Condition

Multiple Sclerosis (MS) in Adults

Editors: Joseph R. Berger MD; Unsong Oh MD; Zbigniew Fedorowicz PhD, MSc, DPH, BDS, LDSRCS; Alexander Rae-Grant MD, FRCPC, FAAN

Produced in collaboration with American College of Physicians

Overview and Recommendations
Algorithms
Background Information
History and Physical
Diagnosis
Management
Complications
Prognosis
Prevention and Screening
Guidelines and Resources
Patient Information
References

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Background Information

Description

Multiple sclerosis is a chronic immune-mediated inflammatory disease of the central nervous system, typically characterized by episodes of limb weakness or numbness, impaired vision, poor coordination, and other neurologic deficits due to inflammation-induced demyelination and neuroaxonal injury. ^1
,2

Types

Clinically isolated syndrome (CIS) and radiologically isolated syndrome (RIS):
- CIS is the first clinical episode suggestive of a central nervous system inflammatory demyelinating disorder, which improves with or without treatment. CIS is reported to progress to MS in about 50% of patients.
- RIS refers to demyelination features on brain magnetic resonance imaging (MRI) that fulfill the imaging criteria of MS, but in the absence of any clinical features of the disease.
- See Clinically and Radiologically Isolated Syndromes for additional information.
Relapsing-remitting MS (reported in about 85% of patients with MS) is characterized by repeated episodes of neurologic symptoms and disability lasting ≥ 24 hours in the absence of fever or infection, followed by partial or complete recovery. ^1
,2
,3
- Symptoms of a relapse usually peak after several days or weeks, followed by a period of recovery lasting weeks or months.
- The typical age of onset is 25-29 years, but patients may present from the first to seventh decades of life.
Secondary progressive MS is reported to occur in about 80% of patients with relapsing-remitting MS within 20 years, in which neurologic symptoms begin to progress over time even in the absence of relapses (although relapses can be superimposed on progression). Conversion rates to secondary progressive MS may be lower in patient on newer disease-modifying therapies (J Neurol 2019 Jul 30).
Primary progressive multiple sclerosis (reported in about 15% of patients with MS) is characterized by slow and progressive accumulation of neurologic disability (most commonly gait impairment, but may also include sensory symptoms and sphincter dysfunction) starting at disease onset without a relapsing course. The typical age of onset is 39-41 years.^1
,2
Fulminant multiple sclerosis is a rare phenotype with a severe rapidly progressive course, resulting in significant disability or death in relatively short time after disease onset (Neurol Sci 2011 Oct;32(5):953).
The MS Phenotype Group recommended in 2013 that the diagnosis of relapsing-remitting, primary progressive, and secondary progressive MS include a current time-defined assessment of patient's disease activity and progression.
- Disease activity definitions (recommended to be assessed annually in most cases, but assessments can be performed at shorter or longer intervals as appropriate):
  - "Active" disease is defined by a clinical relapse and/or MRI activity (contrast-enhancing lesions; new or unequivocally enlarging T2 lesions) during the assessment period.
  - "Not active" disease is defined by the absence of relapses, gadolinium-enhancing activity, or new or unequivocally enlarging T2 lesions during the assessment period.
  - "Indeterminate" disease activity is applied to patients not assessed over a designated time frame.
- Disease progression definitions (recommended to evaluated annually by history or objective measures):
  - Disease "with progression" is defined by clinical disease progression during the assessment period.
  - Disease "without progression" is defined by lack of clinical disease progression during the assessment period.
- Reference - Neurology 2014 Jul 15;83(3):278

Epidemiology

Incidence/Prevalence

The typical ages of onset for MS are a mean age of 25-29 years for relapsing-remitting MS and a mean age of 39-41 years primary progressive MS.¹
Women are more likely to get MS than men (the reported female-to-male ratios are 2.3-3 to 1), as are persons residing further from equator (northern or southern latitudes) before adolescence.^1
,3
Pockets of high MS frequency occur in certain geographical regions such as Sardinia, Italy, and the Orkney and Shetland islands, UK (Mult Scler 2020 Mar;26(3):372, J Epidemiol Community Health 1980 Dec;34(4):229).
MS is the most frequent central nervous system (CNS) disease to cause permanent disability in young adults.¹
STUDY SUMMARY
global age-standardized incidence of MS in 2019 was 0.7 cases per 100,000 persons, with the highest incidences occurring in regions with a high socio-demographic index
POPULATION-BASED SURVEILLANCE: Front Public Health 2023;11:1073278
based on population-based surveillance

2019 Global Burden of Diseases, Injuries, and Risk Factors (GBD) study database was assessed for epidemiological data from multiple sclerosis from 1990-2019

59,345 incident cases of MS and 22,439 deaths attributed to MS occurred in 2019 globally

global age-standardized rate of incident MS in 2019
0.7 cases per 100,000 persons overall

higher with higher regional socio-demographic index (SDI) (indicating higher-income/higher-resource regions)
2.5 cases per 100,000 persons in high SDI regions

