrated to
be higher in progressive MS and, in combination with spinal cord gray matter
atrophy, correlates with disability severity in progressive MS.24,26,27 Although
understanding of both the shared and distinct features of progressive MS has
increased markedly, much remains yet to be elucidated regarding the definitive
pathophysiology of progressive MS.17 In addition, while relapsing and
progressive MS have been characterized as distinct phenotypes clinically,
expanding research indicates that features of both the inflammatory and
neurodegenerative processes in MS exist in parallel across varying disease
subtypes.19

RISK FACTORS
Studies in MS have identified several environmental, lifestyle, and genetic risk
factors relevant in both the risk of MS disease onset and course following
diagnosis.

Ultraviolet Radiation and Vitamin D

The prevalence of MS increases in a geographic gradient, with a higher
prevalence occurring in northern regions.1 Proposed reasons for this geographic
gradient include exposure to ultraviolet B (UVB) radiation and vitamin D. Living
in areas with high ambient UVB and increased summer sun exposure during
childhood is associated with decreased risk of MS.28,29 UVB exposure may also
influence MS risk independently of vitamin D.30
In humans, vitamin D is obtained via UVB-induced production in skin or
dietary intake through vitamin D–rich foods or supplementation. Vitamin D–rich
foods include fatty fishes (such as salmon, tuna, mackerel, and trout), some
mushrooms, and egg yolks.31-33 However, few foods contain significant amounts
of vitamin D, and dietary intake alone is often insufficient to meet total needs.32
Vitamins D3 (cholecalciferol, synthesized in skin via UVB-mediated production)
and D2 (ergocalciferol, found in plant sources of vitamin D) are metabolized to
25(OH)D3 and then ultimately to 1,25(OH)2D3, the active metabolite.32 In innate
immune cells, vitamin D may enhance pathogen elimination and immune
tolerance. Effects of vitamin D in adaptive immune cells include inducing
differentiation to regulatory T and B cells, decreased production of
proinflammatory cytokines, and increased secretion of anti-inflammatory
cytokines.31 In addition to these potential immunomodulatory effects, direct
effects of vitamin D on neural cells have also been observed, including promoting
oligodendrocyte maturation.34
Multiple studies have demonstrated associations between low vitamin D levels
and increased MS risk.31,35,36 Low vitamin D has also been associated with
increased risk of conversion from clinically isolated syndrome (CIS) to clinically
definite MS37 and increased risk of MS relapse.31,38,39 Exact mechanisms by which
vitamin D contributes to MS are multifactorial and are also likely influenced by

992 AUGUST 2022

Copyright © American Academy of Neurology. Unauthorized reproduction of this article is prohibited.

other genetic and environmental risk factors.31 For example, genetic KEY POINT
polymorphisms in the vitamin D pathway have been associated with both serum
● Low vitamin D levels are
vitamin D levels and relapse rates in pediatric MS patients,39 and vitamin D and associated with an
its associated receptors may interact with EBV nuclear antigens to contribute to increased risk of MS.
MS pathogenesis.34 Finally, lower increases in serum vitamin D levels after Current trials aim to clarify
supplementation have been observed in patients with MS compared with the role of supplementation
and vitamin D goal levels in
controls, suggesting that in patients with MS vitamin D metabolism may also
patients with MS.
be altered.40
Despite mounting evidence regarding the relationship between low vitamin D
levels and the risk of MS and MS relapse, data are mixed regarding efficacy of
vitamin D supplementation on clinical and radiographic outcome measures.41 To
date, studies have been limited by small sample sizes, short durations, and
concurrent use of DMTs, which may have confounded results.31,42 Recent
meta-analyses have not clearly identified benefits of vitamin D in the treatment
of MS.41,42 Larger, more sufficiently powered studies are underway and will
hopefully provide clearer evidence regarding the role of vitamin D
supplementation in both MS and CIS.43,44
Risks of vitamin D toxicity include hypercalcemia, hyperphosphatemia,
hypercalciuria, and renal failure. Most trials evaluating the effects of vitamin D
supplementation in MS excluded patients with contraindications for high-dose
vitamin D supplementation, including renal impairment, granulomatous disease,
and primary hyperparathyroidism.31 Otherwise, for most adults, risks of vitamin
D supplementation are low, and toxicity typically does not occur in levels less
than 150 ng/mL.32,45 While awaiting results of more definitive trials regarding the
role of supplementation, assessing vitamin D status in patients with CIS and MS
is often considered reasonable in clinical practice. The following discussion
regarding clinical assessment of vitamin D refers to serum 25(OH)D3 level, as this
is most representative of total body stores and is most often measured in clinical
practice.31 Consensus has not been reached regarding goal vitamin D levels and
optimal supplement dosing in patients with MS. In the general adult population,
Endocrine Society guidelines suggest that vitamin D levels of 30 ng/mL are
sufficient.46 At least 1500 international units (IU) to 2000 IU daily of
supplemental vitamin D may be needed to maintain these levels, with some
patients requiring higher doses.46 Some MS specialists recommend a goal vitamin
D level of 40 ng/mL to 60 ng/mL, which may require even higher dosing
(2000 IU to 5000 IU daily).47 For patients with MS, repeat monitoring of vitamin
D levels is suggested 3 months after starting supplementation to direct further
dose adjustments.47

Genetics
The human leukocyte antigen (HLA) complex contains multiple genes related to
immune system functioning, and HLA genotype has been increasingly well
characterized regarding MS risk.48 HLA-DRB1*15:01 is associated with increased
risk of MS and is present in up to 30% of the population in the United States and
northern Europe.49 HLA-A*02 is associated with decreased MS risk.48 Many
other normal-variant single nucleotide polymorphisms, which are located
outside the HLA complex but typically near genes associated with immune
functions, have also been associated with MS risk to varying degrees.48,49
Combinations of genetic factors also likely contribute to disease risk; for
example, the presence of HLA-DRB1*15:01 and the lack of HLA-A*02 are

CONTINUUMJOURNAL.COM 993

Copyright © American Academy of Neurology. Unauthorized reproduction of this article is prohibited.

