See discussions, stats, and author profiles for this publication at: https://www.researchgate.

net/publication/327945310

Neurology Board Review: Multiple Sclerosis

Article · June 2018

CITATIONS READS
0 1,577

2 authors, including:

Michael John Bradshaw

Rosalind Franklin University of Medicine and Science
45 PUBLICATIONS   216 CITATIONS   

SEE PROFILE

Some of the authors of this publication are also working on these related projects:

Neurosarcoidosis View project

Rocky Mountain spotted fever encephalitis View project

All content following this page was uploaded by Michael John Bradshaw on 28 September 2018.

The user has requested enhancement of the downloaded file.

Neurology Neurology
Board Review
MULTIPLE SCLEROSIS

Board Review
JUNE 2018

MULTIPLE SCLEROSIS

June 2018 S1

A SUPPLEMENT TO NEUROLOGY REVIEWS

NR_MS Board Review Supplement 2018_v10.indd 1 5/24/18 11:35 AM

 T:7.875”
B:8.125”
S:7.325”
T:7.875”
S:7.325”

In Multiple Sclerosis–
In Multiple Sclerosis–
THE ART OF BRAIN PRESERVATION
THE ART
Adding Grey OF
to the BRAIN
Palette CompletesPRESERVATION
the Picture
Adding Grey to the Palette Completes the Picture
GREY MATTERS, TOO
GREY MATTERS, TOO

T:10.5”
S:10”
T:10.5”
S:10”

Learn more about Multiple Sclerosis at MSBrainPreservation.com/art

Learn more about Multiple Sclerosis
© 2018 Celgene Corporation at MSBrainPreservation.com/art
All rights reserved. 04/18 USII-CELG180103

© 2018 Celgene Corporation All rights reserved. 04/18 USII-CELG180103

NR_MS Board Review Supplement 2018_v10.indd 2 5/24/18 11:35 AM

N Neurology
N Board Review
MULTIPLE SCLEROSIS
MICHAEL J. BRADSHAW, MD
Clinical Fellow in Neurology
Partners Multiple Sclerosis Center
Brigham and Women’s Hospital
Massachusetts General Hospital
Harvard Medical School
Boston, Massachusetts
INTRODUCTION
Multiple sclerosis (MS) is the most common immune-mediated
demyelinating disease of the central nervous system (CNS) and
is the most common nontraumatic cause of disability among
young adults, with enormous societal implications.1,2 MS affects
approximately 400,000 persons in the United States (prevalence
of 90 per 100,000 population) and nearly 2.5 million persons
worldwide.3 Women are affected 3 times more often than men
and the median age of diagnosis is 30 years, with approximately
5% of patients presenting before age 18 years (pediatric-onset
B:10.75”
MS) or after age 50.4,5 The precise etiopathogenesis remains
T:10.5”
S:10”
unclear, but MS appears to develop in individuals with specific
B:10.75”
T:10.5”
S:10”
genetic predispositions in response to certain environmental
factors.6 Genome-wide association studies have identified more
than 200 gene variants that influence the risk for MS, most of
which are associated with immune pathways. Individuals with
a first-degree relative with MS have a 3% to 5% risk for devel-
oping the disease, while monozygotic twins have a 20% to
39% risk for MS, compared to a 0.1% risk in the general popula-
tion.7–9 Environmental risk factors include greater distance from
the equator (which may be related to decreased sunlight and/
or vitamin D concentrations), tobacco exposure, diet, obesity,
and infectious agents such as the Epstein-Barr virus.10 The influ-
ence of the intestinal microbiome on the risk of MS is an area of
active investigation.11
The diagnosis of MS requires demonstration of disease
dissemination in space (disease-related changes in multi-
ple neuroanatomic localizations) and time (multiple episodes
or the development of lesions over time), and the exclusion
of alternative etiologies such as infection, malignancy, and
other immune-mediated disorders that can affect the CNS
(Table 1).12,13 Magnetic resonance imaging (MRI) has revolu-
tionized the diagnosis and management of patients with MS,
and MRI findings correlate well with pathological changes.14
DISCLOSURES: The authors have no financial relationships to disclose.
Cover image: © Evan Oto/Science Source Images
© 2018 Frontline Medical Communications Inc.
NR_MS Board Review Supplement 2018_v10.indd 3
MARIA K. HOUTCHENS, MD, MMSC
Director, Women’s Health Program
Partners Multiple Sclerosis Center
Brigham and Women’s Hospital
Harvard Medical School
Boston, Massachusetts
Historically, MS was considered a disease of the white mat-
ter, but it is now well recognized that both the white and gray
matter are involved,15 and in addition to focal lesions, there is
whole brain atrophy thought to reflect more global processes at
work, though these remain poorly understood.
MS can be classified based on clinical disease course,
disease activity, and neuropathological involvement of spe-
cific CNS compartments. In the 1990s, 4 clinical phenotypes
were described:16
• Relapsing-remitting
• Secondary progressive
• Primary progressive
• Progressive relapsing
These phenotypes are still commonly referenced, but were
updated in 2013 (Table 2) to better reflect the contemporary
understanding of MS, which incorporates both inflammatory
(active/relapsing MS) and neurodegenerative (progressive
MS) aspects.17 In the 2013 update, relapsing and progressive
MS were given modifiers (Table 2).
Most patients (85%) develop active relapsing MS at the
onset of their illness, typified by multiple discrete exacerbations
of focal neurologic deficits that typically develop and prog-
ress over hours to days and persist without abating for at least
24 hours and up to several months before gradual resolution.17
There is a variable degree of recovery, and approximately 30%
of relapses leave residual deficits that contribute to long-term
disability.18 The focal neurologic syndrome for each exacer-
bation depends upon the specific neuroanatomic structures
affected by active lesion(s), which are focal areas of inflamma-
tion, demyelination, axonal loss, and glial reaction.19
The clinical manifestations of MS are widely variable
and may include:
• Sensory changes: dysesthesias, paresthesias, hypoes-
thesia, pain
June 2018 S3
5/24/18 11:35 AM
 Neurology
Board Review
MULTIPLE SCLEROSIS

TABLE 1. 2017 McDonald Criteria for the TABLE 2. Clinical Description of Subtypes of
Diagnosis of Multiple Sclerosis Multiple Sclerosis
Clinical Additional Data Needed 1996 Clinical 2013 Clinical
Presentation for Diagnosis Description of Subtypes Description of Subtypes
≥ 2 clinical attacks and None Relapsing-remitting Clinically isolated syndrome
objective evidence of multiple sclerosis - Activea
≥ 2 lesions - With full recovery from - Not active
≥ 2 clinical attacks and DIS: an additional attack relapses
objective evidence of implicating a different CNS site - Without full recovery Relapsing-remitting multiple
1 lesion OR by MRIa
sclerosis
- Active
- Not active
1 clinical attack and DIT: an additional clinical attack
objective clinical evidence OR by MRIb Progressive disease Primary progressive disease
of ≥ 2 lesions OR - Primary progressive - Active and with progressionb
multiple sclerosis - Active but without progression
CSF-specific oligoclonal bands
- Secondary progressive - Not active but with progression
1 clinical attack and DIS: an additional clinical attack multiple sclerosis - Not active and without
objective evidence implicating a different CNS site - Progressive relapsing progression (stable disease)
of 1 lesion OR by MRIa multiple sclerosis
OR
Progressive after initially
DIT: an additional clinical attack
relapsing course
OR by MRIb
- Active and with progression
OR
- Active but without progression
CSF-specific oligoclonal bands
- Not active but with progression
Adapted from Thompson AJ, Banwell BL, Barkhof F, et al. Diagnosis of multiple sclerosis: - Not active and without
2017 revisions of the McDonald criteria. Lancet Neurol. 2018;17:162–73. progression (stable disease)
Abbreviations: CNS, central nervous system; CSF, cerebrospinal fluid; DIS, disseminated
in space; DIT, disseminated in time; MRI, magnetic resonance imaging.
a
DIS by MRI: new lesions on follow-up imaging or both gadolinium-enhancing and Adapted from Lublin FD, Reingold SC, Cohen JA, et al. Defining the clinical course of
non-enhancing lesions on single MRI. multiple sclerosis: the 2013 revisions. Neurology. 2014;83:278–86.
b
DIS by MRI: ≥ 1 symptomatic or asymptomatic lesion in ≥ 2 areas including cortical/
a
Active is defined by the presence of clinical relapses and/or magnetic resonance
juxtacortical, periventricular, infratentorial, or spinal. imaging activity (gadolinium-enhancing lesions, new or unequivocally enlarging
T2 lesions).
b
Progressive disease is defined by the steady accumulation of clinical neurologic
dysfunction/disability without unequivocal recovery.
• Weakness: typically upper motor neuron pattern
monoparesis, hemiparesis, or paraparesis
• Incoordination: cerebellar or sensory ataxia, decreased setting of overheating (Uhthoff phenomenon) or systemic
fine motor skills, impaired gait illness and is sometimes called pseudorelapse. An eloquent
• Cranial nerve deficits: vision loss (optic neuritis), topographical model of MS was proposed in 2016 that pro-
diplopia, trigeminal neuralgia vides a unified description of MS across phenotypes.20
• Cognitive impairment: attention and memory deficits, Neuropathologically, several basic histological pro-
bradyphrenia, fatigue cesses drive the formation and evolution of MS lesions
• Bowel and bladder dysfunction: urgency, frequency, (ie, plaques): inflammation, myelin breakdown, astroglio-
retention, sphincter dyssynergia sis, oligodendrocyte injury, axonal loss, neurodegeneration,
As persons with MS age and undergo immunosenes- and remyelination. Inflammation is present in all phases of
cence, most have fewer relapses/new lesions. However, the disease and all lesion types, but its severity decreases
many with relapsing MS develop progressive MS a decade or with patient age and disease duration. MS lesions evolve
2 after diagnosis. As neurological reserve/resilience decreases differently in early and chronic phases of the disease, with
with age, recovery and the ability to compensate for prior active lesions predominant early in the disease, while in
neurologic damage is hindered, and patients may develop later phases, smoldering, inactive, and remyelinated lesions
progressive decline in function, or secondary progressive MS (“shadow plaques”) predominate.21 Acute active plaques
(SPMS). In contrast, patients with primary progressive MS are hypercellular demyelinated lesions massively infil-
(PPMS) usually present at an older age and have a steady, trated by macrophages, with perivascular and parenchymal
progressive deterioration with few or no relapses/new inflammatory infiltrates composed predominantly of CD8+
lesions from the beginning of the illness. Transient recrudes- cytotoxic T cells and, to a lesser extent, CD4+ helper T cells.19
cence or unmasking of subclinical deficits can develop in the B cells and plasma cells accumulate in the perivascular

