REVIEW ARTICLE

Diagnosis of Multiple
Sclerosis

C O N T I N UU M A UD I O
I NT E R V I E W A V AI L A B L E
ONLINE
By Jiwon Oh, MD, PhD, FRCPC

ABSTRACT
PURPOSE OF REVIEW: The diagnosis of multiple sclerosis (MS) can be made
based on clinical symptoms and signs alone or a combination of clinical
and paraclinical features. Diagnostic criteria for MS have evolved over
time, and the latest version facilitates earlier diagnosis of MS in those
presenting with typical clinical syndromes. This article summarizes the
current diagnostic criteria for MS, typical and atypical presentations of
MS, and when diagnostic criteria should be applied with caution.

RECENT FINDINGS: The most recent version of the MS diagnostic criteria has
the benefits of simplicity and greater sensitivity in comparison to previous
iterations. However, misdiagnosis remains a significant issue in MS clinical
care, even at MS specialty centers. It is, therefore, evident that careful
clinical application of the current version of the diagnostic criteria is
CITE AS:
necessary and that tools improving the diagnostic accuracy of MS would
CONTINUUM (MINNEAP MINN)
2022;28(4, MULTIPLE SCLEROSIS be of substantial clinical utility. Emerging diagnostic biomarkers that may
AND RELATED DISORDERS): be useful in this regard, including the central vein sign, paramagnetic rim
1006–1024.
lesions, and fluid biomarkers, are discussed.
Address correspondence to
Dr Jiwon Oh, 30 Bond St, 17-742 SUMMARY: Current MS diagnostic criteria facilitate the early diagnosis of MS
PGT, Toronto, Ontario M5B1W8, in people presenting with typical clinical syndromes but should be used
Canada, JIWON.OH@
unityhealth.to. cautiously in those presenting with atypical syndromes and in special
populations. Clinical judgment and existing paraclinical tools, including
RELATIONSHIP DISCLOSURE:
sequential MRIs of the neuraxis and laboratory tests, are useful in
Dr Oh has received personal
compensation in the range of minimizing misdiagnosis and facilitating the accurate diagnosis of MS.
$500 to $4999 for serving as a Diagnostic biomarkers that may facilitate or refute a diagnosis of MS in
consultant for Biogen,
Bristol-Myers Squibb Company,
these settings, and emerging imaging and fluid biomarkers may eventually
and Novartis AG and in the become available for use in clinical settings.
range of $5000 to $9999 for
serving as a consultant for EMD
Serono, F. Hoffmann-La Roche
Ltd, and Sanofi. The institution
of Dr Oh has received research INTRODUCTION

M
support from Biogen, EMD ultiple sclerosis (MS) is often described as a chronic neurologic
Serono, and F. Hoffman-La
condition with lesions disseminated in time and space. Before
Roche Ltd.
the availability of paraclinical tests, the diagnosis of MS
UNLABELED USE OF necessitated demonstration of these hallmark principles from a
PRODUCTS/INVESTIGATIONAL
USE DISCLOSURE:
clinical standpoint, based on clinical history and neurologic
Dr Oh reports no disclosure. examination findings. Contemporary diagnostic criteria also have been built on
the principles of dissemination in space and dissemination in time and require
© 2022 American Academy demonstration of these features clinically or in conjunction with paraclinical
of Neurology. tests, which typically include MRI and CSF studies.1,2

1006 AUGUST 2022

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 Because of the transient nature of clinical symptomatology, the myriad clinical KEY POINTS
symptoms that can constitute a first relapse related to MS, the variability of
● Typical clinical features
disease course across individuals, and subjectivity related to individual variability of a first multiple sclerosis
in symptom reporting, the diagnosis of MS can be challenging. More recent (MS) relapse last for a
iterations of the McDonald diagnostic criteria, while facilitating an early minimum of 24 hours and
diagnosis of MS, have increased the risk of misdiagnosis when applied too present with unilateral visual
changes and eye pain,
liberally. The simultaneous expansion of disease-modifying therapies with
unilateral sensory or motor
immunosuppressive properties increases the risk of misdiagnosis. Moreover, symptoms with or without
current diagnostic criteria are limited with respect to generalizability to different accompanying bladder or
populations, including different ethnic populations and pediatric patients.1 bowel dysfunction, or
infratentorial symptoms.
This article reviews typical clinical and paraclinical features of MS, diagnostic
red flags, the latest diagnostic criteria, limitations of the current diagnostic ● The 2017 McDonald
criteria, and emerging tools that may become useful diagnostic tools in the criteria facilitate the
near future. diagnosis of MS in patients
presenting with typical
clinical syndromes.
DIAGNOSIS OF CLINICALLY ISOLATED SYNDROME/RELAPSING-
REMITTING MULTIPLE SCLEROSIS ● The diagnosis of
Typical clinical features suggestive of a first clinical relapse of MS include relapsing-remitting MS can
unilateral visual changes and eye pain suggestive of optic neuritis and unilateral be made based on clinical
criteria alone, but MRI of the
sensory or motor symptoms with or without accompanying bladder or bowel
brain and cervical spinal
dysfunction, as well as infratentorial symptoms that can include imbalance, cord, if possible, is
incoordination, diplopia, or vertigo. The typical duration of clinical recommended in all patients
symptomatology is a minimum of 24 hours, but these symptoms frequently can where the diagnosis is being
considered.
persist for days to weeks. Accompanying clinical signs are required on neurologic
examination to meet clinical criteria (TABLE 2-1).1 ● Dissemination in time and
Although seemingly straightforward at first glance, with the subjective nature space can be demonstrated
of symptom reporting (where individual patients have differing thresholds of by using clinical and
reporting or noticing symptoms) and the requirement for the persistence of these paraclinical criteria.
symptoms for a minimum of 24 hours, it is not uncommon in the real world that ● Misdiagnosis in MS is not
it can be ambiguous whether symptoms strictly meet these stipulations. In uncommon.
addition, it is well known that symptoms such as fatigue, cognitive dysfunction,
and mood symptoms are commonly observed in MS and frequently accompany ● MS diagnostic criteria
should be applied only to
MS relapses.3,4 However, these symptoms in isolation cannot be classified as an
patients presenting with
MS relapse, although it is not uncommon that patients will report one of these typical clinical syndromes
symptoms as one of the most dominant features of a relapse. As such, if a patient because they were never
presents with fatigue, cognitive dysfunction, or mood symptoms in combination designed to differentiate
or isolation, this is considered an “atypical” presentation and, strictly speaking, between MS and other
neurologic conditions.
cannot be considered a clinically isolated syndrome (CIS) or first presentation of
MS. The idea of a cognitive relapse, however, is gaining increasing recognition ● Even in those presenting
and has been demonstrated in clinical settings and clinical trial settings.4 As of yet with typical clinical
though, cognitive dysfunction alone cannot be classified as a “typical” presenting syndromes who meet MS
diagnostic criteria, the
symptom of MS. neurologist should use
clinical judgment and
DIAGNOSTIC CRITERIA appropriate tests to ensure
Diagnostic criteria in MS facilitate a rapid diagnosis of CIS or relapsing-remitting no better clinical
explanation for the patient’s
MS (RRMS) in patients who present with typical demyelinating syndromes that
clinical presentation is
were highlighted in the previous section. Previous criteria, including the Poser present.
criteria, focused exclusively on clinical symptoms and signs.2 The emergence of
the McDonald criteria in 2001 marked a new era in the diagnosis of MS where
paraclinical criteria (namely, MRI features) were incorporated so that the