MS EPIDEMIOLOGY AND PATHOPHYSIOLOGY

associated with higher risk of MS than the presence of HLA-DRB1*15:01 alone.48

Gene–environmental interactions that may contribute to MS pathogenesis
include vitamin D levels,39 obesity in childhood,50 EBV infection,49 and
smoking.48 However, in clinical practice, testing for genetic variants associated
with MS risk is not currently recommended even in patients with a family history
of MS.49

Epstein-Barr Virus
EBV is a herpes virus frequently acquired in childhood and is often
asymptomatic. Later-onset infection in adolescence and adulthood is more
commonly associated with clinical illness manifesting as infectious
mononucleosis.51 Following infection, latent EBV remains in host B
lymphocytes.52 Across multiple meta-analyses, EBV antibody seropositivity and
infectious mononucleosis have consistently been associated with MS risk.53 Even
more definitively, a recent large study by Bjornevik and colleagues52 indicated
that MS is almost always preceded by EBV infection and that EBV may be a
primary cause of MS. That being said, EBV seropositivity is high not only in
patients with MS but also in the general population; thus, the role of EBV in MS
pathogenesis is likely multifactorial and may include interactions between EBV,
predisposing genetic factors, and environmental risk factors.49,54
EBV nuclear antigen 1 (EBNA1) is expressed in EBV-infected B cells and
contributes to transcription regulation and viral genome maintenance.54
Proposed mechanisms by which EBV may contribute to MS pathogenesis include
molecular mimicry between EBNA1 and glial cell adhesion molecules expressed
by CNS oligodendrocytes and astrocytes resulting in cross-reactive antibodies.55
In human tissue studies, a significantly higher number of EBV-related proteins
were present in chronic MS lesions compared with non-MS controls, and 85% of
patients with MS had EBV-encoded RNA-positive B cells in their brains
compared with rare occurrence in control brains.56 In another study, EBV
infection was also demonstrated directly in astrocytes and microglia of patients
with MS and was not solely confined to B cells.57
Several other potential viral contributors to MS risk, including human herpes
virus 6, cytomegalovirus, herpes simplex virus, and human endogenous
retroviruses, have been explored, but thus far have less well-established
associations with MS pathogenesis than EBV.49

Smoking
Smoking has been associated with increased risk of MS,58 as well as
conversion from CIS to clinically definite MS33 and conversion of relapsing
to secondary progressive MS.59,60 Smoking may also reduce efficacy of at
least some DMTs including interferon and natalizumab.61,62 Passive smoke
exposure has also been associated with increased MS risk.48 Interestingly, use
of oral tobacco has been associated with decreased risk of MS, suggesting that
lung inflammation from smoking may be the driver of increased MS risk
in smokers.48
Genetic factors may influence the effect of smoking on MS risk. For example,
one Swedish study found that among patients who had HLA-DRB1*15:01 and
lacked HLA-A*02, smoking contributed to development of MS in 41% of cases.63
This illustrates the importance of smoking, including passive exposure, as a
modifiable risk factor both for disease development and disease course in MS.

994 AUGUST 2022

Copyright © American Academy of Neurology. Unauthorized reproduction of this article is prohibited.

Small studies indicate that patients are often unaware of the MS-specific risks of KEY POINTS
smoking and that education by MS clinicians and referral to quit support services
● Human leukocyte antigen
may be an opportunity for improvement in clinical practice.64,65 (HLA)-DRB1*15:01 genotype
increases MS risk, whereas
Obesity HLA-A*02 may be
Obesity in adolescence and childhood has been associated with increased risk protective. Other single
nucleotide polymorphisms
of both pediatric and adult-onset MS, with a seemingly stronger association
influencing MS risk have also
in females compared with males.66,67 In pediatric patients, obesity may been identified.
precede MS diagnosis by several years.67 Abdominal obesity has also been
associated with more severe disability in patients with known MS.68 Proposed ● Epstein-Barr virus
mechanisms by which obesity may be involved in MS pathogenesis seropositivity and infectious
mononucleosis are
include promotion of a proinflammatory milieu,48 decreased vitamin D associated with increased
bioavailability,48 and interactions with predisposing genetic MS risk factors50 risk of MS. Other viral
and EBV infection.69 associations with MS have
been less clearly defined.
Microbiome and Diet ● Smoking, including
The human body contains more microbial cells than human cells, and most passive smoke exposure,
human microbes reside in the gut. Gut colonization in early life is influenced by a has been associated with
variety of factors including method of delivery, breastfeeding, antibiotic both MS risk and disease
progression. Smoking
exposure, and genetic, environmental, and maternal factors. Diet significantly
cessation should be
influences microbiome composition throughout the remainder of an individual’s encouraged, and dedicated
life.70-72 Species of Bacteroides and Firmicutes within the gut use indigestible fiber education by clinicians may
and complex carbohydrates to produce short chain fatty acids that can ultimately increase the likelihood of
cessation.
increase production of regulatory T cells important in suppressing autoreactive
immune cells in MS.71,73 Bacteria can also produce cytokines that can influence ● Childhood and
both pro- and anti-inflammatory immune cells.71 Multiple studies have adolescent obesity have
demonstrated differing gut microbiomes in patients with MS compared with been associated with
controls, although exact bacterial compositions have been mixed.71 Much increased MS risk, and
abdominal obesity has also
remains to be determined regarding the exact role of diet in MS pathogenesis and been associated with a
disease course, and a unifying ideal MS diet has not been established. To date, degree of MS-related
studies have primarily evaluated the influence of diets high in vegetables, fruits, disability.
and whole grains and limited in the amounts of fats and animal products on both
● Gut microbiome may
microbiome composition and clinical outcomes. Consistent associations between
influence systemic
diet, relapse rate, and disability progression in MS have not been demonstrated, inflammation. A unifying
but there have been some associations between diet quality and symptomatic “MS microbiome” has not
issues such as fatigue and depression.74-77 been demonstrated, and the
role of diet in MS outcomes
has yet to be clearly
Comorbidities and Multiple Sclerosis Disease Course defined, but a higher quality
Comorbid conditions are common in patients with MS and increase with age.78 diet may assist in improving
Comorbid conditions can contribute to delays in MS diagnosis and treatment common symptomatic
initiation79 and adversely affect health-related quality of life.80 At the time of MS issues.

diagnosis, common comorbidities include depression, anxiety, hypertension,

chronic lung disease, and hyperlipidemia.81 Vascular comorbidities (including
hypertension, hyperlipidemia, diabetes, and peripheral vascular disease) and
obstructive lung disease have been associated with disability progression in
MS.82,83 Psychiatric comorbidities, including anxiety and mood disorders, have
been associated with relapse risk,78 disability progression,84 and adherence to MS
treatments.85,86 Many patients with MS have more than one comorbidity, and the
cumulative number of comorbid conditions that a patient has may increase their
risk of relapse78 and has been associated with higher disability scores.87

CONTINUUMJOURNAL.COM 995

Copyright © American Academy of Neurology. Unauthorized reproduction of this article is prohibited.

MS EPIDEMIOLOGY AND PATHOPHYSIOLOGY

Comorbidities may also affect treatment decisions, response, and adherence in

patients with MS.88,89
Potentially modifiable MS risk factors are summarized in TABLE 1-1.

POPULATIONS OF SPECIAL INTEREST

Recognition and understanding of specific subgroups within the MS community
have increased in recent years.