0.4 cases per 100,000 persons in middle SDI regions

0.4 cases per 100,000 persons in low SDI regions

Reference - Front Public Health 2023;11:1073278
STUDY SUMMARY
global prevalence of MS 30.1 cases per 100,000 persons in 2016
SYSTEMATIC REVIEW: Lancet Neurol 2019 Mar;18(3):269
Family_Medicine Internal_Medicine Neurologic_Disordersglobal prevalence of MS 30.1 cases per 100,000 persons in 2016 (Lancet Neurol 2019 Mar)09/05/2019 03:19:57 PM
based on systematic review of observational studies

systematic review of 167 observational studies published from 1990 to 2016 reporting on epidemiology of MS (from The Global Burden of Diseases, Injuries, and Risk Factors Study)

estimated prevalences calculated from Bayesian meta-regression framework DisMod-MR 2.1

global prevalence of MS 30.1 cases per 100,000 persons (95% uncertainty interval 27.5-33)

age-standardized prevalences of MS
highest in North America (164.6 cases per 100,000 persons), western Europe (127 cases per 100,000 persons), and Australasia (91.1 cases per 100,000 persons)

lowest in eastern sub-Saharan Africa (3.3 cases per 100,000 persons), central sub-Saharan Africa (2.8 cases per 100,000 persons), and Oceania (2 cases per 100,000 persons)

global age-standardized prevalence increased by 10.4% between 1990 and 2016

Reference - Lancet Neurol 2019 Mar;18(3):269
STUDY SUMMARY
estimated 10-year cumulative prevalence of MS 309.2 cases per 100,000 persons in United States in 2010; prevalences were highest in non-Hispanic White and non-Hispanic Black persons
POPULATION-BASED SURVEILLANCE: Neurology 2019 Mar 5;92(10):e1029POPULATION-BASED SURVEILLANCE: JAMA Neurol 2023 Jul 1;80(7):693
based on 2 population-based surveillance studies

analysis of administrative health claims datasets of adults in United States from 2008 to 2010, including Optum and Truven Health datasets (representing private health insurance) and Medicaid, Medicare, and the Department of Veteran Affairs (VA) datasets (representing public health insurance programs)
diagnostic algorithm defined MS as accumulation of ≥ 3 MS-related hospitalizations, outpatient visits, or prescriptions for MS disease-modifying therapy within 1-year period

cumulative 3-year prevalence determined for 2008-2010 which was adjusted to estimate cumulative 10-year prevalence

adjusted 10-year cumulative MS prevalence 309.2 per 100,000 persons (95% CI 308.1-310.1)

female-to-male prevalence ratio 2.8

adjusted 10-year prevalence by geographic region of United States
northeast 377.4 per 100,000 persons (95% CI 375.2-379.7)

midwest 353.1 per 100,000 persons (95% CI 351.1-355.2)

west 272.7 per 100,000 persons (95% CI 271-274.4)

south 272.6 per 100,000 persons (95% CI 271.2-273.9)

Reference - Neurology 2019 Mar 5;92(10):e1029

in a separate analysis of administrative health claims datasets of adults in United States from 2008 to 2010 (including the Optum dataset and Medicaid, Medicare, and the VA datasets, but excluding the Truven Health dataset from above), using an identical diagnostic algorithm and estimated cumulative 10-year prevalence calculations as above
10-year cumulative MS prevalence in 2010 (adjusted for uninsured persons) was
373.5 per 100,000 persons (95% CI 373.1-384.8) overall

by race and ethnicity:
non-Hispanic White 423.5 per 100,000 persons (95% CI 422.7-424.7)

non-Hispanic Black 358.1 per 100,000 persons (95% CI 355.7-360.6)

non-Hispanic other 247.1 per 100,000 persons (95% CI 244.5-245.6)

Hispanic 214.4 per 100,000 persons (95% CI 212.5-216.1)

Reference - JAMA Neurol 2023 Jul 1;80(7):693

Risk Factors

Genetic Risk Factors

Having a first-degree relative with MS is associated with an increased risk of developing MS. The is risk reported to be 2%-4%, compared to 0.1% in the general population (N Engl J Med 2018 Jan 11;378(2):169).
The concordance rate for MS in twins is reported to be 25% in monozygotic twins and 5.4% in dizygotic twins¹
Polymorphisms in several different classes of genes may be associated with slightly increased risk of MS, including:
- The immunity-related genes HLA-DR, IL2RA, IL4, IL6, IL12B, IL17R, IRF5, CD24, CD58, and EVI5
- The vitamin D metabolism genes VDR and CYP27B1
- The fibrinolysis gene PAI-1
- The central nervous system function and repair genes ApoE and DPP6
- Particular genes in mitochondrial DNA
- Reference - Cytokine 2018 Jun;106:154

Environmental and Lifestyle Risk Factors

Reduced Ultraviolet Light Exposure

Low levels of seasonal sunlight and exposure to ultraviolet (UV) light are associated with increased risk of MS. This suggests a possible association between low vitamin D levels and risk of MS.³
STUDY SUMMARY
higher UV-B light exposure, especially in childhood and adolescence, associated with decreased risk of MS
CASE-CONTROL STUDY: Neurology 2018 Apr 3;90(14):e1191
based on case-control study

151 women with MS (mean age at diagnosis 39 years) and 235 age-matched controls in the United States were evaluated via biennial questionnaires for lifetime ambient UV-B exposure (women from Nurses' Health Study)

ambient UV-B
estimated by composite measure based on latitude, altitude, and cloud cover according to patients' state of residence during period in question

grouped as low, medium, or high exposure based on tertiles from respective controls