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DIAGNOSIS OF MULTIPLE SCLEROSIS

hallmark features of dissemination in space and dissemination in time could be

met using a combination of clinical and MRI features.5
The McDonald criteria have since undergone numerous revisions (2005, 2010,
and most recently 2017).1,5-7 The latest revisions of the McDonald criteria have
the benefit of higher sensitivity but also have a slight decrease
in specificity compared with previous iterations.1
When an individual presents with a typical clinical syndrome with appropriate
objective evidence of a neurologic deficit on examination, the 2017 revisions of
the McDonald criteria stipulate that the principles of dissemination in space and
dissemination in time can be established through a variety of means (TABLE 2-1).
If a patient has a prior history of a suggestive neurologic syndrome with objective
findings in a distinct region on examination, then the patient meets the diagnosis
of RRMS based on clinical features alone. However, even if a diagnosis can be
made based on clinical features alone, it is always prudent, if possible, to obtain
an MRI of the brain and, if clinically indicated, the spinal cord.1

TABLE 2-1 2017 McDonald Criteria for Diagnosis of Relapse-Onset Multiple Sclerosisa,b

Number of lesions with Additional data needed for a

Number of clinical attacks objective clinical evidence diagnosis of multiple sclerosis

≥2 clinical attacks ≥2 Nonec

≥2 clinical attacks 1 (and clear-cut historical evidence of Nonec

a prior attack involving a lesion in a
distinct anatomic location)d

≥2 clinical attacks 1 Dissemination in space demonstrated by an additional

clinical attack implicating a different central nervous
system (CNS) site or by MRI

1 clinical attack ≥2 Dissemination in time demonstrated by an additional

clinical attack or by MRI or CSF-specific oligoclonal
bands

1 clinical attack 1 Dissemination in space demonstrated by an additional

clinical attack implicating a different CNS site or by
MRI
AND
Dissemination in time demonstrated by an additional
clinical attack or by MRI
OR
Demonstration of CSF-specific oligoclonal bands

CSF = cerebrospinal fluid; MRI = magnetic resonance imaging.

a
Modified with permission from Thompson AJ, et al, Lancet Neurol.1 © 2018 Elsevier Ltd.
b
If the 2017 McDonald criteria are fulfilled and there is no better explanation for the clinical presentation, the diagnosis is multiple sclerosis. If
multiple sclerosis is suspected by virtue of a clinically isolated syndrome but the 2017 McDonald criteria are not completely met, the diagnosis is
possible multiple sclerosis. If another diagnosis arises during the evaluation that better explains the clinical presentation, the diagnosis is not
multiple sclerosis.
c
No additional tests are required to demonstrate dissemination in space and time. However, unless MRI is not possible, brain MRI should be
obtained in all patients in whom the diagnosis of multiple sclerosis is being considered.
d
Clinical diagnosis based on objective clinical findings for two attacks is most secure. Reasonable historical evidence for one past attack, in the
absence of documented objective neurologic findings, can include historical events with symptoms and evolution characteristic of a previous
inflammatory demyelinating attack; at least one attack, however, must be supported by objective findings. In the absence of residual objective
evidence, caution is needed.

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 If a patient has no prior neurologic history, dissemination in space and
dissemination in time can be met by using either MRI or laboratory criteria
(TABLE 2-2).1 Specifically, dissemination in space criteria can be met by
demonstrating T2-hyperintense MRI lesions in two of the four typical anatomic
locations where MS-related white matter lesions are often identified
(periventricular, juxtacortical/cortical, infratentorial, spinal cord). Of note, the
2017 revisions of the McDonald criteria now include cortical lesions as a
characteristic anatomic location of MS-related lesions, with the awareness that
specialized MRI sequences are required to detect such lesions.
Dissemination in time criteria can be fulfilled by demonstrating the simultaneous
presence of gadolinium-enhancing and nonenhancing lesions. In addition, the 2017
McDonald Criteria state that dissemination in time can be demonstrated by the
presence of CSF-specific oligoclonal bands, as long as dissemination in space
criteria are met and the patient presents with a typical clinical syndrome.1
In addition to the aforementioned changes, the 2017 McDonald criteria allow
for the inclusion of symptomatic lesions to constitute dissemination in space and
dissemination in time, which simplifies the use of MRI lesions compared with
previous iterations. Specific changes of the 2017 McDonald criteria compared
with the 2010 McDonald criteria are summarized in TABLE 2-3.
Compared with previous iterations, the 2017 McDonald criteria have the
benefit of simplicity, particularly regarding MRI criteria, thus facilitating a rapid
diagnosis of MS and increasing sensitivity for a diagnosis of MS in people
presenting with typical clinical syndromes. However, specificity is slightly
compromised relative to previous diagnostic criteria, meaning that the risk of
misdiagnosis is increased.1 Misdiagnosis in MS is not uncommon, even at MS
specialty centers, and has been estimated to be between 10% and 15%, although