Race-specific Considerations
Data regarding people of color have historically been underrepresented in the MS
literature.90 MS has long been considered to predominantly affect White people
of Northern European ancestry, but this assumption has been challenged in
recent demographic data. Studies suggest a higher incidence of MS in the US
Black population than previously characterized (CASE 1-2) and up to a 47%
higher risk of MS in Black women compared with White women in the US.6,91,92
Black patients are more likely than White patients to present with multifocal
symptoms, more frequently develop transverse myelitis, and may have worse
visual impairment from acute optic neuritis and more rapid retinal nerve fiber
loss leading to greater vision dysfunction.5,93,94 Rates of relapsing versus
progressive disease are similar between Black patients and White patients.5 MS
occurs more frequently in Black Americans than Africans, which may relate to

TABLE 1-1 Potentially Modifiable Multiple Sclerosis Risk Factors

Risk factor Association in multiple sclerosis Interventions in clinical practice

Vitamin D Increased risk of multiple sclerosis (MS)/clinically
deficiency isolated syndrome (CIS)31,35,36
Increased risk of MS relapse31,38,39
Consider assessing serum total vitamin D level for
patients with MS/CIS
Definitive goal level for patients with MS not yet
established; Endocrine Society guidelines
recommend goal level of 30 ng/mL for the general
population,46 and some MS specialists recommend
goal level of 40-60 ng/mL47

Smoking Associated with increased risk of MS/CIS58,60 Encourage cessation and educate patients regarding
and increased risk of disease progression59,60 MS-specific smoking risks, consider referral to
smoking cessation support services64,65

Obesity Childhood/adolescent obesity associated with Counsel patients regarding MS-specific obesity
increased MS risk66,67 concerns, encourage healthy weight67
Abdominal obesity associated with worse MS
disability67

Diet and Gut microbiome may contribute to systemic Discuss potential role of higher quality diet in MS
microbiome inflammation71,73 symptom management
Unifying ideal MS diet has not yet emerged, but
diet may contribute to symptom management74-77

Comorbid Systemic and psychiatric comorbidities may Inform patients of importance of managing
conditions contribute to relapse risk,78 degree of disability,84,87 comorbidities
and adherence to treatment85,86

996 AUGUST 2022

Copyright © American Academy of Neurology. Unauthorized reproduction of this article is prohibited.

differences in both genetic and environmental risk factors.5 Black patients may KEY POINTS
develop earlier ambulatory dysfunction, requiring cane assistance several years
● Comorbid conditions are
earlier than White patients.5 Disability owing to hand and visual dysfunction is common in patients with
more common in Black patients compared with White patients,95 and more MS. Comorbidities influence
severe cognitive processing involvement has been demonstrated in Black relapse risk, disability
patients with MS, as well.96 Higher lesion burden and accelerated rates of both scores, health-related
quality of life, and treatment
brain volume loss and retinal atrophy in Black patients may contribute to greater
adherence.
accumulation of disability.96,97
Compared with White and Black patients, Asian, Native American, and ● The incidence of MS is
Hispanic patients appear to have a lower incidence of MS.6,91,92,95 Adult Hispanic higher than previously
people with MS tend to have a younger age of disease onset compared with recognized in Black people
in the United States, and
White and Black patients.6 Among Hispanic immigrants to the United States, Black, Asian, and Hispanic
immigration before adolescence was associated with younger age at MS onset patients may be at risk for
compared with later immigrants and hints at a potential role of age-dependent more severe disability
environmental risk factors in disease pathogenesis. Later age at immigration has related to MS.
been associated with worse disability in Hispanic patients.98 Hispanic patients may ● Among Hispanic
be more likely to present with optic neuritis (at least in patients from the western immigrants to the United
United States),93,99,100 may more frequently develop transverse myelitis,93,100 and States, immigration before
may have a more aggressive disease course compared to White patients.101 adolescence has been
associated with younger age
Historical data suggest that, similar to Black and Hispanic patients with MS,
at MS onset, and later
Asian patients with MS are at higher risk of optic nerve and spinal cord immigration has been
involvement compared with White patients, which may lead to more significant associated with worse
ambulatory disability.93 However, it is important to note that some of these data disability.
were obtained before formalized diagnostic criteria and antibody testing for
neuromyelitis optica spectrum disorders (NMOSD) as separate disease entities
from MS. Therefore, regardless of race, it is important to consider and evaluate
for alternative diagnoses (eg, NMOSD) in patients presenting with predominantly
optic nerve and spinal cord disease involvement to guide appropriate treatment
decision making.93
Few data are available regarding MS in Native Americans, but Native
American ancestry has been associated with risk of optic neuritis as a presenting
symptom in Hispanic patients,102 as well as increased risk of neuromyelitis optica
in Mexican populations.103
Disparities in care across racial backgrounds have been demonstrated for
several chronic neurologic conditions, including MS. One US study found that
Black and Hispanic patients with MS were less likely than White patients to see a
neurologist.104 Treatment responses to DMT between White patients and
patients of color may also differ; prior studies have suggested lower response to
interferon therapies in Black patients.105 The ability to draw race-specific
conclusions about DMT efficacy in patients of color has been limited by
disproportionately small numbers of participants of color enrolled in clinical
trials.106,107 Ongoing research will hopefully yield better understanding of
race-specific considerations in MS pathogenesis, disease course, and treatment
optimization, including in subpopulations of racial and ethnic cohorts that are
often grouped together but have varying ancestral genetic admixtures.98,100

LGBTQAI Populations
Limited data exist regarding lesbian, gay, bisexual, transgender, queer (or
questioning), asexual (or allied), and intersex (LGBTQAI)-specific
considerations in MS. In a prior analysis of 5604 patients with MS enrolled in the

CONTINUUMJOURNAL.COM 997

Copyright © American Academy of Neurology. Unauthorized reproduction of this article is prohibited.

MS EPIDEMIOLOGY AND PATHOPHYSIOLOGY

North American Research Committee on Multiple Sclerosis registry, 95.4% of

patients identified as heterosexual and 4.6% of patients identified as lesbian, gay,
or other sexual orientation (see the article by Khayambashi and colleaguees108 for
the full description of available responses in this survey). Patients who identified
as lesbian, gay, or another orientation were less likely to report that their provider
knew their sexual orientation and were less comfortable discussing sexual health
with their providers. In the same study, 0.45% of patients identified as

CASE 1-2 A 53-year-old man presented with a 1-year history of progressively

worsening gait, muscle stiffness, incomplete urinary emptying, and
cognitive difficulty without discrete focal events. He had experienced
daytime fatigue and physical lassitude for approximately 3 years prior to
onset of his other neurologic symptoms. He had a history of smoking.
Examination revealed increased tone in his lower extremities, spastic
gait, and hyperreflexia. Brain MRI revealed periventricular, subcortical, and
juxtacortical lesions in a pattern consistent with multiple sclerosis (MS)
(FIGURES 1-2A and 1-2B). MRI of his cervical and thoracic spine also revealed
demyelinating lesions (FIGURE 1-2C). No lesions enhanced with contrast. His
vitamin D level was low at 28 ng/mL (normal ≥30). He was Black.
One year of progressive neurologic symptoms, characteristic lesions on
brain and spinal cord MRI, and no other more likely diagnosis met criteria for
a diagnosis of primary progressive multiple sclerosis, and lumbar puncture
was not completed. He stopped smoking shortly after diagnosis. He was
treated with B cell–depleting therapy with clinical stabilization. Repeat
vitamin D level following initiation of supplementation was 41 ng/mL.