S4 June 2018

NR_MS Board Review Supplement 2018_v10.indd 4 5/24/18 11:35 AM


space.19 The damaged blood-brain barrier, identifiable on
MRI as gadolinium enhancement, allows increased infiltra-
tion of immune cells.
Chronic plaques are more often seen in progressive
MS and include both active and inactive lesions. Chronic
inactive plaques are well-demarcated demyelinated lesions
with loss of axons, oligodendrocytes, astrogliosis and minor
infiltration with macrophages, microglia, and lymphocytes.
Chronic active plaques are well-circumscribed demyelin-
ated lesions with myelin-laden macrophages concentrated
at the centrifugally expanding lesion edges with an inactive
hypocellular core. Smoldering lesions are slowly expanding
with a rim of activated microglia that contain few myelin
degradation products and have an inactive core.
Herein, we review the clinical manifestations, differential
diagnosis, diagnostic approach, treatment options, and progno-
sis of MS through a series of cases with a range of presentations.
RADIOLOGICALLY ISOLATED SYNDROME
Case Presentation 1
A 34-year-old woman with a history of migraines presents
with a change in her headache pattern concerning for low-
pressure headaches. She undergoes brain MRI as well as lumbar
puncture with cerebrospinal fluid (CSF) analysis. She has never
had an episode suggesting an MS exacerbation, but brain MRI
(Figure 1) demonstrates multiple lesions suggestive of MS.
She is referred to an MS specialist for evaluation. CSF analysis
reveals 8 nucleated cells (95% lymphocytes) and the presence
of 6 unmatched oligoclonal bands but is otherwise normal.
What neuroimaging features are seen in MS?
Neuroimaging features of MS include T2/fluid-attenuated
inversion recovery (FLAIR) hyperintense lesions and T1
gadolinium-enhancing lesions in the brain, brainstem, and
spinal cord, as well as T1 hypointense brain lesions and
atrophy.22 Typically, the T2 hyperintense lesions seen in MS
are oval to ovoid in morphology and greater than 5 mm in
diameter. Many patients develop finger-like T2 hyperin-
tense periventricular lesions oriented perpendicularly to the
ventricles known as Dawson’s fingers. These often involve
the corpus callosum and are the hallmark lesions of MS.
A central vein may be identified on MRI, which can help
to distinguish MS from cerebrovascular disease, inflammatory
CNS vasculopathies, and aquaporin-4 (AQ-4) antibody–
positive neuromyelitis optica spectrum disorder (NMOSD).23–25
In contrast, nonspecific lesions are punctate (< 3 mm), round,
and subcortical and can be seen in a number of causes of inflam-
mation, demyelination, gliosis, edema, Wallerian degeneration,
and axonal damage.21
T1 gadolinium-enhancing lesions reflect active disrup-
tion of the blood-brain barrier and infiltration of inflammatory
lymphocytes into the parenchyma. MS lesions enhance for an
average of 3 weeks in the absence of treatment.26 A subset of
NR_MS Board Review Supplement 2018_v10.indd 5
Neurology
Board Review
MULTIPLE SCLEROSIS
A1 B1 C1 D1
A2 B2 C2 D2
FIGURE 1. Brain and spine magnetic resonance imaging (MRI)
findings in Case 1 include 2 T2/FLAIR hyperintense periventricular
lesions oriented perpendicularly to the ventricles (A1, C1) suggestive
of multiple sclerosis lesions (Dawson’s fingers). There are also
2 nonspecific periventricular lesions in the right parietal area (B1)
and several juxtacortical lesions (not shown). All lesions correlate
with T1 hypointense “black holes” (A2, B2, C2), none of which
are gadolinium-enhancing. MRI of the spine demonstrates 2
T2 hyperintense intramedullary cord lesions at T1 (D1) and T4 (D2).
T2 hyperintense lesions appear hypointense on non-contrast
T1-weighted sequences, colloquially known as “black holes.”
In the acute setting, these are nonspecific pathologically and
may resolve or persist over time. When they persist for more
than 6 to 12 months, they reflect irreversible demyelination
and axonal loss and correlate more closely with clinical
disability than T2 hyperintense lesions.27
Atrophy can be detected in both the brain and spinal cord
of patients with MS and correlates with axonal loss, neuronal
loss, and neurologic disability.28–30 Regional and whole-brain
atrophy serve as reliable biomarkers of disease severity and
progression31 and are clinically relevant, but are not yet rou-
tinely incorporated into MRI metrics in clinical practice.
What is radiologically isolated syndrome?
What is the risk for progression to a first clinical event,
and what factors contribute to that risk?
Radiologically isolated syndrome (RIS) refers to inciden-
tally identified lesions on brain MRI that are suggestive
of MS, but which occur in a patient who has not had any
events consistent with demyelinating disease and who
has no other identifiable etiology for the abnormalities.32
Neurologists are frequently asked to evaluate patients with
incidentally discovered MRI findings that might suggest
MS. Often the MRI findings are nonspecific and do not
suggest an underlying demyelinating disease; however, in
some cases lesions are highly suggestive of MS. The diag-
nostic criteria for MS cannot be applied to patients with
RIS because these patients lack a clinical syndrome sug-
gesting a demyelinating event. Separate diagnostic criteria
for RIS were proposed in 2009. 33 In such cases, rigorous
clinical evaluation and serial MRI are necessary to identify
June 2018 S5
5/24/18 11:35 AM
 Neurology
Board Review
MULTIPLE SCLEROSIS

patients with an alternative diagnosis and those at risk for neck. It is important to recognize that the neurologic history
developing demyelinating disease. and examination may suggest a localization more caudal than
Patients with RIS can be advised that as a group, approx- the actual site of pathology when the spinal cord is affected.
imately 34% will develop a first clinical event over 5 years,
and nearly 80% by 15 years.34 Factors that increase the risk What is the diagnostic approach and differential
for developing a first clinical event (confirming the diagnosis diagnosis of myelopathy and myelitis?
of MS after RIS) include younger age (< 37 years), male gen- Myelopathy is an umbrella term that refers to spinal cord
der, the presence of gadolinium-enhancing lesions and spi- dysfunction from any of a number of etiologies. Myelitis is
nal cord lesions,34 and, in children, the presence of oligoclonal spinal cord dysfunction with evidence of inflammation. A com-
bands.35 Those with spinal cord involvement have an approxi- prehensive history and examination are critical for identifying
mately 55% risk for developing a first clinical event at 5 years, clues to the underlying etiology. The first step in the approach
and the highest risk group (men, < 37 years of age with spinal to a patient who presents with myelopathy is to discern the
cord lesions) has a nearly 90% risk by 3 years.34 Whether treat- temporal profile and localization. The diagnostic approach and
ment should be offered to patients with RIS is unclear at this differential diagnosis are outlined in Figure 2.
time, and there is an ongoing clinical trial of dimethyl fumarate The patient in Case 2 presented with acute (days) pro-
(Assessment of Tecfidera in Radiologically Isolated Syn- gressive myelopathy without trauma or signs/symptoms of
drome [ARISE]) intended to address this question.36 Even in infection. Spinal cord MRI with gadolinium should be per-
the absence of data, treatment should be considered for RIS formed as the next diagnostic step in Case 2 (see Figure 3 for
patients at the highest risk of conversion to clinically definite Case 2 MRI findings). Given the absence of historical features
MS (CDMS), particularly those who have new or enhancing suggesting an infectious etiology, it would be reasonable to
lesions on follow-up MRI. perform brain MRI with and without contrast to investigate
for lesions suggesting MS, as long as this would not delay
MYELITIS/CLINICALLY ISOLATED SYNDROME MRI of the spinal cord. The temporal profile (subacute pro-
Case Presentation 2 gressive) and evidence of inflammation on MRI (contrast
A 32-year-old previously healthy woman presents for evalua- enhancement) in this case implicates an inflammatory etiol-
tion of subacute, progressive, painful paresthesias that began in ogy, although malignancy may present similarly.
both feet and ascended the legs over 4 days,
and that by the end of the week involved
the trunk to the xiphoid process (T6). She
Patient  with  acute/subacute  myelopathy
reports painful electric-like shocks down Evidence  of  inflammation:  myelitis  
her spine with neck movements (Lhermitte
phenomenon) and mild urinary retention.
MRI  spine  with/without  contrast Serum:  ESR,  
ESR,  CRP,  ANA,  ANCAs,  Lyme  serologies
There is no antecedent infection or infectious CSF:  HSV1/2  PCR,  VZV  PCR  and  IgM/IgG,  VDRL  
symptoms and she denies prior episodes of Systemic  imaging  in  appropriate  context

neurologic dysfunction. She has decreased Gadolinium-­‐enhancing  intrinsic  cord  lesion?