2017 McDonald Criteria for Demonstration of Dissemination in Space and TABLE 2-2
Time by MRI in a Patient With a Clinically Isolated Syndromea

Dissemination in space
◆ Can be demonstrated by one or more T2-hyperintense lesionsb that are characteristic of
multiple sclerosis in two or more of four areas of the central nervous system:
◇ Periventricular
◇ Cortical or juxtacortical
◇ Infratentorial brain regions
◇ Spinal cord
Dissemination in time
◆ Can be demonstrated by:
◇ The simultaneous presence of gadolinium-enhancing and nonenhancing lesionsb at any time
◇ A new T2-hyperintense or gadolinium-enhancing lesion on follow-up MRI, with reference
to a baseline scan, irrespective of the timing of the baseline MRI

MRI = magnetic resonance imaging.

a
Modified with permission from Thompson AJ, et al, Lancet Neurol.1 © 2018 Elsevier Ltd.
b
Unlike the 2010 McDonald criteria, no distinction between symptomatic and asymptomatic MRI lesions is
required.

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DIAGNOSIS OF MULTIPLE SCLEROSIS

the true prevalence is unknown.8-10 Misdiagnosis can have substantial personal,

medical, professional, and societal repercussions; therefore, great care must be
taken to use the MS diagnostic criteria appropriately, and the specific caveats of
these criteria need to be kept in mind when using them in clinical practice.
Specifically, these criteria should be applied only to those patients with typical
clinical syndromes because the intention of the diagnostic criteria is to
facilitate diagnosis in an individual who already has a high likelihood of having
MS, based on clinical symptomatology, signs, and demographics. In addition,
even if an individual presents with a typical clinical syndrome and meets
dissemination in space and dissemination in time criteria, the diagnostic criteria
stipulate that the clinical presentation should have no better explanation, which
necessitates a reasonable workup and consideration of other differential
diagnoses. Because the MRI-based section of the McDonald criteria was not
designed to differentiate between MS and other neurologic conditions, in
situations where atypical clinical features are present, the threshold to pursue
additional tests (MRIs of the neuraxis, serial MRI, CSF studies, and other
laboratory testing to investigate alternate diagnoses) should be low. In cases with
atypical clinical features, longitudinal follow-up and the demonstration of typical
clinical or MRI findings supportive of the diagnosis of MS, while ruling out
alternative diagnoses, are essential to prevent misdiagnosis and the inappropriate
exposure to immunomodulating/immunosuppressant therapies in a situation
where MS is ultimately not the diagnosis.1
Another noteworthy point is that the McDonald diagnostic criteria have been
predominantly validated in White adult European and North American patient
populations, which limits the generalizability of these criteria. Therefore, in
certain populations, which include pediatric and ethnically diverse populations,
additional caution must be taken when using these criteria. Studies in 2012 and
2014, however, demonstrated that the current diagnostic criteria may be valid in
ethnically diverse populations, but larger studies are needed.11-14
Finally, visual system structural changes demonstrated by using MRI, optical
coherence tomography, or evoked potentials do not yet constitute paraclinical
evidence of dissemination in space because of a lack of sufficient evidence.
Including MRI or evoked potential evidence of a lesion in the anterior visual
system as a fifth typical anatomic location resulted in a nominal increase in
sensitivity but a decrease in specificity, which prevented the inclusion of this
region in the 2017 McDonald Criteria.1 However, with increasing access and
improvements in technology, it is possible that this may change in future

TABLE 2-3 Features of the 2017 McDonald Criteria That Differ From the 2010 Criteria

◆ Cortical lesions (together with juxtacortical lesions) can be used to fulfill MRI criteria for
dissemination in space
◆ Both symptomatic and asymptomatic lesions can be used to fulfill dissemination in space or
dissemination in time criteria
◆ Presence of CSF-specific oligoclonal bands can demonstrate dissemination in time in
those presenting with a typical clinical syndrome and meeting dissemination in space criteria

CSF = cerebrospinal fluid; MRI = magnetic resonance imaging.

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iterations of the MS diagnostic criteria, given the importance of the visual system
in MS pathophysiology.

CLINICAL AND PARACLINICAL RED FLAGS

Clinicians should be aware of several clinical and paraclinical red flags that
should raise caution about a diagnosis of MS (TABLE 2-43 and TABLE 2-515); among
these are transient neurologic symptoms lasting less than 24 hours, severe and
bilateral optic neuritis, severe unilateral optic neuritis with poor recovery, severe
transverse myelopathy with hyperacute onset and bilateral sensorimotor
symptoms, multiple cranial neuropathies, complete gaze palsy, headache and
meningismus, isolated fatigue, and generalized weakness (TABLE 2-4).
Numerous useful reviews have summarized atypical clinical features of MS in
detail and can provide more detailed information.3,16
From an imaging standpoint, MRI features that should be considered red flags
for a diagnosis of MS include symmetric lesions, meningeal enhancement,
siderosis, indistinct and increasing lesions, hemorrhages, infarcts, extensive

Typical and Atypical Presentations of Clinically Isolated Syndrome or TABLE 2-4

Relapsing-Remitting Multiple Sclerosisa

Typical presentations
◆ Acute unilateral optic neuritis
◆ Double vision due to an internuclear ophthalmoplegia or sixth nerve palsyb
◆ Facial sensory loss or trigeminal neuralgiab
◆ Cerebellar ataxia and nystagmus
◆ Partial myelopathy
◆ Sensory symptoms in a central nervous system pattern
◆ Lhermitte symptom
◆ Asymmetric limb weakness
◆ Urge incontinence or erectile dysfunction
Atypical or red flag presentations that may suggest an alternative diagnosis
◆ Bilateral optic neuritis or unilateral optic neuritis with a poor visual recovery
◆ Complete gaze palsy or fluctuating ophthalmoparesis
◆ Intractable nausea, vomiting, or hiccups
◆ Complete transverse myelopathy with bilateral motor and sensory involvement
◆ Encephalopathy
◆ Subacute cognitive decline
◆ Headache or meningism
◆ Isolated fatigue or asthenia
◆ Constitutional symptoms

a
Modified with permission from Brownlee WJ, et al, Lancet.3 © 2017 Elsevier Ltd.
b
In a young adult (younger than 40 years of age).