COMMENT Recent studies suggest that the incidence of MS in Black patients in the
United States is higher than previously characterized and similar to the
incidence in White patients. Black patients may be more likely to have visual
and spinal cord disease involvement and may develop ambulatory
dysfunction earlier than White patients. Patients of color have historically
been underrepresented in clinical trials of MS disease-modifying
therapies.
Low vitamin D levels have been associated with an increased risk of MS,
and although the role of supplementation has not been clearly defined, it is
often considered in clinical practice. Consensus has not yet been reached
regarding goal vitamin D levels for patients with MS, but levels of at least
40 ng/mL to 60 ng/mL have been suggested. Smoking has been associated
with both risk of MS and disease course, and education regarding
MS-specific risks of smoking may influence the likelihood of cessation.
Another modifiable risk factor for MS that did not apply in this case
includes obesity, especially in adolescence and childhood. Abdominal
obesity in particular may have associations with the degree of MS-related
disability. Nonmodifiable MS risk factors include Epstein-Barr virus (EBV)
infection (at least currently, given widespread seropositivity in the general
population and lack of definitive treatment for EBV) and genotype.

998 AUGUST 2022

Copyright © American Academy of Neurology. Unauthorized reproduction of this article is prohibited.

transgender. Only 62.5% of 25 transgender patients reported that their provider
was aware of their gender identity, and provider awareness of gender identity
was associated with increased patient satisfaction. Patients who identified as
transgender were also less comfortable discussing sexual health with their
providers.108 Sexual dysfunction is common in patients with MS in general, may
be at least indirectly associated with mood symptoms,109 and is rarely asked
about by physicians.110 Better physician understanding regarding sexual

FIGURE 1-2
Imaging from the patient in CASE 1-1. Brain axial (A) and sagittal (B) fluid-attenuated inversion
recovery (FLAIR) MRI demonstrating periventricular lesions consistent with multiple
sclerosis. Axial T2-weighted MRI (C) of cervical spine demonstrating a demyelinating lesion.

CONTINUUMJOURNAL.COM 999

Copyright © American Academy of Neurology. Unauthorized reproduction of this article is prohibited.

MS EPIDEMIOLOGY AND PATHOPHYSIOLOGY

KEY POINTS
● Physician awareness
regarding patients’ gender
identity and sexual
orientation is an important
opportunity for improved
comprehensive care and
patient satisfaction.
● Socioeconomic factors
contribute to MS outcomes,
and costs of care related to
MS have steadily increased.
Many patients with MS
experience financial worry,
and costs may affect patient
adherence and quality
of life.
orientation and gender identity may be an opportunity for optimization of
comprehensive MS care, and more data are needed regarding LGBTQAI-specific
considerations in MS.
Socioeconomic Status
Socioeconomic factors, including income, employment, access to health
insurance, and education are increasingly recognized as contributors to clinical
outcomes in MS.111 Lower socioeconomic status has been associated with worse
disability,112-114 and adjusting for socioeconomic status attenuates some racial
differences in degree of disability.95 Lower socioeconomic status has also been
associated with worse MS-related symptoms including fatigue, depression, and
anxiety.110,113 Nearly three-fourths of patients at one MS center experienced
financial worry, and cost of care contributed to nonadherence to clinic visits,
imaging, or medications in more than one-third of patients at the same center.115,116
On a larger population level, the 2019 total estimated US economic burden
of MS was $85 billion, and prescription medications (DMT and non-DMT)
accounted for almost $40 billion of direct MS medical costs.117 In recent years,
costs of DMT have risen significantly, drastically out of proportion to the rate of
inflation, and far outpace spending for clinical services.118 Costs of care rise with
increasing disability, and in prior meta-analyses MS ranked second only to
congestive heart failure in direct cost of care for chronic medical conditions.119
Cooperative efforts between physicians and health insurance plans may provide
opportunities for improvements in cost stewardship as well as equity and quality
of care.120

CONCLUSION
MS occurs in patients of all backgrounds and can develop in childhood through
adulthood. The prevalence of MS has increased in recent decades, and the
economic impacts of the disease on both individual patients and the health care
system at large are considerable. MS pathogenesis likely results from complex
interactions between genetic and environmental risk factors. Recent decades
have yielded marked advances regarding understanding of MS disease processes,
and treatment options have also significantly expanded. Still, much remains to be
elucidated regarding MS disease mechanisms, including the importance of
individual variation in inflammatory dysfunction, early and sustained impact of
risk factor and comorbid disease mitigation, and pathobiologic differences
between relapsing and progressive disease. Further understanding of these areas
will have important and meaningful implications for disease prevention and
individual therapeutic options. Future studies are needed, especially regarding
the discussed unique subgroups of patients with MS who have historically been
underrepresented in MS-related research and clinical trials.

REFERENCES

1 Wallin M, Culpepper W, Campbell J, et al. The
prevalence of MS in the United States: a
population-based estimate using health claims
data. Neurology 2019;92(10):e1029-e1040. doi:
10.1212/WNL.0000000000007035
2 Geladaris A, Häusler D, Weber M. Microglia: the
missing link to decipher and therapeutically
control MS progression? Int J Mol Sci 2021;22(7):
3461. doi:10.3390/ijms22073461

1000 AUGUST 2022

Copyright © American Academy of Neurology. Unauthorized reproduction of this article is prohibited.