sensation to light touch from the toes to the No Yes

Infectious
Viral:  HSV1/2,  VZV,  CMV,  EBV,  enterovirus,  
xiphoid. She has absent vibration sense to flavivirus,  other
CSF  examination  
the knees and hyperreflexia in the legs, and Bacterial:  pyogenic,  Lyme,  syphilis,  other
Fungal:  rare  in  immunocompetent  patients  
Romberg sign is present. The remaining gen-
Pleocytosis  or  elevated  protein,  IgG  index,  or   Immune-­‐mediated  
eral and neurologic examinations are normal. OCBs? Without  systemic  disease:  CIS,  NMOSD
Yes With  systemic  disease: lupus,  Behçet  disease,  
No
Sjögren  syndrome,  ANCA-­‐associated  vasculitis,  
What is the likely site of pathology in Correct  localization?   neurosarcoidosis
Consider  repeat  imaging  if  early  in  course
this patient? Consider  non-­‐inflammatory  myelopathies
• Compressive
Neuroanatomically, the lesion localizes best • Vascular:  AVF,  cord  infarct  (hyperacute)
to the midline posterior columns (gracile • Metabolic:  B12,  copper  deficiency
• Degenerative
fasciculi) at approximately the T6 spinal level.
These first-order, large myelinated sensory
fibers supply discriminative touch, vibration, FIGURE 2. Basic diagnostic approach and differential diagnosis of acute/subacute
and proprioception to the legs and trunk from myelopathy.
approximately the T6 spinal level distally. Abbreviations: ANA, antinuclear antibody; ANCA, antineutrophil cytoplasmic antibodies; AVF, arteriovenous fistula;
CIS, clinically isolated syndrome; CMV, cytomegalovirus; CRP, C-reactive protein; CSF, cerebrospinal fluid;
The more lateral posterior columns (cuneate EBV, Epstein-Barr virus; ESR, erythrocyte sedimentation rate; HSV, herpes simplex virus; MRI, magnetic
fasciculi) contain the fibers from above resonance imaging; NMOSD, neuromyelitis optica spectrum disorder; OCB, oligoclonal bands; PCR, polymerase
chain reaction; VDRL, Venereal Disease Research Laboratory; VZV, varicella zoster virus.
approximately T6 through the arms and

S6 June 2018

NR_MS Board Review Supplement 2018_v10.indd 6 5/24/18 11:35 AM


C what factors contribute to that risk?
A B D (myelitis). Multiple risk factors for conversion from CIS to
FIGURE 3. Magnetic resonance imaging (MRI) findings in Case
2. Mid-sagittal T2 and T1 post-contrast MRI of the cervical spine
demonstrates a (A) midline dorsal T2 hyperintense, (B) gadolinium-
enhancing lesion at the level of the C4 vertebral body. (C) T2 axial
and (D) T1 post-contrast axial images demonstrating the lesion are
shown as well. The brain MRI was unremarkable.
After MRI has excluded compressive etiologies, and
with evidence of inflammation on MRI, the next step in the
diagnostic approach is lumbar puncture with CSF analy-
sis (Figure 2). In addition to historical features that might
suggest infection, clues to an infectious myelitis include
CSF pleocytosis (especially if neutrophil-predominant), ele-
vated protein, and/or hypoglycorrhachia, although these
are not reliably present, especially in viral etiologies or
immunocompromised individuals. A modest pleocytosis
(< 50 cells/µL) with otherwise bland-appearing CSF is typ-
ical but not specific for MS. The detection of oligoclonal
bands has a diagnostic  sensitivity  of approximately 88%
and a  specificity  of at least 86% for MS  in the appropriate
clinical context.37,38
Case 2 Continued
CSF analysis reveals 9 nucleated cells (100% lymphocytes),
normal protein and glucose levels, an elevated IgG index of
1.1, and 6 unmatched oligoclonal bands. Infectious studies
from the CSF are negative, as are serum rheumatologic tests.
What is the next diagnostic step after other causes of
myelitis have been excluded?
The fundamental diagnostic objective once other causes of
myelitis have been excluded is to determine if the patient meets
the diagnostic criteria for MS based on the 2017 McDonald
criteria, which require evidence of disease dissemination in
space and time (Table 1).12 MRI of the brain and cervical and
thoracic spine with and without gadolinium contrast should be
obtained in order to identify any clinically silent lesions consis-
tent with MS or suggestive of another pathology.12
NR_MS Board Review Supplement 2018_v10.indd 7
Neurology
Board Review
MULTIPLE SCLEROSIS
Case 2 Continued
The patient is diagnosed with presumed immune-mediated
myelitis/clinically isolated syndrome (CIS) because she does
not meet the dissemination in space criteria for MS.
What is the risk for developing CDMS after CIS, and
CIS describes the first clinical episode of a patient with signs,
symptoms, and a diagnostic evaluation that suggests a demy-
elinating event, but which does not meet the dissemination
in space or time criteria.39 MS often presents for the first time
as CIS affecting the optic nerve (optic neuritis), brainstem/
cerebellum (acute brainstem syndrome), or spinal cord
CDMS have been explored, including clinical, genetic, envi-
ronmental, and immunological factors as well as MRI and
CSF metrics.39 Among these, only MRI and CSF metrics are
routinely used in clinical practice. The long-term risk of con-
version to CDMS is roughly 20% for those with no lesions
beyond the symptomatic site and about 80% for those with
additional abnormal lesions on MRI, with a greater number
of lesions predicting a higher risk.40–42 Although most studies
have followed patients with optic neuritis, brain lesions have
also been shown to predict conversion to CDMS in patients with
myelitis and brainstem syndromes.41,43 For patients with nega-
tive MRI, the presence of oligoclonal bands increases the risk for
conversion from 4% to 23%.44 In addition, the 2017 McDonald
criteria allow for the presence of oligoclonal bands to act as a
surrogate in order to fulfill the dissemination in time criteria.12
OPTIC NEURITIS/CLINICALLY DEFINITE
MULTIPLE SCLEROSIS
Case Presentation 3
A 26-year-old previously healthy woman reports blurred,
“cloudy” vision in her right eye with mild retro-orbital pain on
extraocular movements. She notes that this has gradually pro-
gressed over the course of 3 days, and she now has decreased
color perception to red tones. Upon questioning, she reports
an episode of left leg paresthesias 2 years prior to evaluation,
which she attributed to a sports injury and for which she
did not seek medical attention. The paresthesias started dis-
tally in the left foot, ascended to the level of the umbilicus
on the left side, and may have been accompanied by some
subtle weakness. There was no associated bladder or bowel
dysfunction. That episode lasted less than 1 week and resolved
completely. On neurologic examination, visual acuity is
20/80 OD, 20/20 OS, with right eye red desaturation and a
relative afferent pupillary defect on the right; funduscopic
examination is unremarkable. There is decreased vibration
and asymmetric hyperreflexia in the left Achilles and patellar
tendons. The remainder of the neurologic and general exam-
inations is only significant for mildly increased spastic muscle
tone in the left leg with Babinski sign on the left.
June 2018 S7
5/24/18 11:35 AM
 Neurology
Board Review
MULTIPLE SCLEROSIS

What are the clinical features of optic neuritis and what TABLE 3. Differential Diagnosis of Optic Neuritis
is the differential diagnosis?
Broadly, the localization of monocular vision loss is anywhere Immune-mediated
from the surface of the eye through the intraocular structures Without systemic disease
and optic nerve to the optic chiasm. In a young patient with Clinically isolated syndrome
acutely progressive monocular vision loss accompanied by Multiple sclerosis
signs of optic nerve dysfunction (decreased acuity, dyschro- AQ-4 astrocytopathy (NMO) and AQ-4–negative NMOSD
matopsia, afferent pupillary defect), optic neuritis is the pri- Autoimmune (eg, CRMP5 autoimmunity)
mary diagnostic consideration.45 Alternative localizations Anti-MOG oligodendrogliopathy
such as the cornea, uvea, retina, vitreous, and orbit should With systemic disease
be excluded, as appropriate to the clinical presentation, with Post-infectious
ophthalmologic evaluation that includes dilated funduscopy. Sarcoidosis
Optic neuritis is inflammation of the optic nerve and is a Lupus
clinical diagnosis based on the history and neurologic exam- Vasculitides (eg, granulomatosis with polyangiitis)
ination. The typical presentation consists of acutely progressive
Infectious
(hours to days) monocular vision changes, decreased visual acu-
Lyme disease
ity that may be accompanied by scotoma, and dyschromatopsia
Syphilis
(blue/yellow is more common in the acute setting and red/green
Meningitis
chronically)46; periorbital pain is variably present, with lesions
Neuroretinitis (eg, viruses, toxoplasmosis, Bartonella henselae)
more posterior to the eye less likely to cause pain.47 Positive
phenomena, such as phosphenes (bright flashes of light asso- Vascular
ciated with extraocular movements), can also occur and should Ischemic optic neuropathy
be distinguished from scintillating scotoma. The Pulfrich effect is Retinal hemorrhage
a patient-reported stereoscopic perception of objects in motion Giant cell arteritis
that is related to asymmetric conduction between the optic
nerves. Uhthoff phenomenon, worsening of vision with eleva- Malignancy
tions in body temperature, may also be described. Optic disc Glioma
swelling is present in one third of cases, but is typically absent in Meningioma
retrobulbar optic neuritis.48 Afferent pupillary defect is common, Metastasis
but may be masked by bilateral optic nerve involvement. The dif- Lymphoma
ferential diagnosis for optic neuritis is outlined in Table 3.
Toxic/metabolic
What diagnostic tests should be considered in the B12 and folate deficiencies
evaluation of a patient with optic neuritis? Drugs
Although MRI is not necessary for the diagnosis of optic neu- Genetic
ritis in the appropriate clinical context, orbital MRI with fat Leber hereditary optic neuropathy
suppression and gadolinium helps evaluate for alternative eti- Kjer-type autosomal dominant optic atrophy
ologies. In most cases of immune-mediated optic neuritis, MRI
demonstrates gadolinium enhancement and/or T2 hyperin- Trauma
tensity of the optic nerve.49 Brain and spine MRI are important
for identifying patients for whom optic neuritis represents the Abbreviations: AQ-4, aquaporin-4; CRMP5, collapsin response-mediator protein-5; MOG,
myelin oligodendrocyte glycoprotein; NMO, neuromyelitis optica; NMSOD, neuromyelitis
first clinical presentation of MS. Serum studies including com- optica spectrum disorder.
plete blood count, comprehensive metabolic panel, erythrocyte
sedimentation rate, C-reactive protein level, Lyme serologies,
antinuclear antibody and antineutrophil cytoplasmic antibody Case 3 Continued
assays, B12 and folate levels, and AQ-4 IgG level should be con- Serum screening studies are normal. MRI of the orbits with
sidered in most patients; additional studies such as tuberculo- gadolinium and fat suppression demonstrates a short-
sis and syphilis testing should be considered in the appropri- segment, gadolinium-enhancing T2 hyperintense lesion in
ate clinical context. Older patients and those with an atypical the right optic nerve. Brain MRI reveals multiple T2 hyperin-
clinical course should be evaluated for underlying malignancy. tense lesions in the brain and several short-segment intra-
Lumbar puncture is not routinely required, but its diagnostic medullary lesions in the dorsal cervical and thoracic spinal
and prognostic utility in optic neuritis is similar to that in myeli- cord (Figure 4). This patient fulfills the 2017 McDonald
tis, as described above. criteria for the diagnosis of MS (Table 1).12