98% of women self-identified as White

compared to low-exposure, high ambient UV-B exposure associated with lower risk of developing MS in adjusted analyses
for exposure at age 5-15 years, adjusted relative risk (RR) 0.49 (95% CI 0.27-0.9)

for exposure at other ages (birth, 16-20 years, and 21-30 years), there was a nonsignificant reduced risk (adjusted RR for each age group had upper limit of 95% CI ≤ 1.07)

high self-reported summer outdoor exposure in areas of high ambient UV-B exposure associated with lower risk of MS for most age groups
5-15 years (adjusted RR 0.45, 95% CI 0.21-0.96)

16-20 years (adjusted RR 0.54, 95% CI 0.27-1.06)

21-30 years (adjusted RR 0.36, 95% CI 0.15-0.88)

31-40 years (adjusted RR 0.18, 95% CI 0.05-0.71)

Reference - Neurology 2018 Apr 3;90(14):e1191
STUDY SUMMARY
birth in high-latitude regions and low maternal exposure to UV radiation in first trimester associated with increased risk of MS in offspring
COHORT STUDY: BMJ 2010 Apr 29;340:c1640
based on cohort study

1,524 patients with MS born in Australia between 1920 and 1950 were analyzed

increased risk of MS significantly associated with
lower ambient UV radiation in first trimester

region of birth (higher latitudes)

birth during November-December (vs. birth during May-June)

month of birth not associated with risk of MS after adjustment for ambient UV radiation exposure during early pregnancy

Reference - BMJ 2010 Apr 29;340:c1640

Smoking

Smoking is associated with an increased risk of MS, including an increased risk of conversion of clinically isolated syndrome to definite MS. Passive exposure to tobacco smoke also increases this risk (Continuum (Minneap Minn) 2022 Aug 1;28(4):988).
STUDY SUMMARY
current smoking, history of smoking, and passive exposure to smoke may each be associated with increased risk of MS
SYSTEMATIC REVIEW: PeerJ 2016;4:e1797
based on systematic review of observational studies

systematic review of 5 cohort and 21 case-control studies evaluating association between smoking and MS in 642,676 persons

0.13% prevalence of MS in cohort studies (601,492 persons)

compared to no reported exposure to smoking, increased risk of MS in persons
currently smoking or with history of smoking (odds ratio [OR] 1.55, 95% CI 1.48-1.62) in analysis of 24 studies

currently smoking (OR 1.83, 95% CI 1.42-2.37) in analysis of 7 studies

with history of smoking (OR 1.35, 95% CI 1.25-1.46) in analysis of 6 studies

with passive exposure to smoke (OR 1.24, 95% CI 1.03-1.49) in analysis of 4 studies

Reference - PeerJ 2016;4:e1797

Obesity

Childhood and adolescent obesity is associated with increased risk of pediatric and adult-onset MS, particularly in females (Continuum (Minneap Minn) 2022 Aug 1;28(4):988).
STUDY SUMMARY
self-reported overweight body type during childhood or young adulthood may each be associated with increased risk of MS in women
CASE-CONTROL STUDY: Obes Res Clin Pract 2014 Sep;8(5):e435
based on case-control study

1,235 adults with MS and 697 controls in northern California, United States were assessed via telephone interview for body weight characteristics at age 10 years and age 20 years, and height and highest and lowest nonpregnancy weights during ages 20-40 years
ethnicities other than White were not included

analyses excluded MS cases for which MS onset occurred during period being assessed (for example, cases of MS diagnosed at age ≤ 15 years were excluded from analyses evaluating association between weight characteristics during childhood and MS)

self-reported overweight body type at any age ≤ 30 years not associated with increased risk of MS in men in adjusted analyses

risk of MS in women evaluated with multivariate analyses controlling for year of birth, history of smoking, college education, history of infectious mononucleosis, and genotype (women without genotype data were excluded)

in women, factors associated with increased risk of MS in multivariate analyses include
overweight at age 10 years (adjusted odds ratio [OR] 1.63, 95% CI 1.21-2.21)

overweight at age 20 years (adjusted OR 1.7, 95% CI 1.21-2.39)

mean body mass index ≥ 30 kg/m²during age 20-29 years (adjusted OR 2.98, 95% CI 1.49-5.94)

body mass index at age 30-39 years not associated with increased risk of MS in women

Reference - Obes Res Clin Pract 2014 Sep;8(5):e435
STUDY SUMMARY
obesity at age 18-20 years associated with increased risk of MS
COHORT STUDY: Neurology 2009 Nov 10;73(19):1543
based on pooled analysis of 2 cohort studies

238,371 women from Nurses' Health Study and Nurses' Health Study II provided information on body size at ages 5, 10, and 20 years, weight at age 18 years, and weight and height at baseline

593 incident cases of MS reported over 40-year follow-up

factors associated with increased risk of MS
body mass index ≥ 30 kg/m² at age 18 years (p < 0.001)

large body size at age 20 years (p = 0.009)

no significant association between body mass later in adulthood and risk of MS

Reference - Neurology 2009 Nov 10;73(19):1543

Stress-related Disorder

STUDY SUMMARY
stress-related disorder associated with increased risk of MS
COHORT STUDY: JAMA 2018 Jun 19;319(23):2388
Neurologic_Disorders Pediatricsstress-related disorder associated with increased risk of MS (JAMA 2018 Jun 19)07/23/2018 12:23:00 PM29922828
based on retrospective cohort study

7,689,628 Swedish-born persons from National Patient Register were assessed for diagnosis of stress-related disorders from 1981 to 2014