3 Grzegorski T, Losy J. Multiple sclerosis—the 17 Kamma E, Lasisi W, Libner C, et al. Central
remarkable story of a baffling disease. nervous system macrophages in progressive
Rev Neurosci 2019;30(5):511-526. doi:10.1515/ multiple sclerosis: relationship to
revneuro-2018-0074 neurodegeneration and therapeutics.
J Neuroinflammation 2022;19:45. doi:10.1186/
4 Firth D. The case of Augustus d’Este (1794-1848):
s12974-022-02408-y
the first account of disseminated sclerosis:
section of the history of medicine. Proc R Soc 18 Luchinetti C, Bruck W, Parisi J, et al.
Med 1941;34(7):381-384. Heterogeneity of multiple sclerosis lesions:
implications for the pathogenesis of
5 Cree B, Khan O, Bourdette D, et al. Clinical
demyelination. Ann Neurol 2000;47(6):707-717.
characteristics of African Americans vs
doi:10.1002/1531-8249(200006)47:6
Caucasian Americans with multiple sclerosis.
Neurology 2004;63(11):2039-2045. doi:10.1212/01. 19 Lassmann H. Pathogenic mechanisms associated
wnl.0000145762.60562.5d with different clinical courses of multiple
sclerosis. Front Immunol 2019;9:3116. doi:10.3389/
6 Langer-Gould A, Brara S, Beaber B, Zhang J.
fimmu.2018.03116
Incidence of multiple sclerosis in multiple racial
and ethnic groups. Neurology 2013;80(19): 20 Tsouki F, Williams A. Multifaceted involvement of
1734-1739. doi:10.1212/WNL.0b013e3182918cc2 microglia in gray matter pathology in multiple
sclerosis. Stem Cells 2021;39:993-1007. doi:
7 Dendrou CA, Fugger L, Friese MA.
10.1002/stem.3374
Immunopathology of multiple sclerosis. Nat Rev
Immunol 2015;15(9):545-558. doi:10.1038/nri3871 21 Lucchinetti C, Popescu B, Bunyan R, et al.
Inflammatory cortical demyelination in early
8 Wagner CA, Roque PJ, Goverman JM. Pathogenic
multiple sclerosis. N Engl J Med 2011;365(23):
T cell cytokines in multiple sclerosis. J Exp Med
2188-2197. doi:10.1056/NEJMoa1100648
2020;217(1):e20190460. doi:10.1084/jem.20190460
22 Eshagi A, Prados F, Brownlee WJ. Deep gray
9 Comi G, Bar-Or A, Lassmann H, et al. Role of B
matter volume loss drives disability worsening in
cells in multiple sclerosis and related disorders.
multiple sclerosis. Ann Neurol 2018;83:210-222.
Ann Neurol 2021;89(1):13-23. doi:10.1002/
doi:10.1002/ana.25145
ana.25927
23 Calabrese M, Poretto V, Favaretto A, et al.
10 Bar-Or A, Fawaz L, Fan B, et al. Abnormal B-cell
Cortical lesion load associates with progression
cytokine responses a trigger of T-cell-mediated
of disability in multiple sclerosis. Brain 2012;
disease in MS? Ann Neurol 2010;67(4):452-461.
135(Pt 10):2952-2961. doi:10.1093/brain/aws246
doi:10.1002/ana.21939
24 Correale J, Gaitan MI, Ysrraelit MC, Fiol MP.
11 Correale J, Farez M, Razzitte G, et al. Helminth
Progressive multiple sclerosis: from pathogenic
infections associated with multiple sclerosis
mechanisms to treatment. Brain 2017;140:
induce regulatory B cells. Ann Neurol 2008;64(2):
527-546. doi:10.1093/brain/aww258
187-199. doi:10.1002/ana.21438
25 Cree BAC, Arnold DL, Chataway J, et al.
12 Magliozzi R, Howell O, Vora A, et al. Meningeal
Secondary progressive multiple sclerosis: new
B-cell follicles in secondary progressive multiple
insights. Neurology 2021;97(8):378-388. doi:
sclerosis associate with early onset of disease
10.1212/WNL.0000000000012323
and severe cortical pathology. Brain 2007;
130(Pt 4):1089-1104. doi:10.1093/brain/awm038 26 Kearney H, Altmann DR, Samson RS, et al.
Cervical cord lesion load is associated with
13 Lisak RP, Benjamins JA, Nedelkoska L, et al.
disability independently from atrophy in MS.
Secretory products of multiple sclerosis B cells
Neurology 2015;84:367-373. doi:10.1212/
are cytotoxic to oligodendroglia in vitro.
WNL.0000000000001186
J Neuroimmunol 2012;246(1-2):85-95. doi:10.1016/j.
jneuroim.2012.02.015 27 Schlaeger R, Papinutto N, Zhu AH, et al.
Association between thoracic spinal cord gray
14 Guerrero BL, Sicotte NL. Microglia in multiple
matter atrophy and disability in multiple
sclerosis: friend or foe? Front Immunol 2020;11:
sclerosis. JAMA Neurol 2015;72(8):897-904. doi:
374. doi:10.3389/fimmu.2020.00374
10.1001/jamaneurol.2015.0993
15 Zrzavy T, Hametner S, Wimmer I, et al. Loss of
28 Tremlett H, Zhu F, Ascherio A, Munger K. Sun
‘homeostatic’ microglia and patterns of their
exposure over the life course and associations
activation in active multiple sclerosis. Brain 2017;
with multiple sclerosis. Neurology 2018;90(14):
140(7):1900-1913. doi:10.1093/brain/awx113
e1191-e1199. doi:10.1212/WNL.0000000000005257
16 Lassmann H, Horssen J, Mahad D, et al.
29 Sebastian P, Cherbuin N, Barcellos LF, et al.
Progressive multiple sclerosis: pathology and
Association between time spent outdoors and
pathogenesis. Nat Rev Neurol 2012;8(11):647-656.
risk of multiple sclerosis. Neurology 2022;98:
doi:10.1038/nrneurol.2012.168
e267-e278. doi:10.1212/WNL.0000000000013045
30 Lucas R, Ponsonby A, Dear K, et al. Sun exposure
and vitamin D are independent risk factors for
CNS demyelination. Neurology 2011;76(6):
540-548. doi:10.1212/WNL.0b013e31820af93d

CONTINUUMJOURNAL.COM 1001

Copyright © American Academy of Neurology. Unauthorized reproduction of this article is prohibited.