S8 June 2018

NR_MS Board Review Supplement 2018_v10.indd 8 5/24/18 11:35 AM


What other inflammatory conditions of the CNS are
commonly considered when evaluating a patient with
possible MS?
The differential diagnosis of MS is broad. Diagnostic consid-
erations of myelitis and optic neuritis have been addressed; in
addition to those considerations, other inflammatory disorders
of the CNS should be distinguished from MS as outlined below.50
Several variants of MS are recognized, including tume-
factive MS, Baló concentric sclerosis, and fulminant MS.
Large (> 2 cm) “tumefactive” lesions may develop at the
onset or at any time in the course of MS and can be difficult
to distinguish from primary CNS neoplasia.51 Patients with
Baló concentric sclerosis can present with an MS-like clinical
syndrome, although the most common manifestations resem-
ble those of intracerebral mass lesions such as headache,
seizures, weakness, and other focal neurologic deficits. The
syndrome is characterized on MRI by 1 or more lesions with
lamellar concentric rings of hyperintense and hypointense T2
signal (Figure 5). The hyperintense rings likely represent areas
of demyelination associated with hypoxia/ischemia, while the
hypointense rings represent relatively preserved myelin asso-
ciated with activation of hypoxia-inducible factors.52
Fulminant MS, also known as the Marburg variant, is an
acute, aggressive, and rapidly progressive form of MS with clini-
cal manifestations that may include encephalopathy, motor and
sensory deficits, seizures, and aphasia and that is poorly respon-
sive to treatment.53 On MRI, there are multifocal, bilateral, large
T2 hyperintense lesions that may all be gadolinium-enhancing
simultaneously. Prognosis is generally poor, and no form of
therapy has been consistently proven effective. However, early
aggressive treatment with high-dose glucocorticoids and/or
immunosuppression may improve the prognosis.54
Fulminant MS can be confused with acute disseminated
encephalomyelitis (ADEM). ADEM is an acute, immune-
mediated demyelinating condition that primarily affects
children and typically occurs following an infection or vac-
cination.55 ADEM is clinically characterized by encephalop-
athy and multifocal neurologic deficits that progress rapidly
to a clinical nadir, typically within 2 to 5 days. MRI demon-
strates reversible, often large, poorly defined white matter
lesions commonly involving the thalamus and basal ganglia
and not infrequently the spinal cord, which may enhance
with gadolinium. Treatment consists of high-dose intra-
venous glucocorticoids (1000 mg intravenously daily for
5–7 days); for those who do not improve with steroids,
intravenous immunoglobulin or plasma exchange can be
considered. Acute treatment should be followed by an oral
prednisone taper. ADEM is almost always a monophasic
illness, although so-called “recurrent” or “relapsing” ADEM
has been reported and the distinction from fulminant MS
is unclear. Such patients should be evaluated for the pres-
ence of serum antibodies targeting myelin oligodendrocyte
glycoprotein (MOG).56 Patients with ADEM, especially those
NR_MS Board Review Supplement 2018_v10.indd 9
Neurology
Board Review
MULTIPLE SCLEROSIS
A B D
C
FIGURE 4. Magnetic resonance imaging (MRI) findings in Case
3. (A) T1 fat-suppressed post-gadolinium MRI of the orbits
demonstrates gadolinium enhancement of the right optic nerve
(arrow). (B and C) MRI of the spine demonstrates several T2
hyperintense intramedullary lesions in the dorsolateral spinal
cord. (D) MRI of the brain reveals multiple periventricular white
matter lesions (arrows) and several nonspecific subcortical lesions
(arrowhead).
over 18 years old, should be followed closely with serial
imaging and a high index of suspicion for fulminant MS,
which would require disease-modifying therapy (DMT).
Neuromyelitis optica (NMO, or Devic disease) is an
autoimmune astrocytopathy that was previously thought
to be a phenotypically unique subset of MS character-
ized by relapses affecting predominantly the optic nerves,
brainstem, and spinal cord. NMO is now well established
as a pathophysiologically distinct disease. IgG antibodies
targeting the AQ-4 water channel have been shown to be
directly pathogenic and are a critical diagnostic marker of
the disease.57,58 The AQ-4 channel is heavily expressed on
astrocytic foot processes of the optic nerves, brainstem, and
spinal cord. Once AQ-4 IgG was recognized as a marker
of the disease, the spectrum of NMO expanded and now
the current nomenclature refers to AQ-4–positive and
AQ-4–negative NMOSD. In the absence of AQ-4 IgG,
NMOSD remains a phenotypic categorization of what
likely represents several distinct pathophysiological enti-
ties, including MOG oligodendrogliopathy.59 The presence
of AQ-4 IgG can be detected by several methods, the best
of which is a cell-based assay that is sensitive (76%) and
highly specific (99%)60 for NMOSD; AQ-4 IgG should
be sought in the serum rather than CSF given superior
sensitivity and equal specificity.61 The core clinical features
of NMOSD include optic neuritis, myelitis, the area post-
rema syndrome (intractable nausea/vomiting and hiccups),
acute brainstem syndrome, symptomatic narcolepsy or acute
diencephalic clinical syndrome, and symptomatic cerebral
syndrome, any of which may occur in relapsing episodes.62,63
June 2018 S9
5/24/18 11:35 AM
 Neurology
Board Review
MULTIPLE SCLEROSIS

Longitudinally extensive optic neuritis and/or longitudinally

extensive myelitis (≥ 3 spinal segments) on MRI suggest the
diagnosis. The treatment of NMOSD is different from that
of MS, and several MS DMTs can worsen NMOSD (inter-
ferons, natalizumab, and possibly fingolimod). In contrast to
MS, most of the disability accumulated in NMOSD occurs
during relapses.
Susac syndrome is a rare presumed immune-mediated
vasculopathy of the small arterial vessels of the retina, inner
ear, and brain classically characterized by the clinical triad of
encephalopathy, branch retinal artery occlusions, and hear-
ing loss (although the complete triad is noted in only about
13% of patients at disease onset).64 As in MS, the typical age
of onset is young adulthood, and women are affected 3 times
more often than men. Distinguishing incomplete presenta-
tions of Susac syndrome from MS is important and includes
a number of clinical and radiological features.65 Diagnostic
criteria for Susac syndrome were proposed in 2016.66
What is the rationale for glucocorticoid treatment in
patients with MS exacerbation?
MS exacerbations are episodes of new or recurrent focal
neurologic dysfunction lasting for more than 24 hours, with-
out any better explanation. It is important to exclude pseu-
dorelapse or recrudescence of prior deficits in a setting of
fever, infection, systemic illness, stress, or heat exposure. It
should be noted that it is possible for infection to trigger
an exacerbation and that high levels of psychological stress67
and the use of some medical treatments (eg, tumor necrosis
factor antagonists) may increase the risk for relapse.68
Acute lesions on MRI strongly correlate with relapse
activity and serve as a marker of inflammatory disease
activity.69 Relapses can produce a spectrum of manifesta-
tions such as optic neuritis; diplopia or trigeminal neural-
gia; monoparesis, hemiparesis, or paraparesis or paralysis;
myelitis; bladder and bowel dysfunction; and, more recently
recognized, pure cognitive relapses. For patients, MS exac-
erbations are associated with decreased quality of life, func-
tional disability, and significant economic cost. Treatment of
MS relapses shortens the duration of acute disability, and
may contribute to patient well-being and a sense of control
over an unpredictable disease.67
Treatment options for MS exacerbations include adrenocor-
ticotropic hormone (ACTH), intravenous methylprednisolone
(IVMP), and oral glucocorticoids (oral glucocorticoids are not
approved by the US Food and Drug Administration [FDA] for
this purpose).67 ACTH gel (40 units intramuscularly twice daily
for 7 days, then 20 units twice daily for 4 days, then 20 units twice
daily for 3 days) is effective for MS exacerbations.70 The Optic
Neuritis Treatment Trial (ONTT) compared oral prednisone
(1 mg/kg/day for 14 days), IVMP (1 g/day for 3 days followed by
oral prednisone 1 mg/kg/day for 11 days), and oral placebo for
14 days for the treatment of optic neuritis in 457 patients and
FIGURE 5. Axial FLAIR magnetic resonance imaging findings of a
patient with Baló concentric sclerosis.
found that visual function improved more quickly in the IVMP
group.71 The IVMP group had better visual fields, contrast sen-
sitivity, and color vision but not acuity at 6 months; however, at
1 year, there were no appreciable differences in visual outcomes
between groups.72 There was, unexpectedly, a higher risk of
recurrent optic neuritis in the oral prednisone group compared
to both the IVMP and placebo groups. However, there was no
significant difference between the oral prednisone and placebo
groups with regard to conversion to CDMS. Trials comparing
IVMP and ACTH have failed to demonstrate a significant dif-
ference between the 2 options,73–76 but IVMP is generally first-
line given its availability, efficacy, and lower costs. The oral
prednisone equivalent of 1 g of IVMP is 1250 mg of prednisone,
so at 1 mg/kg/day (~60 mg/day for most adults), patients in the
oral steroid group of the ONTT were given considerably less
glucocorticoids than those in the IVMP group. Several studies
have found no significant differences between intravenous glu-
cocorticoids compared to oral equivalent doses.77–79 In addition,
patients prefer oral treatment, and in the 2015 COPOUSEP
study it was estimated that substituting oral treatment would
save $7.05 million after 1 year.79
What DMT options are available for this patient, and how
do you select from among the many DMTs currently
used to treat MS?
Selecting from the many treatment options for MS requires not
only detailed familiarity with the existing clinical trial data, side
effects, and contraindications of each therapeutic agent, but
also integration of individual patient parameters such as clin-
ical and neuroimaging metrics of individual disease features,
age, family planning, patient preferences, and ability to adhere