106,464 patients (median age 41 years) with stress-related disorder, and 126,652 siblings of these patients and 1,064,640 age- and sex-matched persons without stress-related disorder were assessed for risk of autoimmune disease
persons developing stress-related disorders during follow-up were moved to exposed group

first year of follow-up after diagnosis of stress-related disorder was excluded from analysis

adjustment disorder and other stress reaction in 49.9%, acute stress reaction in 43.9%, and posttraumatic stress disorder in 6.2%

mean follow-up of 10 years

incidence of MS 0.381 per 1,000 person-years

incidence of autoimmune disease per 1,000 person-years
9.1 in patients with stress-related disorders

6.5 in siblings

6 in matched persons without stress-related disorder

compared to matched persons without stress-related disorder, persons with stress-related disorder had increased risk of
MS (adjusted hazard ratio 1.22, 95% CI 1.05-1.43)

autoimmune disease overall (adjusted hazard ratio 1.36, 95% CI 1.33-1.4)

Reference - JAMA 2018 Jun 19;319(23):2388

Epstein-Barr Virus

STUDY SUMMARY
Epstein-Barr virus (EBV) may be associated with an increased risk of developing MS, and there is some evidence to support a possible pathogenic contribution
NESTED CASE-CONTROL STUDY: Science 2022 Jan 21;375(6578):296
based on nested case-control study

801 active duty United States military personnel who had MS diagnosed after enrollment had their blood samples compared to samples from 1,566 similar United States military personnel without MS matched by age, sex, race or ethnicity, and date of collected samples
participant data from blood samples from Department of Defense Serum Repository (DoDSR) collected from 1993 to 2013

67% were male adults, 78% were < 26 years old when first blood sample was collected, 60% were White, 28% were Black, and 7.5% were Hispanic

up to 3 blood samples per person collected before MS onset (or equivalent date in matched control) were evaluated
earliest available sample (median of 10 years before MS symptom onset among persons with MS)

last sample collected before MS onset (median of 1 year before onset)

a sample from between those dates

800 of 801 persons with MS (99.9%) had positive test for EBV by last blood sample

EBV infection associated with increased risk of developing MS
compared to persistent negative EBV in all blood samples, risk of MS
higher with positive EBV at first sample (hazard ratio 26, p < 0.01)

higher with seroconversion to positive EBV at subsequent samples (hazard ratio 32, p < 0.001) among persons with negative EBV at first sample

among 33 persons with MS and 90 controls who had 3 samples and negative EBV in first sample, seroconversion to positive EBV by third blood sample in
97% of persons with MS (p < 0.001 vs. controls)

57% of controls

cytomegalovirus (CMV) infection not associated with MS
compared to persistent negative test for CMV in all blood samples, risk of MS lower with positive CMV at first sample (p < 0.01) and not altered with seroconversion to positive CMV at subsequent samples among persons with negative CMV at first sample

among 23 persons with MS and 60 controls who had 3 samples and negative EBV and CMV in first sample, seroconversion to positive CMV by third blood sample in 13% of persons with MS and 11.7% of controls (not significant)

serum neurofilament light chain (sNfL) levels higher after EBV infection among persons with MS but not in controls
analyses conducted in 25 persons with MS and 79 controls who had negative EBV in first sample and sNfL levels measured; reported values estimated from figures

mean sNfL levels in persons with MS higher compared to controls in samples taken after EBV infection (about 7.3 pg/mL vs. 6 pg/mL, p < 0.05) but no significant difference between groups in samples taken before EBV infection or around time of first EBV infection (about 5-6 pg/mL)

within-person change in sNfL after EBV infection vs. before EBV infection about 59% among persons with MS (p < 0.05) and 0% in controls

antibody response to EBV higher in persons with MS compared to controls
analyses conducted in 30 randomly selected persons with MS and 30 matched controls with blood samples collected ≤ 3 years before and ≤ 2 years after MS symptom onset (or equivalent date among controls)

blood samples were evaluated for antibodies against most known human pathogenic viruses via an agnostic search of the antivirome antibody response using VirScan

overall antibody response greater for viral peptides associated with EBV among persons with MS than for controls, but similar between groups for peptides associated with other viruses

Reference - Science 2022 Jan 21;375(6578):296, editorial can be found in Science 2022 Jan 21;375(6578):264

DynaMed Commentary
This study provides stronger evidence of a specific link between EBV infection and seroconversion and MS than previous studies. The increased levels of sNfL (a possible biomarker for pathogenic axonal degeneration) after EBV infection in persons with MS suggests that EBV may contribute to pathogenic processes involved with MS.
STUDY SUMMARY
infectious mononucleosis may be associated with increased risk of MS
SYSTEMATIC REVIEW: PLoS One 2010 Sep 1;5(9):e12496
based on systematic review of observational studies

systematic review of 4 cohort studies and 18 case-control studies evaluating association of MS and infectious mononucleosis

data included 19,390 patients with MS and 16,007 controls

infectious mononucleosis associated with MS
relative risk 2.17 (95% CI 1.97-2.39) in overall meta-analysis

relative risk 2.33 (95% CI 1.96-2.78) in analysis limited to 4 cohort studies

Reference - PLoS One 2010 Sep 1;5(9):e12496

Clinically and Radiologically Isolated Syndromes

Clinically isolated syndrome (CIS) refers to the first episode of symptoms and signs suggestive of an inflammatory demyelinating disorder of the central nervous system which improves with or without treatment. Presentations can involve the spinal cord, brainstem, optic nerve (optic neuritis), and the cerebral hemispheres.
- Radiologically isolated syndrome (RIS) is defined as demyelination features on brain MRI that fulfill magnetic resonance imaging criteria for MS without any clinical features of the disease.
- About 50% of patients with CIS will eventually progress to MS. Patients with RIS are also regarded at high risk for developing future MS; 30%-40% of patients diagnosed with RIS will experience 1 or more clinical events over the next 2-5 years, leading to diagnosis of either CIS or MS.
- Risk factors for progression to clinically definite MS include younger age, nonwhite ethnicity, ≥ 1 lesion in infratentorial regions on MRI, and presence of oligoclonal bands in cerebrospinal fluid (CSF).
- See Clinically and Radiologically Isolated Syndromes and Optic Neuritis for additional information.

