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FEBRUARY 2019 PRACTICAL NEUROLOGY 39
M U LT I P L E S C L E R O S I S
Multiple Sclerosis Misdiagnosis Accurate diagnosis requires
correspondence to typical clinical syndromes, correct
interpretation of radiologic and CSF data, and thorough evaluation
for mimics.
By Alexandra Galati, MD and Marwa Kaisey, MD
Accurate diagnosis of multiple sclerosis (MS) hinges on correct
interpretation of a patient’s clini- cal history and radiologic
stud- ies.1 Because there is no single highly specific biomarker
for MS,
misdiagnosis—when a patient without MS receives an incor- rect
diagnosis of MS—is unfortunately common. In a study of 2
independent MS referral centers, 18% of new patients referred with
an established diagnosis of MS were deemed misdiagnosed.2 Those who
are misdiagnosed often carry the diagnosis for multiple years until
being “undiagnosed,” some carrying the diagnosis for a decade or
longer.3 Objective evi- dence of demyelinating disease and
appropriate application of diagnostic criteria is necessary to
prevent misdiagnosis.
Misdiagnosis Ramifications Misdiagnosis of MS has physical,
psychosocial, and financial
ramifications. Misdiagnosed patients often receive MS dis-
ease-modifying therapy (DMT) associated with various risks and side
effects,3 such as injection site or infusion reactions, flu-like
symptoms, bradycardia, infection, and teratogenic- ity.4 In the
above-mentioned misdiagnosis study, more than half of the
misdiagnosed patients received Food and Drug Administration
(FDA)-approved DMTs including glatiramer acetate, dimethyl
fumarate, natalizumab, and fingolimod as well as off-label
medications, such as cyclophosphamide and methotrexate. Almost half
(48%) of the patients in the study received a DMT known to have the
risk of progressive multi- focal leukoencephalopathy (PML), a
disabling and potentially fatal infection. Another contemporary
study reported similar findings: In a group of 110 misdiagnosed
patients, 70% had exposure to DMTs, and almost a quarter received a
DMT with a known risk of PML.3
Along with these physical risks, MS DMTs come at a sig- nificant
cost. The cost of DMT is rising,5 with the median
price in 2018 at $80,000.6 Furthermore, while misdiagnosed patients
are receiving these unnecessary, potentially harmful, and costly
medications, they are also going without treat- ment for their true
diagnoses.
The psychologic burden and practical consequences of eventually
going through an undiagnosis of MS can be sig- nificant.7,8 Many
patients with a diagnosis of MS become involved with and seek
support in their local and national MS communities. Often, MS is
part of their personal iden- tity, and in our experience, this can
make the undiagnosis of MS a very difficult experience.
Misdiagnosis Etiologies Misdiagnosis of MS typically occurs due to
the misap-
plication of the McDonald Criteria.2,3 These criteria were designed
to predict the risk of conversion from clinically isolated syndrome
(CIS) to clinically definite MS, not neces- sarily to distinguish
MS from its mimics. The criteria were developed in 20019 and since
then, they have undergone 3 revisions1,10,11 to allow for earlier
MS diagnosis.
There are 2 independent studies suggesting that more than
two-thirds of patients misdiagnosed with MS pre- sented with a
clinical syndrome that was not typical of MS.2,3 The 2017 McDonald
Criteria stress their use only with clinical syndromes typical of
MS; these include optic neuritis, incomplete transverse myelitis,
and brainstem syndromes such as internuclear ophthalmoplegia and
trigeminal neural- gia. To be considered MS-typical, symptoms
should last at least 24 hours in the absence of fever and
infection. Changes on objective examination or paraclinical testing
should also be seen.
Misdiagnosis of MS also stems from overreliance on radio- graphic
signs, so physicians must be familiar with the MRI characteristics
of both MS and its mimics.12 The Table out- lines atypical clinical
presentations and radiographic findings that should raise suspicion
of a diagnosis alternate to MS.13,14
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40 PRACTICAL NEUROLOGY FEBRUARY 2019
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Typical radiographic changes seen in MS lesions include
juxtacortical, periventricular, and infratentorial brain regions
(Figure 1) as well as the spinal cord. Typically, there will be
multiple focal lesions, with intermediate to low signal on
T1-weighted imaging and associated high signal on T2-weighted
imaging. The lesions usually have distinct mar- gins, though as the
disease progresses, they can converge and appear more confluent
(Figure 2). Lesions typically occur bilaterally but are not usually
symmetrical. Subcortical lesions measuring less than 3 mm, often
labeled nonspe- cific on MRI reports, are insufficient to make the
diagnosis. If using a single MRI to prove dissemination in time,
both enhancing and non-enhancing lesions are required.15
Other disease entities commonly misdiagnosed as MS include small
vessel ischemic disease, fibromyalgia, neuro- myelitis optica
spectrum disorder, clinically or radiographi- cally isolated
syndrome, and idiopathic transverse myelitis.1,2 Migraine is the
most common true diagnosis in a patient misdiagnosed with MS,2,3
and one of the most common in patients referred for evaluation of a
potential MS diagno- sis.16,17 A history of migraine attacks,
especially when associ- ated with focal neurologic symptoms, is
incorrectly dubbed a typical MS syndrome, and migraine-associated
white mat- ter lesions on MRI are used to satisfy imaging criteria.
Small vessel ischemic disease is a common radiographic mimic of MS.