S10 June 2018

NR_MS Board Review Supplement 2018_v10.indd 10 5/24/18 11:35 AM


to/administer DMT. There is wide variation in prescribing prac-
tices. There are 2 broad paradigms for the treatment of MS:
induction therapy and escalation therapy. In addition, a recent
trend in treatment has been to target no evidence of disease
activity, or NEDA, wherein the patient experiences no relapses,
no new or enhancing lesions, and no disability progression.80
This may not be achievable in all patients with the currently
available agents. The efficacy of DMTs in clinical trials and in
clinical practice is measured via several metrics: annualized
relapse rate reduction, reduction in MRI activity (decrease in new
or enhancing lesions while on treatment), and decrease in
disability progression (Table 4).81–100 DMTs can be catego-
rized based on mode of administration: injectable (interferons,
glatiramer), oral (teriflunomide, dimethyl fumarate, fingoli-
mod), and infusion (natalizumab, ocrelizumab, alemtuzumab),
although this categorization does not correlate with mecha-
nism of action, safety, or efficacy. There is a range of efficacy for
annualized relapse rate reduction, from about 30% (glatiramer,
interferons) up to 68% for natalizumab (Table 4). However, in
the absence of randomized clinical trial data directly compar-
ing DMTs, it is not scientifically valid to compare therapeutics
across trials given differences in patient populations, diagnostic
criteria, and other variables.
PROGRESSIVE MULTIPLE SCLEROSIS/
SYMPTOM MANAGEMENT
Case 4 Presentation
A 64-year-old woman with a 32-year history of MS, poorly con-
trolled diabetes, and hypertension presents for another opinion
in the setting of progressive neurologic worsening over the past
2 years. She has had relapsing MS for many years, with mul-
tiple baseline periventricular lesions and intermittent relapses
related to spinal cord and brainstem disease. She has received
interferon therapy, followed by dimethyl fumarate, but had an
incomplete treatment response to these therapies, manifesting
as new lesions/relapses. She switched to fingolimod, which has
been working very well for her for 8 years. However, over the
past 2 years, she has noted a steady worsening of her function,
including memory, right hand dexterity, and balance and gait,
with progressive objective slowing of her timed 25-foot walk.
What is the approach to managing the patient with
progressive neurologic dysfunction?
When a patient with relapsing MS presents with steadily
progressive neurologic dysfunction, the disease may be
shifting to a SPMS course. It is important to distinguish
between progressive MS that is active versus that which
is not active (Table 2) based on the presence of relapses
and the formation of new or enhancing lesions. Clinicians
should avoid premature diagnostic closure, as comorbid dis-
ease may mimic MS progression. For example, spondylotic
myelopathy may mimic progressive MS, and the opportunity
to intervene surgically should not be missed in such cases.
NR_MS Board Review Supplement 2018_v10.indd 11
Neurology
Board Review
MULTIPLE SCLEROSIS
There is no clear evidence for how best to manage patients
who appear to be transitioning to a progressive phenotype;
how to slow progressive disability remains unclear.
The precise mechanisms of progression in MS are uncer-
tain, but proposed mechanisms include repeated episodes
of demyelination, lack of trophic support with consequent
axonal degeneration, chronic mitochondrial failure and oxi-
dative stress produced by macrophages/microglia, dysregu-
lation of iron homeostasis, altered ion channel expression/
activity, and Wallerian degeneration.101 Inflammation is pres-
ent histologically in all stages of MS, and the development
of progressive disease does not obsolesce the value of DMT
per se. It is our practice to offer continuation of DMT for
most patients clinically thought to have progressive MS and
certainly for those with active progressive MS. Ocrelizumab
has been shown to modestly slow progression in PPMS,
but has not been studied in SPMS.97 Siponimod appears to
reduce the risk of disability progression in SPMS but is not
approved by the FDA.102
Patients often inquire about nutritional supplements.
Supplements intended to protect against neurodegener-
ation or reduce inflammation in MS (eg, high-dose biotin,
alpha-lipoic acid, and mitochondrial cofactors such as coen-
zyme Q10) are sometimes used, but these substances have
not been rigorously studied for this purpose.103 Vitamin D
deficiency has been implicated as a risk factor for MS and in
the pathogenesis of MS, and there is some evidence that sup-
plementation may have disease-modifying effects;104 there-
fore, vitamin D deficiency should be corrected in all patients
with MS and our practice is to target serum 25-hydroxyvita-
min D levels of 40 to 70 ng/mL. Clinical trials exploring the
use of vitamin D supplementation in MS are underway.105,106
Irrespective of treatment decisions regarding her DMT,
the patient in Case 4 should be counseled about the impor-
tance of maintaining/improving her neurologic reserve
through a healthy lifestyle, exercise, and controlling her dia-
betes and other chronic medical conditions.
What symptoms are common in patients with MS,
and how can these be ameliorated?
Patients with MS experience a variety of symptoms that are dis-
ruptive and can significantly decrease quality of life. Some may
mistakenly believe that their DMT is not working if they con-
tinue to experience symptoms such as paresthesias or fatigue,
and may wish to change or discontinue therapy unless appro-
priate education and symptom management are provided. Both
lifestyle/nonpharmacologic and pharmacologic approaches are
employed in the management of symptoms and can signifi-
cantly improve a patient’s quality of life.107
Wearable biosensors can help track patient’s physical
activity and other biometrics.108 Physical activity, stretching,
and physiotherapy such as pool exercise serve as the founda-
tion for management of spasticity. Medications include oral
June 2018 S11
5/24/18 11:35 AM
 TABLE 4. Drug Therapies for Multiple Sclerosis
Clinical Outcome
Agent Route/Frequency MRI Outcome Measures Adverse Effects Monitoring Parameters
Measures
IFNβ-1b81,82 (Betaseron) SQ every other day ARR: 34% reduction CELs: 83% reduction Flu-like symptoms, leukopenia, • CBC/diff

S12 June 2018

Neurology

WM-Ls: 23% reduction LFT elevation, injection- • LFT every 3 mo initially,

site reactions, neutralizing then every 6 mo
Board Review

IFNβ-1a83,84 (Rebif) SQ 3 times/wk ARR: 32% reduction CELs: 78% reduction antibodies (2% with Avonex,
WM-Ls: median increase 30% with Rebif and Betaseron)
MULTIPLE SCLEROSIS

of 10.9% in placebo group, Pregnancy category: C

median decrease of 1.2%

NR_MS Board Review Supplement 2018_v10.indd 12

and 3.8% in 22 and 44 μg
groups

IFNβ-1a85,86 (Avonex) IM weekly ARR: 32% reduction CELs: 33% reduction

Glatiramer acetate87 SQ daily or ARR: 29% reduction Not reported Injection-site reactions, None
(Copaxone) 3 times/wk lipoatrophy, systemic reaction
(flushing, chest pain, anxiety,
throat tightness, palpitations)
usually self-limited (few minutes)
Pregnancy category: B

Teriflunomide88 (Aubagio) Oral daily ARR: 31.2% (7-mg dose) CELs: 57% (7-mg dose) Diarrhea, nausea, hair thinning, • TB and pregnancy tests
and 31.5% (14-mg dose) and 80% (14-mg dose) ALT elevations, reactivation pre-treatment
reduction reduction of TB • LFT monthly for first
WM-Ls: 44% and Pregnancy category: X 6 mo, then every 3 mo
76.7% reduction with CBC/diff
• Must use contraception if
childbearing age (both men
and women)
• Cholestyramine washout if
pregnancy occurs
• Long half-life (19 days)