Evidence Synopsis

Demyelinating CNS lesions on MRI in patients with CIS or in patients without any clinical signs (RIS) are associated with increased risk of eventual development of MS. CSF oligoclonal bands in patients with CIS are also predictive of eventual conversion to MS.

STUDY SUMMARY
63% of patients with CIS develop MS within 20 years, with highest rates associated with presence of CNS MRI lesion at baseline
COHORT STUDY: Brain 2008 Mar;131(Pt 3):808
based on prospective cohort study

107 patients (mean age 32 years, 66% women) with CIS were followed for mean of 20 years

CIS were optic neuritis (51%), brainstem syndrome (23%), or spinal cord syndrome (26%)

conversion to clinically definite MS in patients with CIS within 20-year follow-up
63% of all patients

21% of patients without CNS MRI lesions at baseline

82% of patients with 1 CNS MRI lesion at baseline (similar rates in patients with ≥ 2 lesions)

rates of MS conversion similar among different types of CIS

Reference - Brain 2008 Mar;131(Pt 3):808

similar rates of conversion to MS seen in 15-year follow-up of ONT trial (see summary here)
STUDY SUMMARY
presence of CSF oligoclonal bands and greater number of lesions on MRI associated with increased risk of progression to MS in patients with CIS
COHORT STUDY: Mult Scler 2015 Jul;21(8):1013
based on retrospective cohort study

1,047 patients (median age 32 years, 68% women) with CIS were assessed via medical records and analyses of stored serum samples and followed for ≥ 2 years (median of 4.3 years)
patients had serum, CSF, and MRI testing at CIS diagnosis

60% of patients were diagnosed with clinically definite MS at median of 3 years

factors associated with increased risk of conversion to MS in multivariable analysis include
presence of CSF oligoclonal bands (hazard ratio [HR] 2.18, 95% CI 1.71-2.77)

greater number of lesions on T2-weighted MRI
≥ 10 lesions (HR 2.74, 95% CI 2.04-3.68)

2-9 lesions (HR 1.97, 95% CI 1.52-2.55)

increased age of CIS onset associated with minimally reduced risk of conversion to MS (HR per 1-year increase 0.98, 95% CI 0.98-0.99)

Reference - Mult Scler 2015 Jul;21(8):1013
STUDY SUMMARY
spinal cord lesions on MRI associated with increased risk of conversion to clinically definite MS in patients with nonspinal CIS
COHORT STUDY: Neurology 2013 Jan 1;80(1):69
based on prospective cohort study

121 patients with CIS and spinal cord or brain symptoms were assessed with MRI of brain and spinal cord for diagnosis of MS using 2010 revisions to McDonald criteria

at baseline, 52% had symptoms attributable to spinal cord and 48% had symptoms attributable to brain

clinically definite MS defined as second episode of new symptoms occurring after ≥ 1 month not attributable to other disease

45.5% converted to clinically definite MS during median follow-up of 64 months

compared to no spinal cord lesion, presence of spinal cord lesion associated with increased risk of conversion to clinically definite MS
in overall analysis (odds ratio [OR] 3.53, 95% CI 1.52-8.17)

in patients with nonspinal CIS (OR 6.48, 95% CI 2.34-17.95)

in patients with nonspinal CIS who did not fulfill McDonald brain MRI criteria (OR 14.4, 95% CI 2.6-80)

no significant association between spinal cord lesions and conversion to clinically definite MS in subgroup analysis of patients with spinal CIS

Reference - Neurology 2013 Jan 1;80(1):69
STUDY SUMMARY
subclinical demyelinating lesions identified by MRI in asymptomatic patients associated with clinical conversion to MS in 33% within 5 years
COHORT STUDY: Arch Neurol 2009 Jul;66(7):841
based on cohort study

70 patients (mean age 35 years) with subclinical demyelinating lesions identified during first brain MRI for medical problems other than MS were analyzed

demyelinating lesions defined using Barkhof/Tintoré criteria

clinical conversion to symptomatic MS in 23 patients (33%) during 5-year follow-up
6 to optic neuritis

6 to myelitis

5 to brainstem symptoms

4 to sensory symptoms

1 to cerebellar symptoms

1 to cognitive deterioration

Reference - Arch Neurol 2009 Jul;66(7):841

Evidence Synopsis

Abnormal brain MRI is associated with an increased risk of conversion to MS in patients with optic neuritis. Other risk factors include oligoclonal bands in the CSF, preceding viral symptoms, incomplete recovery of visual acuity, visual evoked potential abnormalities, and normal optic disc appearance at presentation.