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DIAGNOSIS OF MULTIPLE SCLEROSIS

spinal cord lesions, and lesions sparing U fibers, among others. The mnemonic
MIMICS has been proposed to summarize features of MRI red flags (TABLE 2-5).
A detailed discussion of atypical MRI features is summarized in a 2018 review.15
Finally, the absence of CSF-specific oligoclonal bands, as well as significant CSF
pleocytosis (eg, greater than 50 cells/mm3), significantly elevated CSF protein (eg,
greater than 100 mg/dL), and the presence of atypical cells (neutrophils,
eosinophils, other atypical cells) should be considered laboratory-based red flags
when MS is being considered as a diagnosis.1 CSF-specific oligoclonal bands are
seen in approximately 90% of people with MS, which is why their absence should
make clinicians consider alternative diagnoses.17 It is important to keep in mind,
however, that CSF-specific oligoclonal bands are not specific for MS and can be
seen in a variety of other neurologic disorders, including neuromyelitis optica,
neurosarcoidosis, and central nervous system vasculitis, among others. In
addition, it is important to adequately rule out other neurologic disorders in the
inflammatory and noninflammatory spectrum by using appropriate laboratory
tests (systemic autoimmune screen, metabolic screen, genetic tests) when
clinically indicated (TABLE 2-6).
CASE 2-1 and CASE 2-2 illustrate typical and atypical clinical presentations
of RRMS.

PRIMARY PROGRESSIVE MULTIPLE SCLEROSIS

The diagnosis of primary progressive MS can be made when an individual
demonstrates neurologic progression over a minimum of 1 year and fulfills two of
four additional criteria, outlined in TABLE 2-7.1 These criteria emphasize the
importance of insidious neurologic progression and MRI-based spinal cord
lesions, which are known to be more dominant in progressive forms of MS
compared with relapsing forms.1

TABLE 2-5 MRI Red Flags Mnemonica

Letter Red flag MRI features

M Meningeal enhancement

I Indistinct lesions
Increasing lesions
M Macrobleeds
Microbleeds
I Infarcts

C Cavities
Complete ring enhancement
S Symmetric lesions
Sparing of U fibers
Siderosis
Spinal cord longitudinally extensive lesions (≥3 spinal
cord segments)

MRI = magnetic resonance imaging.

a
Modified with permission from Geraldes R, et al, Nat Rev Neurol.15 © 2018 Nature Publishing Group.

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 Similar to the diagnostic criteria for RRMS, these diagnostic criteria can be
challenging to apply early in the disease course when neurologic signs are
minimal, no evident functional decline is seen, and it is not overtly evident
whether a symptom is truly progressing or not. In such situations, the diagnosis
of primary progressive MS is dependent on an individual’s subjective perception
of symptoms. When symptoms are subtle and cause minimal impairment of
functioning, it can be understandably difficult to know definitively whether clear
progression has occurred. Moreover, other factors can affect the perception of
neurologic worsening, including mood disorders and fatigue, as well as
deconditioning (or conversely, conditioning), as illustrated by CASE 2-3. Because
of all of these factors, the diagnosis of primary progressive MS can often be
delayed by many years.

OTHER RELEVANT DISORDERS

Relevant disorders in the spectrum of MS, including radiologically isolated
syndrome (RIS) and solitary sclerosis, can be challenging from a clinical
management perspective. Both disorders share common characteristics with MS,
and it is known that a proportion of those with RIS and solitary sclerosis carry a

Laboratory Investigations to Consider in Atypical Clinical Presentations TABLE 2-6

Atypical or red flag presentations Laboratory and other investigations to consider

Bilateral optic neuritis or unilateral optic
neuritis with poor visual recovery
Anti–aquaporin-4 (AQP4) antibody (neuromyelitis optica [NMO]-IgG),
anti–myelin oligodendrocyte glycoprotein (MOG) antibody, toxic/metabolic
(vitamin B12, copper, etc), infectious screen (Bartonella, syphilis, Lyme,
tuberculosis, etc), systemic autoimmune screen (erythrocyte sedimentation
rate [ESR], C-reactive protein [CRP], antinuclear antibody [ANA], extractable
nuclear antigen [ENA], angiotensin-converting enzyme [ACE]), genetic tests
(eg, Leber hereditary optic neuropathy), optical coherence tomography

Complete gaze palsy or fluctuating Chest imaging (chest x-ray or CT)/positron emission tomography (PET)
ophthalmoparesis scan/tissue biopsy to assess for sarcoid, malignancy screen (imaging, CSF
cytology, and flow cytometry), systemic autoimmune screen, infectious
screen (viral, tuberculosis, Lyme, fungal, etc), additional imaging to assess
for ischemic/vascular etiologies, neuromuscular etiologies

Intractable nausea, vomiting, or hiccups Anti-AQP4 antibody (NMO-IgG), anti-MOG antibody

Complete transverse myelopathy with
bilateral motor and sensory involvement
Anti-AQP4 antibody (NMO-IgG), anti-MOG antibody, systemic autoimmune
screen (ESR, CRP, ANA, ENA), ACE, infectious screen (herpes viruses,
mycoplasma, tuberculosis, human immunodeficiency virus [HIV], human
T-cell lymphotropic virus type I [HTLV-I], etc), additional imaging (spinal
magnetic resonance angiography, digital subtraction angiography) to assess
for vascular causes (ischemia, vascular lesion), toxic/metabolic screen
(vitamin B12, copper, ceruloplasmin, etc)

Encephalopathy, subacute cognitive decline, Infectious screen, malignancy screen (imaging, CSF cytology, and flow
headache or meningism, isolated fatigue or cytometry), systemic autoimmune/vasculitis screen (ESR, CRP, ANA, ENA,
asthenia, constitutional symptoms antineutrophil cytoplasmic antibodies), toxic/metabolic screen,
paraneoplastic antibody panel

CSF = cerebrospinal fluid; CT = computed tomography; IgG = immunoglobulin G.

