Evaluation and Diagnosis of Multiple Sclerosis in Adults

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Evaluation and diagnosis of multiple sclerosis in adults

Authors: Michael J Olek, DO, Jonathan Howard, MD
Section Editor: Francisco González-Scarano, MD
Deputy Editor: John F Dashe, MD, PhD
All topics are updated as new evidence becomes available and our peer review process is complete.
Literature review current through: Nov 2019. | This topic last updated: Oct 30, 2019.
INTRODUCTION
Multiple sclerosis (MS) is the most common immune-mediated inflammatory demyelinating disease of the central nervous system.
MS is characterized pathologically by multifocal areas of demyelination with loss of oligodendrocytes and astroglial scarring. Axonal
injury is also a prominent pathologic feature, especially in the later stages. Certain clinical features are typical of MS, but the disease
has a highly variable pace and many atypical forms.
The diagnosis and differential diagnosis of MS are reviewed here. Other aspects of MS are discussed separately:
Pathogenesis and epidemiology of multiple sclerosis
Clinical presentation, course, and prognosis of multiple sclerosis in adults
Manifestations of multiple sclerosis in adults
Management of clinically and radiologically isolated syndromes suggestive of multiple sclerosis
Treatment of acute exacerbations of multiple sclerosis in adults
Disease-modifying treatment of relapsing-remitting multiple sclerosis in adults
Treatment of progressive multiple sclerosis in adults
WHEN TO SUSPECT MS
The diagnosis of MS should be suspected when the clinical presentation is suggestive of focal or multifocal demyelination involving
the central nervous system.
The typical patient presents as a young adult with one or more clinically distinct episodes of central nervous system dysfunction such
as optic neuritis, long tract symptoms/signs, a brainstem syndrome, or a spinal cord syndrome, followed by at least partial resolution.
Symptoms usually develop over the course of hours to days and then gradually remit over the ensuing weeks to months, though
remission may be incomplete. Presenting symptoms and signs may be either monofocal (consistent with a single lesion) or multifocal
(consistent with more than one lesion).
While there are no clinical findings that are unique to MS, some are highly characteristic (table 1). The diagnosis of MS is relatively
straightforward for patients who present with symptoms and characteristic magnetic resonance imaging (MRI) findings and who have
a relapsing-remitting course [1]. In some patients, clinically definite MS can be diagnosed at the time of a first attack, based upon the
clinical, MRI, and/or cerebrospinal fluid findings, using the McDonald Criteria (see 'McDonald diagnostic criteria' below). Primary
progressive MS refers to an MS presentation and course with insidious neurologic worsening and accumulation of disability, such as
from spastic paraparesis or cerebellar ataxia. This pattern is observed in approximately 10 to 15 percent of patients with MS.
Clinically isolated syndrome and radiologically isolated syndrome are related diagnostic situations:
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● A clinically isolated syndrome refers to a monosymptomatic attack that does not fulfill diagnostic criteria for MS but may
predispose to clinically definite MS. (See "Clinical presentation, course, and prognosis of multiple sclerosis in adults", section on
'Clinically isolated syndrome'.)
● A radiographically isolated syndrome describes MRI brain lesions that are characteristic of MS but are found in patients who lack
any symptoms of MS. The MRI lesions are often discovered incidentally in the diagnostic workup for other conditions (eg,
headache or head injury). (See 'Radiologically isolated syndrome' below.)
EVALUATION
The evaluation of suspected MS begins with a detailed clinical history and examination. The clinical history should inquire specifically
about the possibility of prior attacks with symptoms and evolution characteristic of an inflammatory demyelination in the central
nervous system. Unless otherwise contraindicated, all patients being evaluated for MS should have at least a brain magnetic
resonance imaging (MRI) without and with contrast.
For patients with a typical presentation who have insufficient clinical and MRI evidence to confirm the diagnosis of MS by the
McDonald criteria (see 'McDonald diagnostic criteria' below), additional testing with lumbar puncture for cerebrospinal fluid-specific
oligoclonal bands (see 'CSF analysis and oligoclonal bands' below), visual evoked potentials (see 'Evoked potentials' below), and/or
optical coherence tomography (see 'Optical coherence tomography' below) can be used to support the diagnosis, though optical
coherence tomography is not part of the formal diagnostic criteria [2]. Of importance, these studies cannot be used to support optic
nerve lesions in the absence of clear symptoms related to a current or historical attack.
For patients with an atypical history, examination, or MRI, additional testing with spine MRI, lumbar puncture, and/or autoantibody
determination for aquaporin-4 (AQP4) and myelin-oligodendrocyte glycoprotein (MOG) antibodies (see 'Autoantibody testing' below)
is warranted to investigate alternatives in the differential diagnosis.
The neurological examination may reveal findings consistent with previous or current demyelinating events in the central nervous
system, including optic neuritis (eg, relative afferent pupillary defect, color desaturation, visual loss), eye movement abnormalities
(eg, internuclear ophthalmoplegia, pendular nystagmus), upper motor neuron signs (eg, spasticity, hyperreflexia, Babinski sign),
ataxia, gait disturbance, hemisensory loss, or bilateral sensory loss and/or paresthesia in extremities due to a spinal cord lesion.
MAGNETIC RESONANCE IMAGING
Magnetic resonance imaging (MRI) is the test of choice to support the clinical diagnosis of MS [3]. The McDonald diagnostic criteria
for MS include specific MRI requirements for the demonstration of lesion dissemination in space and time (see 'McDonald diagnostic
criteria' below) [2]. The diagnostic utility of MRI is high, with sensitivity and specificity of up to 87 and 73 percent, respectively, for the
McDonald criteria requirement of dissemination in space [4]. MRI detects many more MS lesions than computed tomography (CT),
and it is able to detect MS demyelinating plaques in regions that are rarely abnormal on CT such as the brainstem (image 1),
cerebellum, and spinal cord (image 2). Most lesions seen on MRI correlate with pathologic lesions [5].
Lesion characteristics — Focal MRI lesions suggestive of MS are typically found in specific white matter areas, such as the
periventricular and juxtacortical regions, corpus callosum, infratentorial regions (particularly the pons and cerebellum) and the spinal
cord (preferentially the cervical segment) (image 3) [6]. MS lesions (plaques) usually have an ovoid appearance. Preventricular
lesions are characteristically arranged at right angles to the corpus callosum as if radiating from this area; when viewed on sagittal
images, they are referred to as Dawson fingers (image 4). The MS lesions appear hyperintense on proton density and T2-weighted
studies. Many lesions, particularly in long-standing MS, are hypointense on T1-weighted images (so-called black holes); others are
not visible at all.
Conventional T2-weighted MRI techniques may underestimate MS plaque size and thus overall plaque burden, particularly for cortical
lesions. Advanced MRI techniques such as diffusion tensor imaging and magnetic resonance spectroscopy frequently reveal
involvement of normal appearing white matter in patients with MS. However, due to the high frequency of non-specific lesions on
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brain MRI, there is a significant risk for false positive results [7]. Moreover, changes to the McDonald diagnostic criteria in 2017 seem
to exacerbate this problem [8]. (See 'Advances in MRI techniques' below.)
Spinal cord MRI — Spinal cord MRI lesions are nearly as common as brain lesions in patients with MS [9,10], though they are less
likely to be clinically silent than brain lesions. In contrast, the frequency of abnormal signals on spinal cord MRI in normal individuals
is only 2 percent [11], since the non-MS-related hyperintense signal seen in older patients on cranial MRI does not occur in the spinal
cord.
Spinal cord lesions typical of MS are associated with the following MRI characteristics [10,12-15]:
● Little or no cord swelling