STUDY SUMMARY
MS developed within 15 years in 50% of patients with optic neuritis, with higher rates in patients with lesions at baseline brain imaging
COHORT STUDY: Arch Neurol 2008 Jun;65(6):727
based on prospective cohort study

389 patients with acute optic neuritis in Optic Neuritis Treatment Trial followed for up to 15 years

50% of patients developed MS within 15 years, including
25% with no lesions on baseline brain MRI

60% with 1 lesion (hazard ratio [HR] vs. no lesions 2.8, 95% CI 1.7-4.7)

68% with 2 lesions (HR 2.7, 95% CI 1.4-5)

78% with 3 lesions (HR 4.5, 95% CI 3-6.6)

among 179 patients with monofocal optic neuritis (no prior neuritis in other eye, no nonspecific neurologic symptoms, and no lesions on brain MRI), factors associated with increased risk of MS include female sex, preceding viral symptoms, and normal optic disc appearance

Reference - Arch Neurol 2008 Jun;65(6):727
STUDY SUMMARY
elevated permeability of blood brain barrier in normal-appearing white matter on dynamic contrast-enhanced MRI may help predict progression from optic neuritis to MS within 2 years
DIAGNOSTIC COHORT STUDY: Brain 2015 Sep;138(Pt 9):2571
based on diagnostic cohort study without independent validation

39 treatment-naive adults with optic neuritis had dynamic contrast-enhanced MRI within 28 days of symptom onset and were followed for up to 2 years

23 patients started disease-modifying treatment within 6 weeks of baseline visit

44% were diagnosed with MS by 2010 revised McDonald criteria (reference standard) within 2 years

permeability of blood brain barrier in normal-appearing white matter on MRI was increased in patients who progressed to MS vs. patients who did not progress (p = 0.004)

7 patients excluded from analysis (6 patients diagnosed with MS within 1 month of baseline and 1 patient lost to follow-up)

performance of permeability > 0.13 mL/100 g/minute on MRI for predicting development of MS
sensitivity 91%

specificity 71%

positive predictive value 63%

negative predictive value 94%

Reference - Brain 2015 Sep;138(Pt 9):2571

Factors Not Associated With Increased Risk

STUDY SUMMARY
no vaccines are associated with increased risk of MS
SYSTEMATIC REVIEW: J Neurol 2011 Jul;258(7):1197
based on systematic review of observational studies

systematic review of 14 studies (mostly case-control) evaluating association between immunization and risk of MS

no vaccines were associated with an increased risk of MS

vaccines not associated with an altered risk of MS include
hepatitis B (odds ratio [OR] 1, 95% CI 0.74-1.37) in analysis of 6 studies with 50,117 patients with MS and 140,333 controls

influenza (OR 0.97, 95% CI 0.77-1.23) in analysis of 4 studies with 14,997 patients with MS and 10,128 controls

measles, mumps, and rubella (OR 1.02, 95% CI 0.64-1.61) in analysis of 3 studies with 676 patients with MS and 1,879 controls

polio (OR 0.87, 95% CI 0.61-1.25) in analysis of 7 studies with 570 patients with MS and 725 controls

tuberculosis (bacille Calmette-Guerin [BCG] vaccine) (OR 0.96, 95% CI 0.69-1.34) in analysis of 6 studies with 536 patients with MS and 751 controls

typhoid fever (OR 1.05, 95% CI 0.72-1.53) in analysis of 4 studies with 393 patients with MS and 529 controls

vaccines associated with a reduced risk of MS include
diphtheria (OR 0.6, 95% CI 0.4-0.9) in analysis of 3 studies with 237 patients with MS and 387 controls

tetanus (OR 0.68, 95% CI 0.54-0.84) in analysis of 8 studies with 5,526 patients with MS and 1,680 controls

vaccines with an unclear risk (due to heterogeneity or evaluation in ≤ 1 study) include chickenpox (varicella); diphtheria, pertussis, tetanus (DPT); haemophilus influenza B; hepatitis A; human papillomavirus V (HPV); Japanese encephalitis; measles; meningococcal; mumps; pertussis; pneumococcal; rabies; and yellow fever

Reference - J Neurol 2011 Jul;258(7):1197
STUDY SUMMARY
traumatic injury not associated with increased risk of MS
SYSTEMATIC REVIEW: Can J Neurol Sci 2013 Mar;40(2):168
based on systematic review

16 observational studies (13 case-control studies and 3 cohort studies) evaluating association between traumatic injury and onset of MS reviewed

traumatic injury not associated with increased risk of MS in analysis of
8 case-control studies of moderate methodologic quality

3 cohort studies of moderate-to-high methodologic quality

Reference - Can J Neurol Sci 2013 Mar;40(2):168

Hormonal and Reproductive Risk Factors

Evidence Synopsis

A history of pregnancy, longer duration of breastfeeding, and later age of menarche have all been associated with a reduced likelihood or risk for developing MS. However, none of these factors appear to reduce the risk of progression to MS in patients who already have a clinically isolated syndrome. There is no clear evidence that oral contraceptive use is associated with risk for multiple sclerosis.