Dimethyl fumarate89,90 Oral twice daily ARR: 44%–53% reduction CELs: 74%–90% reduction Gastrointestinal upset, flushing • CBC/diff every 6 mo
(Tecfidera) WM-Ls: 71%–85% reduction Pregnancy category: C • LFTs as indicated

Fingolimod (Gilenya)91,92 Oral daily ARR: 39%–54% reduction CELs: 72%–82% reduction Bradycardia, macular edema, • 6-hr first-dose observation
WM-Ls: 46%–74% infection (2 deaths from for bradycardia
reduction disseminated zoster and HSV, • Eye exam pre-treatment and
respectively), elevated LFTs 3–6 mo after starting and for
Pregnancy category: C any vision problems
• CBC/diff (lymphocytes) and
LFTs every 6 mo
(continued)

5/24/18 11:35 AM
 TABLE 4. (continued)
Agent
Fingolimod93 (Gilenya)
Pediatric-onset MS
Clinical Outcome
Route/Frequency MRI Outcome Measures Adverse Effects Monitoring Parameters
Measures
Oral daily ARR: 82% reduction CELs: 66% reduction Seizures in 4 patients, • Not yet published, under
WM-Ls: 52% reduction leukopenia in 2, review at FDA for pediatric-
agranulocytosis in 1, onset MS
second-degree AV block in 1,
hypersensitivity in 1

Natalizumab94,95 IV monthly ARR: 54%–68% reduction CELs: 89%–92% reduction Risk of PML, allergic reactions • LFTs every 3 mo

NR_MS Board Review Supplement 2018_v10.indd 13

(Tysabri) WM-Ls: 83% reduction Pregnancy category: C • JCV antibodies every 6 mo in
those who test negative
• Brain MRI every 6 mo to
monitor for PML

Ocrelizumab96 (Ocrevus) IV every 6 mo ARR: 46% reduction CELs: 94% reduction Infusion-related reactions • Hepatitis B, C serologies
Relapsing MS WM-Ls: 77% reduction 34%, serious infection in pre-treatment
1.3% of ocrelizumab-treated • SPEP, CD19 levels every
patients vs 2.9% of interferon- 6 mo (elevation with relapse
treated patients suggests inadequate dosing
rather than treatment failure)

Ocrelizumab97 (Ocrevus)
Primary progressive MS
IV every 6 mo CDP: 6.3% reduction WM-Ls: 10.8% reduction Neoplasms developed in
BPF: 17.5% less decrease 2.3% of patients on
ocrelizumab vs 0.8% on
placebo; patients should
follow standard cancer
screening precautions
• Pregnancy risk not assigned;
there are no adequate data
on the developmental risk
associated with use of this
drug in pregnant women

Alemtuzumab98,99 IV daily × 5 days
(Lemtrada) once, then daily
× 3 days once
more 1 yr later
ARR: 49%–55% reduction
CELs: 61%–63% reduction
WM-Ls: 32% reduction
Secondary autoimmunity
(thyroid disease, ITP,
anti-GBM disease with
chronic renal insufficiency
in 3 patients), infusion-related
reactions (89.9%)
Pregnancy category: C
• Prescribers and patients
should be familiar with
the detailed monitoring
requirements as detailed
in the alemtuzumab risk
evaluation and mitigation
strategies (REMS)

Adapted from Pawate S, Bagnato F. Newer agents in the treatment of multiple sclerosis. Neurologist. 2015;19:104–17.

Abbreviations: ALT, alanine aminotransferase; anti-GBM, anti-glomerular basement membrane; ARR, annualized relapse rate; BPF, brain parenchymal fraction; CBC/diff, complete blood count with differential; CDP, confirmed disability
progression; CELs, contrast-enhancing lesions; FDA, Food and Drug Administration; hr, hour; IFN, interferon; IM, intramuscular; ITP, idiopathic thrombocytopenic purpura; IV, intravenous; JCV, John Cunningham virus; LFT, liver function
tests; mo, month; PML, progressive multifocal leukoencephalopathy; SPEP, serum protein electrophoresis; SQ, subcutaneous; TB, tuberculosis; wk, week; WM-Ls, white matter lesions; yr, year.

June 2018
MULTIPLE SCLEROSIS
Board Review
Neurology

S13

5/24/18 11:35 AM
 Neurology
Board Review
MULTIPLE SCLEROSIS
baclofen and tizanidine, which can be used in combination if
needed. Intramuscular injections of botulinum toxin are use-
ful when focal increased tone interferes with hygiene (eg, hip
adductor spasticity in patients who self-catheterize). Bowel
and bladder dysfunction are common and can be disabling.
Detrusor muscle hyperreflexia leads to increased contrac-
tility and decreased capacity of the bladder, causing urinary
urgency, frequency, and urge incontinence. Detrusor sphinc-
ter dyssynergia leads to impaired voiding due to contrac-
tion of the detrusor and sphincter simultaneously, producing
both urgency and hesitancy of urination. Medications such as
oxybutynin and tolterodine can help increase bladder capac-
ity and voiding control. Botulinum toxin injections into the
bladder can also be helpful, and pelvic floor physical therapy
is important for all patients with dysfunction. Timed toileting
and a stable bowel regimen are important for bowel dys-
function, and timed gentle laxatives and/or suppositories can
improve predictability of bowel movements.
Fatigue and cognitive dysfunction, although common in
MS, are highly nonspecific and have myriad causes. It is import-
ant to address depression, sleep hygiene, physical activity, and
diet, as these all contribute to fatigue and cognitive dysfunction.
Medications modestly helpful for fatigue include amantadine
and modafinil.107 CNS stimulants such as methylphenidate and
amphetamines can be considered with great caution given the
potential for abuse and prominent side effects such as anxiety
and irritability. Selective serotonin reuptake inhibitors such as
fluoxetine can have an activating effect and should be consid-
ered, particularly for patients who report depression. Tricyclic
antidepressants may be helpful for both depression and bowel/
bladder incontinence due to their anticholinergic effects, but
may worsen cognitive function, urinary retention, and/or con-
stipation. Neuropathic pain is common in patients with MS. This
includes burning, paresthesias, and specific pain syndromes such
as trigeminal neuralgia. Gabapentin, pregabalin, duloxetine, and
tricyclic antidepressants are commonly used for the treatment
of painful paresthesias, and carbamazepine, oxcarbazepine, and
other antiepileptic drugs can be used for trigeminal neuralgia.107
CONCLUSION
Meaningful advances in immunology, clinical and basic neu-
roscience, neuroimaging, and immunotherapy have deep-
ened our understanding of the pathobiology and treatment
options in MS. The past decade has seen a dramatic expan-
sion of therapeutic possibilities for our patients. The hope
for slowing or halting progressive disease and eventually
curing MS has never been greater. Current unmet medical
needs include prevention and treatment of secondary pro-
gression and a personalized approach to DMT selection.
Ongoing investigation is aimed at remyelinating therapy/
repairing damage to the CNS and understanding the role of
the microbiome in the pathogenesis and treatment of MS,
among other promising avenues of investigation. There is a
S14 June 2018
NR_MS Board Review Supplement 2018_v10.indd 14
great need for fellowship-trained neuroimmunologists both
in research and clinical practice to address the increasingly
complex management of patients with MS.
BOARD REVIEW QUESTIONS
Test your knowledge of this topic.
Go to www.mdedge.com/neurologyreviews/MSBoardReview
for Board Review Questions on this topic.
REFERENCES
1. Anderson DW, Ellenberg JH, Leventhal CM, et al. Revised estimate of
the prevalence of multiple sclerosis in the United States. Ann Neurol.
1992;31:333–6.
2. Pugliatti M, Rosati G, Carton H, et al. The epidemiology of multiple
sclerosis in Europe. Eur J Neurol. 2006;13:700–2.
3. Group GBDNDC. Global, regional, and national burden of neurolog-
ical disorders during 1990-2015: a systematic analysis for the Global
Burden of Disease Study 2015. Lancet Neurol. 2017;16:877–97.
4. Waldman A, Ness J, Pohl D, et al. Pediatric multiple sclerosis: Clinical
features and outcome. Neurology. 2016;87:S74–81.
5. Roohani P, Emiru T, Carpenter A, et al. Late onset multiple sclerosis:
Is it really late onset? Mult Scler Relat Disord. 2014;3:444–9.
6. Ascherio A, Munger KL. Epidemiology of multiple sclerosis: from risk
factors to prevention-an update. Semin Neurol. 2016;36:103–14.
7. Hansen T, Skytthe A, Stenager E, et al. Risk for multiple sclerosis in
dizygotic and monozygotic twins. Mult Scler. 2005;11:500–3.
8. Wynn DR, Rodriguez M, O’Fallon WM, Kurland LT. A reappraisal
of the epidemiology of multiple sclerosis in Olmsted County,
Minnesota. Neurology. 1990;40:780–6.
9. Ramagopalan SV, Sadovnick AD. Epidemiology of multiple sclerosis.
Neurol Clin. 2011;29:207–17.
10. Ascherio A. Environmental factors in multiple sclerosis. Expert Rev
Neurother. 2013;13:3–9.
11. Berer K, Gerdes LA, Cekanaviciute E, et al. Gut microbiota from
multiple sclerosis patients enables spontaneous autoimmune
encephalomyelitis in mice. Proc Natl Acad Sci U S A. 2017;
114:10719–24.
12. Thompson AJ, Banwell BL, Barkhof F, et al. Diagnosis of multiple
sclerosis: 2017 revisions of the McDonald criteria. Lancet Neurol.
2018;17:162–73.
13. Brownlee WJ, Hardy TA, Fazekas F, Miller DH. Diagnosis of multiple
sclerosis: progress and challenges. Lancet. 2017;389:1336–46.
14. Filippi M, Rocca MA, Barkhof F, et al. Association between
pathological and MRI findings in multiple sclerosis. Lancet Neurol.
2012;11:349–60.
15. Popescu BF, Lucchinetti CF. Meningeal and cortical grey matter
pathology in multiple sclerosis. BMC Neurol. 2012;12:11.
16. Lublin FD, Reingold SC. Defining the clinical course of multiple scle-
rosis: results of an international survey. National Multiple Sclerosis
Society (USA) Advisory Committee on Clinical Trials of New Agents
in Multiple Sclerosis. Neurology. 1996;46:907–11.
17. Lublin FD, Reingold SC, Cohen JA, et al. Defining the clinical course
of multiple sclerosis: the 2013 revisions. Neurology. 2014;83:278–86.
18. Lublin FD, Baier M, Cutter G. Effect of relapses on development of
residual deficit in multiple sclerosis. Neurology. 2003;61:1528–32.
19. Popescu BF, Pirko I, Lucchinetti CF. Pathology of multiple sclerosis:
where do we stand? Continuum. 2013;19:901–21.
20. Krieger SC, Cook K, De Nino S, Fletcher M. The topographical model
of multiple sclerosis: A dynamic visualization of disease course.
Neurol Neuroimmunol Neuroinflamm. 2016;3:e279.
21. Frischer JM, Weigand SD, Guo Y, et al. Clinical and patholog-
ical insights into the dynamic nature of the white matter multiple
sclerosis plaque. Ann Neurol. 2015;78:710–21.
5/24/18 11:35 AM