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DIAGNOSIS OF MULTIPLE SCLEROSIS

CASE 2-1 A 27-year-old woman presented with numbness and tingling in her
bilateral lower limbs that extend up to her midtorso. Initially, she had a
subtle change in sensation in her legs, but over the course of 5 days, the
abnormal sensations had increased in intensity substantially. She had also
noticed a tight sensation around her torso. She denied any problems with
bladder or bowel function and had not noticed any weakness, although
she felt slightly off balance when walking. She denied any prior history of
transient neurologic symptoms. She had a history of occasional migraines
that were treated effectively with over-the-counter medications but no
other past medical history.
On examination, she had diminished sensation to light touch and an
increased vibration sensation threshold in her toes, which was normal at
the ankles. Neurologic examination was otherwise intact. She had a
sensory level at C5.
MRI of her brain showed a single periventricular lesion orientated
perpendicularly to the lateral ventricle. She had a gadolinium-enhancing
lesion at C6. She had one other subcortical lesion in the left frontal white
matter that was neither juxtacortial nor infratentorial, and the appearance
was nonspecific. A lumbar puncture showed CSF-specific oligoclonal
bands, with no white blood cells or other abnormal findings. Her serum
erythrocyte sedimentation rate, C-reactive protein, antinuclear antibody,
and vitamin B12 values were normal.
This patient had typical clinical features suggestive of clinically isolated
syndrome (CIS) with symptoms consistent with a partial sensory myelitis.
Her neurologic examination corroborated her subjective symptoms. Her
lesion burden, while minimal, met the McDonald criteria for dissemination
in space based on having a characteristic periventricular lesion and a
spinal cord lesion. Because the 2017 revisions enable the use of
symptomatic lesions in diagnosis, the simultaneous presence of
gadolinium-enhancing and nonenhancing lesions meets the criteria for
dissemination in time. Moreover, the presence of CSF-specific
oligoclonal bands is further supportive of dissemination in time.

COMMENT This case is an illustration of a typical case of early relapsing-remitting

multiple sclerosis (RRMS). This patient’s clinical features are consistent with
a typical CIS. In addition, her MRI findings, although minimal, are consistent
with RRMS, and she meets criteria even with this first presentation.
Management considerations at this point include initiating
disease-modifying therapy, which will be a joint decision between the
patient and her neurologist based on a combination of prognostic features,
patient preference, and family planning, in addition to other considerations.

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risk of developing MS over time.18,19 Although more evidence is required to KEY POINTS
better understand the risk of patients with these disorders developing MS and
● It is important to be
where they should fall in the diagnostic spectrum, these situations are not vigilant for clinical and
uncommon in clinical practice and are challenging to manage because of the lack paraclinical red flags when
of formal guidelines for these entities. considering a diagnosis of
Radiologically isolated syndrome refers to individuals with incidentally MS in an individual patient.
identified MRI findings that look indistinguishable from established MS.
● The diagnosis of primary
Diagnostic criteria for RIS are summarized in TABLE 2-8.18,20 The true incidence progressive MS can be made
of RIS is unknown because patients with RIS come to clinical attention when clinical and
serendipitously. Retrospective studies have shown that approximately 50% of paraclinical criteria are
these patients develop MS over a median follow-up of 10 years.21 Factors that fulfilled as outlined in the
2017 McDonald criteria.
increase the likelihood of patients with RIS converting to MS based on
retrospective studies include male sex; age younger than 37 years; presence of ● Radiologically isolated
spinal cord lesions, infratentorial lesions, and CSF-specific oligoclonal bands; and syndrome and solitary
the development of gadolinium-enhancing lesions on follow-up MRI.19,21 sclerosis are not yet
considered in the diagnostic
At the present time, RIS can be challenging from a clinical management spectrum of MS, but this
standpoint, as CASE 2-422,23 illustrates, because no clear, evidence-based may be revisited in future
guidelines for managing these patients have been established. It is clear that a revisions of MS diagnostic
proportion of patients are at a higher risk of developing MS, and based on what is criteria. These disorders can
be challenging to manage
known in established MS, early treatment appears to be key in reducing the risk
from a clinical standpoint
of disability progression over time. Ongoing clinical trials are evaluating the because of a lack of clear
efficacy of disease-modifying therapies (DMTs) that are currently approved for guidelines regarding
use in relapsing MS in decreasing the risk of RIS converting to MS, which will be management.
informative for clinical practice.23,24 In addition, studies are evaluating novel
● Several emerging imaging
imaging and fluid biomarkers that may have prognostic utility in RIS and with and fluid biomarkers are
further validation may enable personalized treatment in patients with RIS who demonstrating utility as
have high-risk prognostic features.25,26 diagnostic biomarkers of
In addition to RIS, interest is increasing in a possible clinical presentation MS. With further validation,
these measures may
before the diagnosis of MS, described as the MS “prodrome.” Studies from facilitate diagnosis and
various regions of the world have demonstrated that, 5 to 10 years before the prevent misdiagnosis in
diagnosis of MS, patients have a higher use of health care services, including clinical practice.
visits to general practitioners and specialists, and use of prescription medication,
and they have a constellation of nonspecific symptoms, including pain,
headache, and fatigue, as well as mood symptoms.27,28
Given the accumulating evidence regarding RIS and the clinical MS prodrome,
it is clear that the pathophysiologic processes underlying MS occur many
years before the onset of recognized typical clinical symptoms. The question
of whether the diagnosis of MS should include patients who are presymptomatic
or in a prodromal stage is clinically and scientifically relevant and may be
revisited in the next iteration of the diagnostic criteria. In addition, although
prior diagnostic criteria, clinical trials, and research studies emphasized the
difference between CIS and RRMS and the clear distinction between progressive
and relapsing MS subtypes, evidence is increasing that all subtypes of MS exist
on a disease continuum and that CIS and “presymptomatic MS” may be
considered along the same diagnostic continuum. As such, it is possible that
future iterations of the diagnostic criteria may substantially revise the existing
classification of MS.
Solitary sclerosis describes individuals with isolated or minimal “critical”
lesions in the central nervous system who demonstrate progressive neurologic
decline related to the single lesion.29,30 These individuals do not meet clinical