MS EPIDEMIOLOGY AND PATHOPHYSIOLOGY
31 Yeh W, Gresle M, Jokubaitis V, et al.
Immunoregulatory effects and therapeutic
potential of vitamin D in multiple sclerosis. Br J
Pharmacol 2020;177(18):4113-4133. doi:10.1111/
bph.15201
32 Sintzel M, Rametta M, Reder A, et al. Vitamin D
and multiple sclerosis: a comprehensive review.
Neurol Ther 2018;7(1):59-85. doi:10.1007/s40120-
017-0086-4
33 National Institutelse of Health. Vitamin D fact
sheet for health care professionals. Accessed
May 12, 2022. ods.od.nih.gov/factsheets/
VitaminD-HealthProfessional/
34 Miclea A, Bagnoud M, Chan A, Hoepner R. A brief
review of the effects of vitamin D on multiple
sclerosis. Front Immunol 2020;11:781. doi:10.
3389/fimmu.2020.00781
35 Munger K, Zhang S, O’Reilley E, et al. Vitamin D
intake and incidence of multiple sclerosis.
Neurology 2004;62(1):60-65. doi:10.1212/01.
wnl.0000101723.79681.38
36 Munger K, Levin L, Hollis B, et al. Serum
25-hydroxyvitamin D levels and risk of multiple
sclerosis. JAMA 2006;296(23):2832-2838. doi:10.
1001/jama.296.23.2832
37 Martinelli V, Dalla Costa G, Colombo B, et al.
Vitamin D levels and risk of multiple sclerosis in
patients with clinically isolated syndrome. Mult
Scler 2014;20(2):147-155. doi:10.1177/
1352458513494959
38 Simpson S, Taylor B, Blizzard L, et al. Higher
25-hydroxyvitamin D is associated with lower
relapse risk in multiple sclerosis. Ann Neurol 2010;
68(2):193-203. doi:10.1002/ana.22043
39 Graves J, Barcellos L, Krupp L, et al. Vitamin D
genes influence MS relapses in children. Mult
Scler 2020;26(8):894-901. doi:10.1177/
1352458519845842
40 Bhargava P, Steele S, Waubant E, et al. Multiple
sclerosis patients have a diminished serologic
response to vitamin D supplementation
compared to healthy controls. Mult Scler 2016;
22(6):753-760. doi:10.1177/1352458515600248
41 Boltjes R, Knippenberg S, Gerlach O, et al.
Vitamin D supplementation in multiple sclerosis:
an expert opinion based on the review of current
evidence. Expert Rev Neurother 2021;21(6):
715-725. doi:10.1080/14737175.2021.1935878
42 Jagannath V, Filippini G, Di Pietrantonj C, et al.
Vitamin D for the management of multiple
sclerosis. Cochrane Database Syst Rev 2018;9(9):
CD008422. doi:10.1002/14651858.CD008422.
pub3
43 Bhargava P, Cassard S, Steele SU, et al. The
vitamin D to ameliorate multiple sclerosis
(VIDAMS) trial: study design for a multicenter,
randomized, double-blind controlled trial of
vitamin D in multiple sclerosis. Contemp Clin
Trials 2014;39(2):288-293. doi:10.1016/j.cct.2014.
10.004
1002
Copyright © American Academy of Neurology. Unauthorized reproduction of this article is prohibited.
44 Clinicaltrialsgov. Efficacy of cholecalciferol
(vitamin D3) for delaying the diagnosis of MS
after a clinically isolated syndrome (D-Lay-MS).
Updated January 10, 2022. Accessed June 6,
2022. clinicaltrials.gov/ct2/show/NCT01817166
45 Galior K, Grebe S, Singh R, et al. Development of
vitamin D toxicity from overcorrection of vitamin
D deficiency: a review of case reports. Nutrients
2018;10(8):953. doi:10.3390/nu10080953
46 Holick M, Binkley N, Bischoff-Ferrari H, et al.
Evaluation, treatment, and prevention of vitamin
D deficiency: an Endocrine Society Clinical
Practice Guideline. J Clin Endocrinol Metab 2011;
96(7):1911-1930. doi:10.1210/jc.2011-0385
47 Shoemaker T, Mowry E. A review of vitamin D
supplementation as disease-modifying therapy.
Mult Scler 2018;24(1):6-11. doi:10.1177/
1352458517738131
48 Olsson T, Barcellos L, Alfredsson L, et al.
Interactions between genetic, lifestyle and
environmental risk factors for multiple sclerosis.
Nat Rev Neurol 2017;13(1):25-36. doi:10.1038/
nrneurol.2016.187
49 Waubant E, Lucas R, Mowry E, et al.
Environmental and genetic risk factors for MS: an
integrated review. Ann Clin Transl Neurol 2019;
6(9):1905-1922. doi:10.1002/acn3.50862
50 Meir Jacobs B, Noyce A, Bestwick J, et al.
Gene-environment interactions in multiple
sclerosis: a UK Biobank study. Neurol
Neuroimmunol Neuroinflamm 2021;8(4):e1007.
doi:10.1212/NXI.0000000000001007
51 Langer-Gould A, Wu J, Lucas R, et al. Epstein-Barr
virus, cytomegalovirus, and multiple sclerosis
susceptibility: a multiethnic study. Neurol 2017;
89(13):1330-1337. doi:10.1212/WNL.
0000000000004412
52 Bjornevik K, Cortese M, Healy BC, et al.
Longitudinal analysis reveals high prevalence of
Epstein-Barr virus associated with multiple
sclerosis. Science 2022;375:296-301. doi:10.1126/
science.abj8222
53 Belbasis L, Bellou V, Evangelou E, et al.
Environmental risk factors and multiple sclerosis:
an umbrella review of systematic reviews and
meta-analyses. Lacet Neurol 2015;14(3):263-273.
doi:10.1016/S1474-4422(14)70267-4
54 Marcucci S, Obeidat A. EBNA1, EBNA2, and
EBNA3 link Epstein-Barr virus and
hypovitaminosis D in multiple sclerosis
pathogenesis. J Neuroimmunol 2020;339:577116.
doi:10.1016/j.jneuroim.2019.577116
55 Lanz T, Brewer RC, Ho PP, et al. Clonally
expanded B cells in multiple sclerosis bind EBV
EBNA1 and GlialCAM. Nature 2022;63:321-327.
doi:10.1038/s41586-022-04432-7
56 Moreno M, Or-Geva N, Aftab B, et al. Molecular
signature of Epstein-Barr virus infection in MS
brain lesions. Neurol Neuroimmunol
Neuroinflamm 2018;5(4):e466. doi:10.1212/NXI.
0000000000000466
AUGUST 2022
57 Hassani A, Corboy JR, Al-Salam S, Khan G.
Epstein-Barr virus is present in the brain of most
cases of multiple sclerosis and may engage more
than just B cells. PLoS One 2018;13(2):e0192109.
doi:10.1371/journal.pone.0192109
58 Hawkes C. Smoking is a risk factor for multiple
sclerosis: a metanalysis. Mult Scler 2007;13(5):
610-615. doi:10.1177/1352458506073501
59 Ramanujam R, Hedstrom A, Manouchehrinia A,
et al. Effect of smoking cessation on multiple
sclerosis prognosis. JAMA Neurol 2015;72(10):
1117-1123. doi:10.1001/jamaneurol.2015.1788
60 Barzegar M, Najdaghi S, Ashari-Safavi A, et al.
Early predictors of conversion to secondary
progressive multiple sclerosis. Mult Scler Relat
Disord 2021;54:103115. doi:10.1016/j.msard.2021.
103115
61 Petersen E, Oturai A, Koch-Henriksen N, et al.
Smoking affects the interferon beta treatment
response in multiple sclerosis. Neurol 2018;90(7):
e593-e600. doi:10.1212/WNL.0000000000004949