22. Klawiter EC. Current and new directions in MRI in multiple sclerosis.
Continuum. 2013;19:1058–73.
23. Maggi P, Absinta M, Grammatico M, et al. Central vein sign differ-
entiates multiple sclerosis from central nervous system inflammatory
vasculopathies. Ann Neurol. 2018;83:283–94.
24. Sparacia G, Agnello F, Gambino A, et al. Multiple sclerosis: High
prevalence of the ‘central vein’ sign in white matter lesions on
susceptibility-weighted images. Neuroradiology J. 2018:1971400918763577.
25. Cortese R, Magnollay L, Tur C, et al. Value of the central vein sign
at 3T to differentiate MS from seropositive NMOSD. Neurology.
2018;90:e1183–e1190.
26. Cotton F, Weiner HL, Jolesz FA, Guttmann CR. MRI contrast uptake
in new lesions in relapsing-remitting MS followed at weekly intervals.
Neurology. 2003;60:640–6.
27. Sahraian MA, Radue EW, Haller S, Kappos L. Black holes in multiple
sclerosis: definition, evolution, and clinical correlations. Acta Neurol
Scand. 2010;122:1–8.
28. Azevedo CJ, Pelletier D. Whole-brain atrophy: ready for implemen-
tation into clinical decision-making in multiple sclerosis? Curr Opin
Neurol. 2016;29:237–42.
29. Popescu V, Agosta F, Hulst HE, et al. Brain atrophy and lesion
load predict long term disability in multiple sclerosis. J Neurology
Neurosurg Psychiatry. 2013;84:1082–91.
30. Cohen AB, Neema M, Arora A, et al. The relationships among
MRI-defined spinal cord involvement, brain involvement, and
disability in multiple sclerosis. J Neuroimaging. 2012;22:122–8.
31. Neema M, Stankiewicz J, Arora A, et al. MRI in multiple sclerosis:
what’s inside the toolbox? Neurotherapeutics. 2007;4:602–17.
32. Okuda DT. Incidental lesions suggesting multiple sclerosis.
Continuum. 2016;22:730–3.
33. Okuda DT, Mowry EM, Beheshtian A, et al. Incidental MRI
anomalies suggestive of multiple sclerosis: the radiologically
isolated syndrome. Neurology. 2009;72:800–5.
34. Okuda DT, Siva A, Kantarci O, et al. Radiologically isolated syndrome:
5-year risk for an initial clinical event. PLoS One. 2014;9:e90509.
35. Makhani N, Lebrun C, Siva A, et al. Radiologically isolated syndrome
in children: clinical and radiologic outcomes. Neurol Neuroimmunol
Neuroinflamm. 2017;4:e395.
36. Assessment of Tecfidera in radiologically isolated syndrome
(RIS) (ARISE). ClinicalTrials.gov website. https://clinicaltrials.gov
/ct2/show/NCT02739542. Accessed March 25, 2018.
37. Dobson R, Ramagopalan S, Davis A, Giovannoni G. Cerebrospinal
fluid oligoclonal bands in multiple sclerosis and clinically isolated
syndromes: a meta-analysis of prevalence, prognosis and effect of
latitude. J Neurol Neurosurg Psychiatry. 2013;84:909–14.
38. Freedman MS, Thompson EJ, Deisenhammer F, et al. Recommended
standard of cerebrospinal fluid analysis in the diagnosis of multiple
sclerosis: a consensus statement. Arch Neurol. 2005;62:865–70.
39. Miller DH, Chard DT, Ciccarelli O. Clinically isolated syndromes.
Lancet Neurol. 2012;11:157–69.
40. Optic Neuritis Study Group. Multiple sclerosis risk after optic
neuritis: final optic neuritis treatment trial follow-up. Arch Neurol.
2008;65:727–32.
41. Fisniku LK, Brex PA, Altmann DR, et al. Disability and T2
MRI lesions: a 20-year follow-up of patients with relapse onset of
multiple sclerosis. Brain. 2008;131(Pt 3):808–17.
42. Tintore M, Rovira A, Rio J, et al. Baseline MRI predicts future
attacks and disability in clinically isolated syndromes. Neurology.
2006;67:968–72.
43. Ruet A, Deloire MS, Ouallet JC, et al. Predictive factors for multi-
ple sclerosis in patients with clinically isolated spinal cord syndrome.
Mult Scler. 2011;17:312–8.
44. Tintore M, Rovira A, Rio J, et al. Do oligoclonal bands add informa-
tion to MRI in first attacks of multiple sclerosis? Neurology. 2008;
70:1079–83.
NR_MS Board Review Supplement 2018_v10.indd 15
Neurology
Board Review
MULTIPLE SCLEROSIS
45. Toosy AT, Mason DF, Miller DH. Optic neuritis. Lancet Neurol.
2014;13:83–99.
46. Katz B. The dyschromatopsia of optic neuritis: a descriptive anal-
ysis of data from the optic neuritis treatment trial. Trans Am
Ophthalmol Soc. 1995;93:685–708.
47. Fazzone HE, Lefton DR, Kupersmith MJ. Optic neuritis: correlation
of pain and magnetic resonance imaging. Ophthalmology.
2003;110:1646–9.
48. The clinical profile of optic neuritis. Experience of the Optic
Neuritis Treatment Trial. Optic Neuritis Study Group. Arch Ophthalmol.
1991;109:1673–8.
49. Kupersmith MJ, Alban T, Zeiffer B, Lefton D. Contrast-enhanced
MRI in acute optic neuritis: relationship to visual performance. Brain.
2002;125:812–22.
50. Katz Sand IB, Lublin FD. Diagnosis and differential diagnosis of mul-
tiple sclerosis. Continuum. 2013;19:922–943.
51. Algahtani H, Shirah B, Alassiri A. Tumefactive demyelinating lesions:
A comprehensive review. Mult Scler Relat Disord. 2017;14:72–9.
52. Hardy TA, Miller DH. Balo’s concentric sclerosis. Lancet Neurol.
2014;13:740–6.
53. Rahmlow MR, Kantarci O. Fulminant demyelinating diseases.
Neurohospitalist. 2013;3:81–91.
54. Freedman MS, Rush CA. Severe, highly active, or aggressive multiple
sclerosis. Continuum. 2016;22:761–84.
55. Pohl D, Alper G, Van Haren K, et al. Acute disseminated encepha-
lomyelitis: Updates on an inflammatory CNS syndrome. Neurology.
2016;87:S38–45.
56. Fernandez-Carbonell C, Vargas-Lowy D, Musallam A, et al.
Clinical and MRI phenotype of children with MOG antibodies. Mult
Scler. 2016;22:174–84.
57. Lennon VA, Kryzer TJ, Pittock SJ, et al. IgG marker of optic-
spinal multiple sclerosis binds to the aquaporin-4 water channel.
J Exp Med. 2005;202:473–7.
58. Hinson SR, Pittock SJ, Lucchinetti CF, et al. Pathogenic potential
of IgG binding to water channel extracellular domain in neuromyelitis
optica. Neurology. 2007;69:2221–31.
59. Sato DK, Callegaro D, Lana-Peixoto MA, et al. Distinction between
MOG antibody-positive and AQP4 antibody-positive NMO spectrum
disorders. Neurology. 2014;82:474–81.
60. Ruiz-Gaviria R, Baracaldo I, Castaneda C, et al. Specificity and sensi-
tivity of aquaporin 4 antibody detection tests in patients with neuro-
myelitis optica: A meta-analysis. Mult Scler Relat Disord. 2015;4:345–9.
61. Majed M, Fryer JP, McKeon A, et al. Clinical utility of testing
AQP4-IgG in CSF: Guidance for physicians. Neurol Neuroimmunol
Neuroinflamm. 2016;3:e231.
62. Wingerchuk DM, Banwell B, Bennett JL, et al. International consen-
sus diagnostic criteria for neuromyelitis optica spectrum disorders.
Neurology. 2015;85:177–89.
63. Katz Sand I. Neuromyelitis optica spectrum disorders. Continuum.
2016;22:864–96.
64. Dorr J, Krautwald S, Wildemann B, et al. Characteristics of Susac syn-
drome: a review of all reported cases. Nat Rev Neurol. 2013;9:307–16.
65. Buzzard KA, Reddel SW, Yiannikas C, et al. Distinguishing Susac’s
syndrome from multiple sclerosis. J Neurol. 2015;262:1613–21.
66. Kleffner I, Dorr J, Ringelstein M, et al. Diagnostic criteria for Susac
syndrome. J Neurol Neurosurg Psychiatry. 2016;87:1287–95.
67. Berkovich RR. Acute multiple sclerosis relapse. Continuum.
2016;22:799–814.
68. TNF neutralization in MS: results of a randomized, placebo-
controlled multicenter study. The Lenercept Multiple Sclerosis Study
Group and The University of British Columbia MS/MRI Analysis
Group. Neurology. 1999;53:457–65.
69. Sormani MP, Li DK, Bruzzi P, et al. Combined MRI lesions and
relapses as a surrogate for disability in multiple sclerosis. Neurology.