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DIAGNOSIS OF MULTIPLE SCLEROSIS

criteria for MS because of the paucity of lesions, yet their clinical course is quite
suggestive of progressive MS. With the emergence of therapies targeted toward
progressive MS subtypes, the question of whether these patients should be
included in the classification of MS is clinically relevant, and more study is
required to better understand how to optimally manage these patients. This
is another disease entity that may be revisited in future iterations of
diagnostic criteria.

TRENDS
Several emerging paraclinical tests may have utility in the diagnosis of MS.
Among candidate MRI measures, the central vein sign stands out as one
imaging measure that has already demonstrated substantial utility as a diagnostic
biomarker in MS, and it is being validated in large, prospective clinical trials.
When appropriate susceptibility-based MRI sequences are used, it is often
possible to visualize central veins within white matter lesions, which are thought
to be suggestive of lesions that have formed due to perivenular inflammation and
demyelination, a pathologic hallmark of MS-related lesions (FIGURE 2-1).31-33

CASE 2-2 A 55-year-old woman presented with an episode of extreme fatigue,

generalized weakness, and cognitive difficulties manifesting as
difficulties with multitasking and working memory that lasted for 2 weeks
and then gradually resolved. She did not have any systemic features such
as fever, rash, respiratory symptoms, or gastrointestinal systems
concurrently. She also noted aching pain in her bilateral lower limbs but
no other focal neurologic symptoms such as changes in vision, hearing,
speech, swallowing, focal weakness, paresthesia or sensation loss, or
bladder or bowel symptoms. She took a few days off of work as an
accountant during this time because she found it difficult to concentrate
and complete routine tasks at work. On further inquiry, she recalled an
episode of numbness in her left face (cheek and lower jaw) 5 years ago
that resolved over 3 weeks. She did not seek medical attention at
that time.
Her past medical history was otherwise only remarkable for
hypercholesterolemia, which was controlled by diet.
On examination, she was awake, alert, and cooperative. Cranial nerve
examination showed no findings. Motor examination showed normal
tone, bulk, power, and reflexes. Sensory examination was intact to light
touch, vibration, and proprioception, and no cerebellar findings or
ambulatory difficulties were present.
MRI of the brain demonstrated three periventricular lesions, one
juxtacortical lesion, and one left lateral pontine lesion. None of the
lesions enhanced with gadolinium. MRI of the spinal cord showed
no lesions.
Although this patient’s brain MRI showed findings suggestive of
multiple sclerosis (MS), she had several clinical red flags that should
make a clinician cautious of a diagnosis of MS. Her atypical presentation,

1016 AUGUST 2022

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Consensus recommendations exist that provide guidance on the optimal
methods to identify the central vein sign within white matter lesions on MRI.33
Numerous studies have demonstrated that people with MS have a high
proportion of white matter lesions demonstrating the central vein sign.31,34,35
Different criteria have been proposed to distinguish MS from other white matter
disorders, but no consensus has been reached as to which set of criteria is most
optimal to use in clinical practice because they differ with respect to sensitivity
and specificity in distinguishing MS from other white matter disorders and
because of the time and labor required for application. The most commonly used
and robust criterion to date seems to be the 40% rule, where if more than 40% of
white matter lesions demonstrate the central vein sign, the likelihood of a
diagnosis of MS is quite high.36 However, this method requires examining all
white matter lesions in an individual MRI scan, which is both time- and labor-
intensive. As such, simplified criteria, including “select 3*”37 (where at least three
lesions have evidence of the central vein sign on specific MRI sequences) and the
“6-lesion rule”31 (where at least six lesions have evidence of the central vein sign
on specific MRI sequences) have been proposed. In comparison with the 40%

lack of examination findings from a historical event that may have been
typical of an MS relapse that took place years ago, and age older than
40 years make the diagnosis of RRMS challenging. In these situations, the
threshold to perform additional paraclinical tests should be low, and
other possible diagnoses need to be ruled out. In addition, longitudinal
follow-up with serial clinical and MRI surveillance, demonstrating typical
radiologic and clinical findings, are essential to confirm the diagnosis.
The patient underwent several additional tests, including CSF studies,
neuromyelitis optica–IgG, and anti–myelin oligodendrocyte glycoprotein
antibody, as well as a systemic autoimmune screen. Her CSF studies
showed 10 white blood cells/mm3 and CSF-specific oligoclonal bands.
The remaining findings were negative.
An MRI the subsequent year showed a new juxtacortical lesion and
cervical spinal cord lesion that occupied only a partial cross-section of
the spinal cord, involving the gray matter and dorsal columns on the left,
which confirmed radiologic dissemination in space and time. The next
year, she presented with left-sided optic neuritis with diminished visual
acuity and red color desaturation. She was treated with steroids with
near-complete recovery.
At that point, the diagnosis of RRMS was confirmed, despite her
atypical initial presentation, and a disease-modifying therapy was
initiated.