62 Petersen E, Bach Søndergaard H, Laursen J, et al.
Smoking is associated with increased disease
activity during natalizumab treatment in multiple
sclerosis. Mult Scler 2019;25(9):1298-1305. doi:10.
1177/1352458518791753
63 Hedstrom A, Olsson T, Alfredsson L, et al.
Smoking is a major preventable risk factor for
multiple sclerosis. Mult Scler J 2016;22(8):
1021-1026. doi:10.1177/1352458515609794
64 Hunter A, Grech L, Borland R, et al. Barriers and
motivators for tobacco smoking cessation in
people with multiple sclerosis. Mult Scler Relat
Disord 2021;54:103085. doi:10.1016/j.
msard.2021.103085
65 Brooker C, Goldman M, Tingen R, et al. Smoking
cessation considerations for people with
multiple sclerosis. Innov Pharm 2020;11(2):
10.24926/iip.v11i2.3210. doi:10.24926/iip.v11i2.3210
66 Liu Z, Zhang T, Yu J, et al. Excess body weight
during childhood and adolescence is associated
with the risk of multiple sclerosis: a meta-
analysis. Neuroepidemiology 2016;47(2):103-108.
doi:10.1159/000450854
67 Brenton N, Woolbright E, Briscoe-Abath C, et al.
Body mass index trajectories in pediatric multiple
sclerosis. Dev Med Child Neurol 2019;61(11):
1289-1294. doi:10.1111/dmcn.14233
68 Fitzgerald K, Salter A, Tyry T, et al. Measures of
general and abdominal obesity and disability
severity in a large population of people with
multiple sclerosis. Mult Scler 2020;26(8):
976-986. doi:10.1177/1352458519845836
69 Hedstrom A, Brenner N, Butt J, et al. Overweight/
obesity in young adulthood interacts with
aspects of EBV infection in MS etiology. Neurol
Neuroimmunol Neuroinflamm 2021;8(1):e912.
doi:10.1212/NXI.0000000000000912
CONTINUUMJOURNAL.COM
Copyright © American Academy of Neurology. Unauthorized reproduction of this article is prohibited.
70 Sender R, Fuchs S, Milo R, et al. Revised
estimates for the number of human and bacteria
cells in the body. PLoS Biol 2016;14(8):1002533.
doi:10.1371/journal.pbio.1002533
71 Mowry EM, Glenn JD. The dynamics of the gut
microbiome in multiple sclerosis in relation to
disease. Neurol Clin 2018;36(1):185-196.
doi:10.1016/j.ncl.2017.08.008
72 Cryan J, O’Riordan K, Sandhu K, et al. The gut
microbiome in neurological disorders. Lancet
Neurol 2020;19(2):179-194. doi:10.1016/S1474-
4422(19)30356-4
73 Dopkins N, Nagarkatti P, Nagarkatti M, et al.
The role of gut microbiome and associated
metabolome in the regulation of
neuroinflammation in multiple sclerosis and its
implications in attenuating chronic inflammation
in other inflammatory and autoimmune
disorders. Immunology 2018;154(2):178-185. doi:
10.1111/imm.12903
74 Sarasella M, Mendozzi L, Rossi V, et al.
Immunological and clinical effect of diet
modulation of the gut microbiome in multiple
sclerosis patients: a pilot study. Front Immunol
2017;8:1391. doi:10.3389/fimmu.2017.01391
75 Yadav V, Marracci G, Kim E, et al. Low-fat,
plant-based diet in multiple sclerosis: a
randomized controlled trial. Mult Scler Relat
Disord 2016;9:80-90. doi:10.1016/j.msard.2016.07.
001
76 Brenton JN, Banwell B, Bergqvist AGC, et al. Pilot
study of a ketogenic diet in relapsing-remitting
MS. Neurol Neuroimmunol Neuroinflamm 2019;
6(4):e565. doi:10.1212/NXI.0000000000000565
77 Fitzgerald K, Tyry T, Salter A, et al. Diet quality is
associated with disability and symptom severity
in multiple sclerosis. Neurology 2018;90(1):e1-e11.
doi:10.1212/WNL.0000000000004768
78 Salter A, Kowalec K, Fitzgerald K, et al.
Comorbidity is associated with disease activity in
MS: findings from the CombiRx trial. Neurology
2020;95(5):e446-e456. doi:10.1212/
WNL.0000000000010024
79 Nelson L, Bourdette D. Two decades of research:
time to incorporate comorbidity management
into the care of MS? Neurology 2020;95(5):
193-194. doi:10.1212/WNL.0000000000010036
80 Berrigan LI, Fisk JD, Patten SB, et al. Health-
related quality of life in multiple sclerosis: direct
and indirect effects of comorbidity. Neurology
2016;86(15):1417-1424. doi:10.1212/WNL.
0000000000002564
81 Marrie R, Patten S, Tremlett H, et al. Sex
differences in comorbidity at diagnosis of
multiple sclerosis: a population-based study.
Neurology 2016;86(14):1279-1286. doi:10.1212/
WNL.0000000000002481
82 Marrie RA, Rudick R, Horwitz R, et al. Vascular
comorbidity is associated with more rapid
disability progression in multiple sclerosis.
Neurology 2010;30;74(13):1041-1047. doi:10.1212/
WNL.0b013e3181d6b125.
1003
MS EPIDEMIOLOGY AND PATHOPHYSIOLOGY
83 Conway D, Thompson N, Cohen J. Influence of
hypertension, diabetes, hyperlipidemia, and
obstructive lung disease on multiple sclerosis
disease course. Mult Scler 2017;23:277-285.
doi:10.1177/1352458516650512
84 McKay KA, Tremlett H, Fisk JD, et al. Psychiatric
comorbidity is associated with disability
progression in multiple sclerosis. Neurology
2018;90(15):e1316-e1323. doi:10.1212/WNL.
0000000000005302
85 Tarrants M, Oleen-Burkey M, Castelli-Haley J,
Lage MJ. The impact of comorbid depression on
adherence to therapy for multiple sclerosis. Mult
Scler Int 2011;2011:271321. doi:10.1155/2011/271321
86 Mohr DC, Goodkin DE, Likosky W, et al. Treatment
of depression improves adherence to interferon
beta-1b therapy for multiple sclerosis. Arch
Neurol 1997;54(5):531-533. doi:10.1001/archneur.
1997.00550170015009
87 Zhang T, Tremlett H, Zhu F, et al. Effects of
physical comorbidities on disability progression
in multiple sclerosis. Neurology 2018;90(5):
e419-e427. doi:10.1212/WNL.0000000000004885
88 Zhang T, Tremlett H, Leung S, et al. Examining the
effects of comorbidities on disease-modifying
therapy use in multiple sclerosis. Neurology 2016;
86(14):1287-1295. doi:10.1212/WNL.
0000000000002543
89 Goldman M, Koenig S, Engel C, et al.
Glucocorticoid-associated blood glucose
response and MS relapse recovery. Neurol
Neuroimmunol Neuroinflamm 2017;4(5):e378. doi:
10.1212/NXI.0000000000000378
90 Khan O, Williams MJ, Amezcua L, et al. Multiple
sclerosis in US minority populations: clinical
practice insights. Neurol Clin Pract 2015;5(2):
132-142. doi:10.1212/CPJ.0000000000000112
91 Wallin M, Culpepper W, Coffman P, et al. The Gulf
War era multiple sclerosis cohort: age and
incidence rates by race, sex and service. Brain
2012;135(Pt 6):1778-1785. doi:10.1093/brain/