STUDY SUMMARY
history of pregnancy associated with decreased likelihood of MS; association of oral contraceptive use with MS is unclear
CASE-CONTROL STUDY: Int J Prev Med 2022;13:89
based on systematic review of case-control studies

systematic review of 4 case-control studies evaluating pregnancy history and oral contraceptive use in the risk of MS

history of pregnancy associated with decreased likelihood of MS compared to no history of pregnancy (pooled odds ratio 0.64, 95% CI 0.53-0.78) in analysis of 3 studies

oral contraceptive use not associated with altered likelihood of MS compared to no use (pooled odds ratio 1.09, 95% CI 0.67-1.76) in analysis of 4 studies, results limited by significant heterogeneity

Reference - Int J Prev Med 2022;13:89
STUDY SUMMARY
longer duration of breastfeeding and later age of menarche associated with decreased risk of MS or CIS
CASE-CONTROL STUDY: Neurology 2017 Aug 8;89(6):563
based on case-control study

397 women with MS or CIS with symptom onset ≤ 3 years previous and 433 controls were evaluated via interview

all women were members of Kaiser Permanente Southern California health plan; controls were matched for age, race/ethnicity, and healthcare facility (surrogate for socioeconomic status)

factors associated with reduced risk of MS or CIS
cumulative duration of breastfeeding ≥ 15 months compared to duration of 0-4 months (adjusted odds ratio 0.47, 95% CI 0.28-0.77) in 501 women who had live births

age of menarche ≥ 15 years compared to ≤ 11 years (adjusted odds ratio 0.56, 95% CI 0.33-0.96)

Reference - MS Sunshine Study (Neurology 2017 Aug 8;89(6):563)
STUDY SUMMARY
later age of menarche associated with slightly decreased risk of MS in women who had ≥ 1 pregnancy
COHORT STUDY: Am J Epidemiol 2017 Apr 15;185(8):712
based on prospective cohort study

77,330 pregnant women in Denmark (mean age 29 years) were assessed via interview for age of menarche and followed for mean of 11.7 years (from Danish National Birth Cohort 1996-2002)

0.29% of women developed MS

increased menarcheal age associated with decreased risk of MS (for each 1-year increase, adjusted hazard ratio 0.89, 95% CI 0.81-0.98)

Reference - Am J Epidemiol 2017 Apr 15;185(8):712
STUDY SUMMARY
age of menarche, pregnancy, and breastfeeding not associated with altered risk of progression to MS or long-term disability in women with CIS
COHORT STUDY: Neurology 2019 Mar 26;92(13):e1507
based on retrospective cohort study

501 women (mean age 31 years) with CIS completed survey regarding reproductive information after mean follow-up of 9.5 years

an additional 207 women who were eligible but did not complete survey were less likely to have findings on brain imaging, be taking disease-modifying therapy, and have shorter follow-up

61% of women were diagnosed with MS using McDonald 2010 criteria by end of follow-up

age of menarche, pregnancy, and breastfeeding were not significantly associated with altered risk of progression to MS or risk of long-term disability in adjusted time-dependent analysis

Reference - Neurology 2019 Mar 26;92(13):e1507

Associated Conditions

Type 1 Diabetes

STUDY SUMMARY
MS associated with increased likelihood of type 1 diabetes
COHORT STUDY: Mult Scler Relat Disord 2018 Jan;19:109
based on retrospective cohort study

472,139 patients from hospital registry in southwest Finland were assessed from 2004 to 2012

1,074 patients with MS (71% women) were compared to about 10,740 age- and sex-matched controls

comparing patients with MS vs. controls
type 1 diabetes in 1.9% vs. 0.9% (odds ratio 2.11, 95% CI 1.32-3.36)

type 2 diabetes in 3.6% vs. 3.6% (odds ratio 1, 95% CI 0.72-1.38)

Reference - Mult Scler Relat Disord 2018 Jan;19:109

Migraine

STUDY SUMMARY
MS associated with increased likelihood of migraine
SYSTEMATIC REVIEW: PLoS One 2012;7(9):e45295
based on systematic review of observational studies

systematic review of 8 studies (7 case-control, 1 cohort study) evaluating association between MS and migraine in 1,864 patients with MS and 261,563 control patients without neurologic condition

compared to controls, patients with MS had increased risk of
migraine (odds ratio 2.6, 95% CI 1.12-6.04)

migraine without aura (odds ratio 2.29, 95% CI 1.14-4.58)

Reference - PLoS One 2012;7(9):e45295

Restless Legs Syndrome

STUDY SUMMARY
MS associated with restless legs syndrome (RLS)
SYSTEMATIC REVIEW: Eur J Neurol 2013 Apr;20(4):605
based on systematic review of observational studies

systematic review of 10 case-control and 14 cross sectional studies evaluating association between MS and RLS

RLS in 12.1%-57.5% of patients with MS and 2.6%-18.3% of patients without MS in individual studies (pooled analysis not conducted due to high statistical heterogeneity)

MS associated with increased likelihood of RLS (odds ratio 3.94, 95% CI 2.81-5.54) in analysis of 8 studies with 70,385 patients

Reference - Eur J Neurol 2013 Apr;20(4):605

Inflammatory Bowel Disease

STUDY SUMMARY
MS associated with increased likelihood of inflammatory bowel disease (IBD)
SYSTEMATIC REVIEW: J Neurol 2017 Feb;264(2):254
based on systematic review of case-control studies

systematic review of 10 case-control studies evaluating association between MS and IBD in 84,330 patients with IBD matched with 441,537 controls and 58,074 patients with MS matched with 502,489 controls

MS was associated with increased likelihood of IBD (pooled risk ratio 1.54, 95% CI 1.4-1.67)