In patients presenting with atypical clinical syndromes, performing COMMENT

additional tests to adequately rule out other diagnoses and longitudinal
follow-up to ascertain the emergence of typical clinical and MRI findings
are essential to prevent misdiagnosis.

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DIAGNOSIS OF MULTIPLE SCLEROSIS

TABLE 2-7 2017 McDonald Criteria for Diagnosis of Primary Progressive Multiple
Sclerosisa

One year of disability progression (retrospectively or prospectively determined)

independent of clinical relapse
AND two of the following criteria:
◆ One or more T2-hyperintense lesionsb characteristic of multiple sclerosis in one or more of
the following brain regions: periventricular, cortical or juxtacortical, or infratentorial
◆ Two or more T2-hyperintense lesions in the spinal cord
◆ Presence of CSF-specific oligoclonal bands

CSF = cerebrospinal fluid.

a
Modified with permission from Thompson AJ, et al, Lancet Neurol.1 © 2018 Elsevier Ltd.
b
Unlike the 2010 McDonald criteria, no distinction between symptomatic and asymptomatic MRI lesions is
required.

CASE 2-3 A 45-year-old, previously healthy man had noticed a change in his gait in
the past 2 years. He was not certain when this started but recalled that he
noticed his left leg was “heavy” and that he ambulated with a slight limp
for a few days after a long hike 2 years ago. After first noticing these
symptoms, he had noted fluctuating heaviness in his left leg with
prolonged exertion and found that he was not able to lift as much with his
left leg at the gym as he did in the past. In addition, he was not able to run
or hike the same 10-mile-long distances that he did in the past without
resting.
When probed further, he did not give a clear history of progression over
the past 2 years. He was clear in that these symptoms were not present
more than 2 years ago, but he was not certain if they had progressed. In
fact, he had noticed some improvement in strength and exertional ability
in the past 6 months since starting sessions with a personal trainer.
On neurologic examination, he had brisk reflexes at the left patella and
ankle at 3+ and an upgoing plantar response. He had no clear weakness in
his left leg, but when he was asked to perform deep knee squats using
only one leg, he struggled more than he did with the right.
MRI of his brain and spine showed numerous periventricular,
juxtacortical, and infratentorial lesions characteristic of demyelinating
disease, as well as three lesions in the cervical spinal cord. He had
CSF-specific oligoclonal bands.
This patient had a likely diagnosis of primary progressive multiple
sclerosis (MS). His clinical features were suggestive of neurologic disease
progression independent of relapse for 1 year, although it was uncertain
whether progression had occurred in the past 6 months after fitness
training. This is not an uncommon scenario with early primary progressive
MS and individuals with milder symptoms. The findings on this patient’s

1018 AUGUST 2022

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rule, these criteria sacrifice specificity but are much more efficient to use from a
clinical perspective. Automated methods of central vein sign detection are also
emerging and may facilitate the application of various criteria for central vein
sign detection.38
Although the optimal criteria to use in clinical settings are yet to be
determined, these studies have uniformly demonstrated the utility of the
central vein sign in distinguishing MS from other white matter disorders. In
addition, and perhaps of equal clinical importance, the utility of the central vein
sign in diagnosing MS in patients presenting with atypical syndromes is
being evaluated in a large, multicenter clinical trial.39 Moreover, the utility of
the central vein sign as a prognostic measure in early MS and RIS is also
being evaluated.25 If adequately validated in these studies, it is possible that
the central vein sign may be incorporated in future iterations of the
diagnostic criteria.
Another emerging imaging biomarker of diagnosis in earlier stages of
development is evaluating for paramagnetic rim lesions, which are thought to be

neurologic examination are further supportive of the diagnosis, and he

meets the paraclinical criteria for primary progressive MS in the 2017
McDonald criteria with three of the three features (CSF-specific
oligoclonal bands, one or more T2-hyperintense lesions in a brain region
characteristic of MS, and more than two T2-hyperintense lesions in the
spinal cord). Finally, no clinical or paraclinical red flags were found, and
therefore, there was no better explanation for his clinical picture.
He had a discussion with his neurologist about the likely diagnosis of
primary progressive MS. They discussed the possibility of
disease-modifying therapy and other measures he could pursue to
minimize further neurologic decline, including regular exercise, strength
training, managing comorbidities, and other healthy-living principles.

The diagnosis of primary progressive MS can often be challenging because COMMENT

of the subtle onset and progression of symptoms. If paraclinical tests
support the diagnosis of primary progressive MS, as illustrated by this case,
a probable diagnosis can be made and appropriate counseling provided.
However, if any clinical or paraclinical red flags are noted, it is important to
adequately rule out other diagnoses and follow patients longitudinally to
confirm a definitive diagnosis.
Over 2 years of follow-up, this patient noticed subtle worsening of his
gait and more evident weakness in his left leg, confirming neurologic
disease progression and a definitive diagnosis of primary progressive MS.
Because of concern about progression, he opted to start a disease-
modifying treatment after a clear discussion of potential risks and benefits
with his neurologist.

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DIAGNOSIS OF MULTIPLE SCLEROSIS

an imaging measure reflective of chronic, active lesions.40,41 This measure may

be useful in diagnosing progressive forms of MS as studies have demonstrated
that patients with progressive MS and greater disability have a higher proportion
of lesions demonstrating paramagnetic rim lesions.42 However, because
paramagnetic rim lesions are visualized even in RIS26 and early RRMS,43 much
like the central vein sign, the appropriate threshold beyond which progressive
MS should be considered will need to be determined in future studies before this
measure can be used as an imaging biomarker in clinical settings.
Several fluid biomarkers are also being evaluated for their potential clinical
utility in the diagnosis of MS. Although blood biomarkers such as serum
neurofilament light chain and glial fibrillary acidic protein (GFAP) have
demonstrated utility in prognostication and in disease monitoring, because these
markers are not specific for MS-related tissue injury in isolation, it is unclear if
they are useful as diagnostic biomarkers.44-47 However, these measures, in
combination with other fluid biomarkers or in conjunction with imaging and
clinical criteria, may have utility in the diagnosis of MS as demonstrated by a
study showing elevated serum neurofilament light chain in presymptomatic
individuals 6 years before the diagnosis of MS.48 In addition, these measures may
enable differentiation between relapsing and progressive forms of MS, which
also has significant diagnostic and therapeutic relevance.49,50
To date, the laboratory measure with greatest clinical utility in the diagnosis
of MS is CSF-specific oligoclonal bands, which are also not entirely specific
for MS, but their absence would raise a red flag with respect to a diagnosis of
MS.51,52 The role of oligoclonal bands in the diagnosis of MS has gained even more
prominence in the latest iteration of the McDonald criteria, as discussed earlier,
because their presence can be a substitute for dissemination in time in patients