aws099
92 Langer-Gould A, Gonzales E, Smith J, Li B, Nelson
L. Racial and ethnic disparities in multiple
sclerosis prevalence [published ahead of print
April 28, 2022]. Neurology. doi:10.1212/
WNL.0000000000200151
93 Rivas-Rodríguez E, Amezcua L. Ethnic
considerations and multiple sclerosis disease
variability in the United States. Neurol Clin 2018;
36(1):151-162. doi:10.1016/j.ncl.2017.08.007
94 Kimbrough DJ, Sotirchos ES, Wilson JA, et al.
Retinal damage and vision loss in African
American multiple sclerosis patients. Ann Neurol
2015;77(2):228-236. doi:10.1002/ana.24308
95 Marrie R, Cuter G, Tyry T, et al. Does multiple
sclerosis-associated disability differ between
races? Neurology 2006;66(8):1235-1240. doi:10.
1212/01.wnl.0000208505.81912.82
1004
Copyright © American Academy of Neurology. Unauthorized reproduction of this article is prohibited.
96 Gray-Roncal K, Fitzgerald KC, Zhovtis Ryerson L,
et al. Association of disease severity and
socioeconomic status in Black and White
Americans with multiple sclerosis. Neurology
2021;97(9):e881-e889. doi:10.1212/
WNL.0000000000012362
97 Caldito N, Saidha S, Sotirchos E, et al. Brain and
retinal atrophy in African-Americans versus
Caucasian-Americans with multiple sclerosis: a
longitudinal study. Brain 2018;141(11):3115-3129.
doi:10.1093/brain/awy245
98 Amezcua L, McCauley JL. Race and ethnicity on
MS presentation and disease course. Mult Scler
2020;26(5):561-567. doi:10.1177/1352458519887328
99 Langer-Gould A, Brara SM, Beaber BE, Zhang J.
The incidence of clinically isolated syndrome in a
multi-ethnic cohort. J Neurol 2014;261:1349-1355.
doi:10.1007/s00415-014-7349-0
100 Amezcua L, Oksenberg JR, McCauley JL. MS in
self-identified Hispanic/Latino individuals living
in the US. Mult Scler J Exp Transl Clin 2017;3(3):
2055217317725103. doi:10.1177/2055217317725103
101 Ventura RE, Antezana AO, Bacon T, Kister I.
Hispanic Americans and African Americans
with multiple sclerosis have more severe
disease course than Caucasian Americans.
Mult Scler 2017;23(11):1554-1557. doi:10.1177/
1352458516679894
102 Amezcua L, Beecham AH, Delgado SR, et al.
Native ancestry is associated with optic neuritis
and age of onset in Hispanics with multiple
sclerosis. Ann Clin Transl Neurol 2018;5(11):
1362-1371. doi:10.1002/acn3.646
103 Romero-Hidalgo S, Flores-Rivera J, Rivas-Alonso,
et al. Native American ancestry significantly
contributes to neuromyelitis optica susceptibility
in the admixed Hispanic population. Sci Rep
2020;10:13706. doi:10.1038/s41598-020-69224-3
104 Saadi A, Himmelstein DU, Woolhandler S, Mejia
NI. Racial disparities in neurologic health care
access and utilization in the United States.
Neurology 2017;88(24):2268-2275. doi:10.1212/
WNL.0000000000004025
105 Cree B, Al-Sabbagh A, Bennett R, et al. Response
to interferon beta-1a treatment in African
American multiple sclerosis patients. Arch
Neurol 2005;62(11):1681-1683. doi:10.1001/
archneur.62.11.1681
106 Avasarala J. Inadequacy of clinical trial designs
and data to control for the confounding impact
of race/ethnicity in response to treatment in
multiple sclerosis. JAMA Neurol 2014;71(8):
943-944. doi:10.1001/jamaneurol.2014.79
107 Onuorah H, Charron O, Meltzer E, et al,
Enrollment of non-white participants and
reporting of race and ethnicity in phase III trials of
multiple sclerosis DMTs. Neurology 2022;98:
e880-e892. doi:10.1212/WNL.0000000000013230
AUGUST 2022
108 Khayambashi S, Salter A, Tyry T, et al. Gender
identity and sexual orientation affect health care
satisfaction, but not utilization. Mult Scler Relat
Disord 2020;37:101440. doi:10.1016/j.
msard.2019.101440
109 Young C, Tennant A, TONiC Study Group. Sexual
functioning in multiple sclerosis: relationships
with depression, fatigue and physical function.
Mult Scler 2017;23(9):1268-1275. doi:10.1177/
1352458516675749
110 Wang G, Marrie RA, Fox RJ, et al. Treatment
satisfaction and bothersome bladder, bowel,
sexual symptoms in multiple sclerosis. Mult Scler
Relat Disord 2018;20:16-21. doi:10.1016/j.
msard.2017.12.006
111 Wang Y, Tian F, Fitzgerald K, et al. Socioeconomic
status and race are correlated with affective
symptoms in multiple sclerosis. Mult Scler Relat
Disord 2020;41:102010. doi:10.1016/j.
msard.2020.102010
112 Harding KE, Wardle M, Carruthers R, et al.
Socioeconomic status and disability progression
in multiple sclerosis: a multinational study. Neurol
2019;92(13):e1497-e1506. doi:10.1212/
WNL.0000000000007190
113 Briggs FBS, Thompson NR, Conway DS, et al.
Prognostic factors of disability in relapsing
remitting multiple sclerosis. Mult Scler Relat
Disord 2019;30:9-16. doi:10.1016/j.msard.2019.
01.045
CONTINUUMJOURNAL.COM
Copyright © American Academy of Neurology. Unauthorized reproduction of this article is prohibited.
114 Calocer F, Dejardin O, Kwiatkowski A, et al.
Socioeconomic deprivation increases the risk of
disability in multiple sclerosis patients. Mult Scler
Relat Disord 2020;40:101930. doi:10.1016/j.
msard.2020.101930
115 Sadigh G, Lava N, Switchenko J, et al. Patient-
reported financial toxicity in multiple sclerosis:
predictors and association with care
non-adherence. Mult Scler 2021;27(3):453-464.
doi:10.1177/1352458520913977
116 Sadigh G, Switchenko J, Lava N, et al. Longitudinal
changes of financial hardship in patients with
multiple sclerosis. Mult Scler Relat Disord 2021;
53:103037. doi:10.1016/j.msard.2021.103037
117 Bebo B, Cintina I, LaRocca N, et al. Economic
burden of multiple sclerosis in the United States:
estimate of direct and indirect costs. Neurology
2022;98:e1810-e1817. doi:10:1212/
WNL.0000000000200150.
118 Hartung DM. Health economics of
disease-modifying therapy for multiple sclerosis
in the United States. Ther Adv Neurol Disord 2021;
14:1756286420987031. doi:10.1177/
1756286420987031
119 Adelman G, Rane SG, Villa KF, et al. The cost
burden of multiple sclerosis in the United States:
a systematic review of the literature. J Med Econ
2013;16(5):639-647. doi:10.3111/
13696998.2013.778268
120 Langer-Gould A, Klocke S, Beaber B, et al.
Improving quality, affordability, and equity of
multiple sclerosis care. Ann Clin Transl Neurol
2020;8(4):980-991. doi:10.1002/acn3.51326
1005