Reference - J Neurol 2017 Feb;264(2):254

Psoriasis

STUDY SUMMARY
MS associated with increased likelihood of psoriasis
SYSTEMATIC REVIEW: Am J Clin Dermatol 2019 Apr;20(2):201
based on systematic review of observational studies

systematic review of 5 case-control, 4 cross-sectional, and 2 cohort studies evaluating association between MS and psoriasis in 43,643 patients with MS and 1,097,374 controls

MS associated with increased likelihood of psoriasis
odds ratio 1.29 (95% CI 1.14-1.45) in analysis of 5 case control and 4 cross-sectional studies

hazard ratio 1.92 (95% CI 1.32-2.8) in analysis of 2 cohort studies (results limited by significant heterogeneity)

Reference - Am J Clin Dermatol 2019 Apr;20(2):201

Etiology and Pathogenesis

Causes

The pathology of MS is initiated by aberrant immune processes, the overall causes of which are unknown but likely involve a multifactorial etiology, with genetically susceptible individuals being exposed to triggering environmental factor(s).^1
,2

Pathogenesis

The precise pathogenesis of MS unclear, but proposed mechanisms involve aberrant immune processes leading to acute and long-term damage.⁵
- Environmental exposures lead to aberrant immune processes involving T-lymphocytes, B-lymphocytes, and innate mechanisms in genetically predisposed individuals.
- The aberrant immune processes access the central nervous system (CNS) and initiate pathological events that result in demyelination, neuroaxonal degeneration, synaptic loss, dying-back oligodendrogliopathy, tissue loss, and astrogliosis
- Downstream immunopathogenic and other events lead to demyelinated areas in both white and gray matter that may indicate loss of oligodendrocytes, loss of myelin sheaths, and astrocytic scars.
- Inflamed areas are associated with blood-brain barrier breakdown and appear as gadolinium-enhancing lesions on MRI
- Relapses are thought to be caused by similar immune processes in eloquent areas of the CNS.
Axonal injury is also present (although is less apparent than demyelination) even at early stages of the disease, and contributes to physical and cognitive disability.
- Neuronal and axonal damage thought to be triggered by the release of damaging molecules by immune cells, excitotoxicity, cytokine release, and reactive oxygen and nitrogen species.
- Demyelination leads to ion channel redistribution and aberrant ion channel expression on axons.
- These events lead to oxidative stress and mitochondrial dysfunction (resulting in "virtual hypoxia" and energy deficiency), leading to calcium influx activation of degrading enzymes, and eventual apoptotic and necrotic neuronaxonal damage.⁵
- Reference - ⁵, Handb Clin Neurol 2014;122:89
MS usually has a long preclinical period with silent lesions on magnetic resonance imaging (MRI) at the time of clinical onset, and patients may show subtle deficits on clinical testing years before symptom onset.⁵
The pathogenic and neurologic effects of aberrant immune processes may worsen over time due to incomplete repair of immune-mediated damage, activation of innate immunity in the CNS, oxidative damage, abnormal energy metabolism, and the development of lymphoid follicle-like structures in the meninges.⁵
The Epstein-Barr virus may be associated with an increased risk of developing MS, and there is some evidence to support a possible pathogenic contribution. See evidence summary for details.
Immune processes may play a smaller role in pathogenesis of progressive stage of MS. Proposed mechanisms of this stage include age-related changes in the injured CNS and ongoing sequestered intrathecal inflammation in the form of meningeal lymphoid aggregates and/or activation of CNS innate immunity (microglial cells in particular).⁵
Areas of the CNS that are frequently affected in MS include periventricular and juxtacortical white matter, cortical gray matter, the cerebellum, the meninges (meningeal B-cell follicles may act as sites of smoldering subarachnoid antibody production), the optic nerves, and the spinal cord.¹
Image 1 of 2
Chronic multiple sclerosis
Non-inflammatory cortical demyelination is prominent in chronic MS. (A) Cortical demyelination in the cingulate gyrus (PLP, scale bar = 5 mm); (B) Cortical demyelination in the frontal lobe (PLP, scale bar = 5 mm); (C) Cortical demyelination in the hippocampus (PLP, scale bar = 2.5 mm); (D) Although the occipital lobe is less frequently affected, cortical demyelination can be very extensive in the occipital lobe of some MS patients (PLP, scale bar = 5 mm). Abbreviations: MS, multiple sclerosis; PLP, proteolipid protein.

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Condition

Multiple Sclerosis (MS) in Adults

Background Information

Description

Types

Epidemiology

Incidence/Prevalence

Details

Details

Details

Risk Factors

Genetic Risk Factors

Environmental and Lifestyle Risk Factors

Reduced Ultraviolet Light Exposure

Details

Details

Smoking

Details

Obesity

Details

Details

Stress-related Disorder

Details

Epstein-Barr Virus

Details

Details

Clinically and Radiologically Isolated Syndromes

Details

Details

Details

Details

Details

Details

Factors Not Associated With Increased Risk

Details

Details

Hormonal and Reproductive Risk Factors

Details

Details

Details

Details

Associated Conditions

Type 1 Diabetes

Details

Migraine

Details

Restless Legs Syndrome

Details

Inflammatory Bowel Disease

Details

Psoriasis

Details

Etiology and Pathogenesis

Causes

Pathogenesis

Images

Videos

Algorithms

Related Topics

DynaMed Levels of Evidence

Quickly find and determine the quality of the evidence.

1Level 1 (likely reliable) Evidence

2Level 2 (mid-level) Evidence

3Level 3 (lacking direct) Evidence

Grades of Recommendation