TABLE 2-8 Radiologically Isolated Syndrome Diagnostic Criteria

The presence of incidentally identified central nervous system (CNS) white matter anomalies
meeting the following MRI criteria:
◆ Ovoid, well-circumscribed, and homogeneous foci with or without involvement of the
corpus callosum
◆ T2 hyperintensities measuring >3 mm and fulfilling Barkhof criteria20 (at least 3 of 4) for
dissemination in space
◆ CNS white matter anomalies
No historical accounts of remitting clinical symptoms consistent with neurologic dysfunction
The MRI anomalies do not account for clinically apparent impairments in social,
occupational, or generalized areas of functioning
The MRI anomalies are not due to the direct physiologic effects of substances (recreational
drug abuse, toxic exposure) or a medical condition
Exclusion of individuals with MRI phenotypes suggestive of leukoaraiosis or extensive white
matter pathology lacking involvement of the corpus callosum
The CNS MRI anomalies are not better accounted for by another disease process

MRI = magnetic resonance imaging.

a
Modified with permission from Okuda DT, et al, Neurology.18 © 2009 American Academy of Neurology.

1020 AUGUST 2022

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 A 32-year-old woman volunteered as a healthy control for a research MRI CASE 2-4
study. She had no significant past medical history.
MRI of her brain showed five periventricular lesions, three juxtacortical
lesions, and two infratentorial lesions, which were flagged by the study
MRI report as lesions that appear suspicious for demyelinating disease.
When she was seen by a neurologist, she denied any prior history of
transient neurologic symptoms. She had a history of migraines, but these
were well controlled on occasional acetaminophen or ibuprofen. Her
neurologic examination was completely unremarkable.
Additional investigations were done, including an MRI of her spinal
cord and CSF studies. She had a single cervical spinal cord lesion that
occupied part of the axial cross-section including a segment of the dorsal
columns and gray matter. She had CSF-specific oligoclonal bands. A
systemic autoimmune workup was negative. Serum vitamin B12 level was
also normal.
This patient met diagnostic criteria for radiologically isolated
syndrome (RIS), in that she had radiologic findings that looked highly
suggestive of established multiple sclerosis (MS) but no current or prior
neurologic symptoms or signs, and no other reasonable explanation for
her MRI findings was found.

The clinical management of RIS is a challenging scenario, where no COMMENT

evidence-based guidelines have been established for optimally managing
these patients. The existing studies show that several risk factors increase
the likelihood of conversion to MS over 5 to 10 years, including male sex,
age younger than 37 years, and the presence of a spinal cord lesion and
CSF-specific oligoclonal bands. However, initiating disease-modifying
therapy even in patients with RIS who have all of these risk factors can be
difficult for logistical reasons (insurance coverage can be an issue in many
regions), and counseling these patients can be challenging. In most
situations, clinicians opt to monitor patients closely from a clinical and
radiologic standpoint. If an increase in radiologic disease activity occurs, an
informed discussion can be had with the patient about the rationale for
treatment and the uncertainty of this approach. Ongoing clinical trials in RIS
are evaluating DMTs that are used in RRMS that will hopefully provide
guidance in the upcoming years.22,23 In addition, imaging and fluid
biomarkers may be able to provide prognostic guidance in clinical practice.
This patient had a number of these risk factors. Her neurologist had a
discussion with her about her diagnosis, the risk of eventually developing
MS, and the lack of clear scientific evidence to guide which patients should
be on treatment.
The patient and neurologist together opted to manage her
conservatively, with annual clinical examinations and MRIs. If evidence of
clinical or radiologic disease activity became a concern, they planned to
revisit the question of treatment at that time.

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DIAGNOSIS OF MULTIPLE SCLEROSIS

FIGURE 2-1
FLAIR* images (a combination of T2* and fluid-attenuated inversion recovery [FLAIR])
showing examples of white matter lesions (arrowheads) with and without central veins.
Double-headed arrows indicate the size of the lesion. Excluded lesions are white matter
lesions that are excluded from the full analysis that evaluates how many white matter lesions
have a central vein, per accepted consensus guidelines, which indicate the following as
exclusion criteria: a lesion that is <3 mm in diameter in any plane, merges with another lesion
(confluent lesions), has multiple distinct veins, or is poorly visible.
Reprinted from Sati P, et al, Nat Rev Neurol.33 © 2016 The Authors.

presenting with typical clinical syndromes and imaging findings who meet
dissemination in space criteria.1

CONCLUSION
Current MS diagnostic criteria facilitate the early diagnosis of MS in people
presenting with typical clinical syndromes, allowing for the initiation of DMT in
appropriate patients. However, the diagnosis can be challenging for several
reasons, and diagnostic criteria should be used cautiously in patients presenting
with atypical syndromes and those in special populations in whom the criteria
have not yet been adequately validated. Clinical judgment and existing
paraclinical tools are useful in minimizing misdiagnosis and facilitating an
accurate diagnosis of MS. Diagnostic biomarkers that may facilitate or refute a
diagnosis of MS are needed in these settings, and emerging imaging and fluid
biomarkers may eventually become useful in this regard.

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