2011;77:1684–90.
June 2018 S15
5/24/18 11:35 AM
 Neurology
Board Review
MULTIPLE SCLEROSIS
70. Rose AS, Kuzma JW, Kurtzke JF, et al. Cooperative study in the
evaluation of therapy in multiple sclerosis. ACTH vs. placebo--final
report. Neurology. 1970;20:1–59.
71. Beck RW, Cleary PA, Anderson MM Jr, et al. A randomized, con-
trolled trial of corticosteroids in the treatment of acute optic neuritis.
The Optic Neuritis Study Group. N Engl J Med. 1992;326:581–8.
72. Beck RW, Cleary PA. Optic neuritis treatment trial. One-year
follow-up results. Arch Ophthalmol. 1993;111:773–5.
73. Abbruzzese G, Gandolfo C, Loeb C. “Bolus” methylprednisolone
versus ACTH in the treatment of multiple sclerosis. Ital J Neurol Sci.
1983;4:169–72.
74. Barnes MP, Bateman DE, Cleland PG, et al. Intravenous methyl-
prednisolone for multiple sclerosis in relapse. J Neurol Neurosurg
Psychiatry. 1985;48:157–9.
75. Milanese C, La Mantia L, Salmaggi A, et al. Double-blind random-
ized trial of ACTH versus dexamethasone versus methylprednis-
olone in multiple sclerosis bouts. Clinical, cerebrospinal fluid and
neurophysiological results. Eur Neurol. 1989;29:10–14.
76. Thompson AJ, Kennard C, Swash M, et al. Relative efficacy of
intravenous methylprednisolone and ACTH in the treatment of
acute relapse in MS. Neurology. 1989;39:969–71.
77. Burton JM, O’Connor PW, Hohol M, Beyene J. Oral versus intrave-
nous steroids for treatment of relapses in multiple sclerosis. Cochrane
Database Syst Rev. 2012;12:CD006921.
78. Morrow SA, Fraser JA, Day C, et al. Effect of treating acute optic
neuritis with bioequivalent oral vs intravenous corticosteroids:
a randomized clinical trial. JAMA Neurol. 2018 Mar 5. doi: 10.1001/
jamaneurol.2018.0024.
79. Le Page E, Veillard D, Laplaud DA, et al. Oral versus intravenous
high-dose methylprednisolone for treatment of relapses in patients
with multiple sclerosis (COPOUSEP): a randomised, controlled,
double-blind, non-inferiority trial. Lancet. 2015;386:974–81.
80. Rotstein DL, Healy BC, Malik MT, et al. Evaluation of no evidence
of disease activity in a 7-year longitudinal multiple sclerosis cohort.
JAMA Neurol. 2015;72:152–8.
81. Paty DW, Li DK, Group UMMS, Group IMSS. Interferon beta-lb
is effective in relapsing-remitting multiple sclerosis. II. MRI anal-
ysis results of a multicenter, randomized, double-blind, placebo-
controlled trial. 1993 [classical article]. Neurology. 2001;57:S10–15.
82. Interferon beta-1b in the treatment of multiple sclerosis: final
outcome of the randomized controlled trial. The IFNB Multiple
Sclerosis Study Group and The University of British Columbia
MS/MRI Analysis Group. Neurology. 1995;45:1277–85.
83. Li DK, Paty DW. Magnetic resonance imaging results of the PRISMS
trial: a randomized, double-blind, placebo-controlled study of inter-
feron-beta1a in relapsing-remitting multiple sclerosis. Prevention
of Relapses and Disability by Interferon-beta1a Subcutaneously in
Multiple Sclerosis. Ann Neurol. 1999;46:197–206.
84. Randomised double-blind placebo-controlled study of inter-
feron beta-1a in relapsing/remitting multiple sclerosis. PRISMS
(Prevention of Relapses and Disability by Interferon beta-1a
Subcutaneously in Multiple Sclerosis) Study Group. Lancet.
1998;352:1498–504.
85. Jacobs LD, Cookfair DL, Rudick RA, et al. Intramuscular interferon
beta-1a for disease progression in relapsing multiple sclerosis.
Ann Neurol. 1996;39:285–94.
86. Simon JH, Jacobs LD, Campion M, et al. Magnetic resonance studies
of intramuscular interferon beta-1a for relapsing multiple sclerosis.
Ann Neurol. 1998;43:79–87.
87. Johnson KP, Brooks BR, Cohen JA, et al. Copolymer 1 reduces relapse
rate and improves disability in relapsing-remitting multiple sclerosis:
results of a phase III multicenter, double-blind placebo-controlled
trial. Neurology. 1995;45:1268–76.
S16 June 2018
NR_MS Board Review Supplement 2018_v10.indd 16
View publication stats
88. O’Connor P, Wolinsky JS, Confavreux C, et al. Randomized trial of
oral teriflunomide for relapsing multiple sclerosis. N Engl J Med.
2011;365:1293–303.
89. Fox RJ, Miller DH, Phillips JT, et al. Placebo-controlled phase 3
study of oral BG-12 or glatiramer in multiple sclerosis. N Engl J Med.
2012;367:1087–97.
90. Gold R, Kappos L, Arnold DL, et al. Placebo-controlled phase 3
study of oral BG-12 for relapsing multiple sclerosis. N Engl J Med.
2012;367:1098–107.
91. Cohen JA, Barkhof F, Comi G, et al. Oral fingolimod or intra-
muscular interferon for relapsing multiple sclerosis. N Engl J Med.
2010;362:402–15.
92. Kappos L, Radue EW, O’Connor P, et al. A placebo-controlled trial
of oral fingolimod in relapsing multiple sclerosis. N Engl J Med.
2010;362:387–401.
93. Novartis PARADIGMS data show children and adolescents with
MS had an 82% lower relapse rate with Gilenya® vs. interferon
beta-1a [press release]. October 28, 2017. https://novartis.gcs-
web.com/Novartis-PARADIGMS-data-show-children-and-
adolescents-with-MS-had-an-82-percent-lower-relapse-rate-with-
Gilenya-vs-interferon-beta-1a. Accessed April 17, 2018.
94. Rudick RA, Stuart WH, Calabresi PA, et al. Natalizumab plus interferon
beta-1a for relapsing multiple sclerosis. N Engl J Med. 2006;354:911–23.
95. Polman CH, O’Connor PW, Havrdova E, et al. A randomized,
placebo-controlled trial of natalizumab for relapsing multiple
sclerosis. N Engl J Med. 2006;354(9):899-910.
96. Hauser SL, Bar-Or A, Comi G, et al. Ocrelizumab versus
interferon beta-1a in relapsing multiple sclerosis. N Engl J Med.
2017;376:221–34.
97. Montalban X, Hauser SL, Kappos L, et al. Ocrelizumab versus
placebo in primary progressive multiple sclerosis. N Engl J Med.
2017;376:209-220.
98. Cohen JA, Coles AJ, Arnold DL, et al. Alemtuzumab versus inter-
feron beta 1a as first-line treatment for patients with relapsing-
remitting multiple sclerosis: a randomised controlled phase 3 trial.
Lancet. 2012;380:1819–28.
99. Coles AJ, Twyman CL, Arnold DL, et al. Alemtuzumab for patients
with relapsing multiple sclerosis after disease-modifying therapy:
a randomised controlled phase 3 trial. Lancet. 2012;380:1829–39.
100. Pawate S, Bagnato F. Newer agents in the treatment of multiple
sclerosis. Neurologist. 2015;19:104–17.
101. Lassmann H, van Horssen J, Mahad D. Progressive multiple sclerosis:
pathology and pathogenesis. Nat Rev Neurol. 2012;8:647–56.
102. Kappos L, Bar-Or A, Cree BAC, et al. Siponimod versus placebo in
secondary progressive multiple sclerosis (EXPAND): a double-blind,
randomised, phase 3 study. Lancet. 2018;391:1263–73.
103. Plemel JR, Juzwik CA, Benson CA, et al. Over-the-counter anti-
oxidant therapies for use in multiple sclerosis: A systematic review.
Mult Scler. 2015;21:1485–95.
104. Sundstrom P, Salzer J.Vitamin D and multiple sclerosis-from epidemi-
ology to prevention. Acta Neurol Scand. 2015;132:56–61.
105. 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;39:288–93.
106. Dorr J, Ohlraun S, Skarabis H, Paul F. Efficacy of vitamin D supple-
mentation in multiple sclerosis (EVIDIMS Trial): study protocol for a
randomized controlled trial. Trials. 2012;13:15.
107. Coyle PK. Symptom Management and lifestyle modifications in mul-
tiple sclerosis. Continuum. 2016;22:815–36.
108. Bradshaw MJ, Farrow S, Motl RW, Chitnis T. Wearable biosensors
to monitor disability in multiple sclerosis. Neurol Clin Pract.
2017;7:354–62.
5/24/18 11:35 AM