Like MS, it can produce multiple focal lesions in the subcortical
white matter; however, unlike MS, the lesions typically spare the
U-fibers and do not involve the cerebel- lum or corpus
callosum.18
Objective findings are key to an accurate MS diagnosis, and a
normal neurologic examination and brain MRI in a patient with
suspected MS should raise a red flag. In a ret- rospective study of
143 patients with neurologic symptoms who did not have associated
abnormalities on neurologic examination or brain MRI, none
progressed to having MS.19
The most recent revision of the McDonald Criteria allows for a
patient with CIS to fulfill criteria for dissemination in time if
they have cerebrospinal fluid (CSF)-specific oligoclonal bands
(OCBs).1 Patients with CSF-specific OCBs have a higher conversion
rate from CIS to MS compared with those without OCBs20; however,
this diagnostic tool lacks specificity, as other central nervous
system (CNS) inflammatory diseases, infec- tions, vascular events,
and tumors are associated with OCBs.21 Other diagnostic tools such
as visual, brainstem-auditory, and somatosensory evoked potentials
lack specificity for MS as well,22 highlighting the importance of
using these tools as sup- portive evidence rather than the basis
for a diagnosis of MS.
Novel Biomarkers Given the increased sensitivity of the 2017
McDonald
Criteria and the relatively high prevalence of MS mis- diagnosis,
there is a need for more specific MS biomarkers. Burgeoning serum
and radiographic biomarkers may allow for increased diagnostic
specificity.
One radiographic biomarker under investigation is the central vein
sign. Autoregulatory T cells enter the CNS through the systemic
circulation, leading to a perivenular distribution of white matter
lesions that may be a helpful distinguishing characteristic of
MS.23 In a prospective study of 29 patients with potential MS in
whom the diagnosis could not be confirmed at initial evaluation,
all patients who ultimately received a diagnosis of MS had central
veins in over 40% of their brain lesions, whereas those who
received an alternative diagnosis had central veins in less than
40% of brain lesions.24 Although promising, this study was com-
pleted at a field strength of 7 Tesla, far higher than what is
presently available in clinical practice.
Serum and CSF biomarkers may also help guide diagnosis of MS.
Neurofilaments are proteins released into the extracel- lular space
during axonal breakdown.25 Elevated levels of CSF neurofilament
light chains (NfL) are associated with risk of progression from CIS
to clinically definite MS.26 Elevated levels of NfL have also been
shown to correlate with disease severity and progression in MS.27
Although this research is promis- ing, elevated NfL levels are
found in many neurodegenerative diseases, and increase with normal
aging.28 Lack of specificity for elevated NfL levels may limit use
for MS diagnosis, but further studies may delineate a use in the
young and other- wise healthy patient presenting for evaluation.
There are also data supporting the use of multiparametric assays
assessing the expression of multiple genes or proteins. In contrast
to a
TABLE. CLINICAL AND RADIOGRAPHIC SIGNS SUGGESTING AN ALTERNATIVE
DIAGNOSIS TO MS
Clinical presentation Radiographic findings
Complete transverse myelopathy
Symmetrically distributed lesions
Subacute cognitive decline Large lesion in center of corpus
callosum
Headache/meningismus Simultaneous enhancement of all lesionsa
Isolated fatigue Infarcts
Intractable nausea, vomiting, hiccups
Longitudinally extensive spinal cord lesion
a Although these suggest an alternative diagnosis, a first attack
or clinically isolated syndrome (CIS) can also occur with all
lesions enhancing or a single lesion that is enhancing.
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FEBRUARY 2019 PRACTICAL NEUROLOGY 41
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Figure 1.Typical lesions of multiple sclerosis are found in the
juxtacortical (A, arrow), periventricular (B), infratentorial (C)
regions
and the corpus callosum (D).
A
C
B
D
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42 PRACTICAL NEUROLOGY FEBRUARY 2019
M U LT I P L E S C L E R O S I S
single biomarker, these assays aim to determine a pattern of
expression of many genes or proteins at once to aid in diag- nosis
and prognosis. One such study investigated serum long noncoding RNA
gene expression to identify clinically definite MS.28 This test
reports a sensitivity of 91% and specificity of 98% for RNA gene
expression tests against healthy controls, but a lower sensitivity
of 79% and specificity of 87% when compared with patients with
autoimmune and other chronic diseases.29 While early in
development, these assays may pro- vide a suitable biomarker to aid
in diagnosis.
Conclusion Accurate diagnosis of MS is challenging, and
misdiagnosis
occurs relatively frequently. This has wide-ranging implica- tions
including the risks and costs of MS treatment as well as
psychologic stress. Though outside the scope of this article,
underdiagnosis also occurs, with some patients presenting to
numerous physicians prior to receiving a diagnosis of MS. To more
accurately diagnose MS, we must be vigilant in our use of the
McDonald Criteria, with careful consider- ation of whether symptoms
correspond to a typical clinical syndrome, corroboration of
symptoms with the neurologic examination, correct interpretation of
radiologic and CSF data, and thorough evaluation for MS mimics.
Identifying and validating novel biomarkers for more accurate MS
diag- nosis will decrease our reliance on radiographic findings and
significantly enhance patient care and outcomes. n
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Figure 2. Confluent lesions may appear later in the course of
multiple sclerosis.
Alexandra Galati, MD Department of Neurology University of
California, Los Angeles Los Angeles, CA
Marwa Kaisey, MD Cedars-Sinai Medical Center Department of
Neurology Los Angeles, CA
Disclosures AG reports no disclosures. MK has received consulting
fees from Biogen and Celgene.
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