● Unequivocal hyperintensity on T2-weighted sequences that is visible in two planes (eg, axial and sagittal)
● Size at least 3 mm but less than two vertebral segments in length
● Occupy only part of the spinal cord in cross-section and are typically located in the dorsolateral part of the cord
● Focal (ie, clearly delineated and circumscribed on T2-weighted sequences)
Spinal cord MRI may increase the likelihood of finding dissemination of lesions in space and improve diagnostic sensitivity compared
with brain MRI alone. The potential utility of spinal MRI in MS is illustrated by a study of 104 patients with early stage MS and low
disability [10]. The diagnosis of MS was made by the 1982 criteria of Poser et al [16]. Abnormal cord MRI lesions were found in 83
percent, and these lesions were typically focal; focal cord lesions were usually multiple (median 3), small (median 0.8 vertebral
segments), and located most often in the cervical cord (56 percent). Diffuse lesions were found in 13 percent, usually in conjunction
with focal lesions. In this cohort of patients, the addition of spinal cord to brain MRI lesions, compared with brain MRI alone,
increased the diagnostic sensitivity of the original 2001 McDonald criteria [17] from 66 to 85 percent.
Longitudinally extensive spinal cord lesions, particularly those that exceed three spinal segments and mainly involve the central cord
on axial MRI sections, are suggestive of neuromyelitis optica (NMO) or NMO spectrum disease. (See 'NMOSD' below.)
Active versus chronic lesions — Acute MS lesions tend to be larger than chronic lesions on MRI and have somewhat ill-defined
margins. As they resolve, they become smaller with sharper margins. This presumably reflects reduction of edema and inflammation
present at the time of acute plaque formation, leaving only residual areas of demyelination, gliosis, and enlarged extracellular space
with remission. The MRI appearance of primary progressive MS shows a smaller total disease burden, a greater preponderance of
small lesions, fewer gadolinium-enhancing new lesions, and acquisition of fewer lesions per unit time than the secondary progressive
form of MS [18].
Gadolinium-diethylenetriamine penta-acetic acid (DTPA), a paramagnetic contrast agent that can cross only disrupted blood-brain
barriers, is useful to assess for active lesions [19]. Gadolinium increases signal intensity on T1-weighted images (image 5). It is not
completely clear if inflammation is the triggering event that causes demyelination and axonal degeneration, but gadolinium
enhancement diminishes or disappears after treatment with glucocorticoids, a therapy thought to restore integrity of the blood-brain
barrier.
Gadolinium-enhancing lesions on T1-weighted MRI often correspond to areas of high signal on T2-weighted and low signal intensity
on unenhanced T1-weighted images, probably due to edema (image 3). The importance of gadolinium-enhancing lesions in MS is
related to the following observations:
● The accumulation of gadolinium in plaques is associated with new or newly active plaques and with pathologically confirmed
acute inflammation in MS.
● The majority of gadolinium-enhancing plaques are clinically asymptomatic, although the presence of ongoing enhancing plaques
suggests continuing disease activity that likely contributes to cumulative pathophysiology.
● Gadolinium enhancement is a transient phenomenon and usually disappears after a few weeks, but it may rarely persist for up to
eight weeks in acute plaques. One study found that the average duration of enhancement was three weeks and the median was
two weeks [20]. Prolonged persistence of enhancement should caution against the diagnosis of MS [21].
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● Longitudinal studies have demonstrated that the presence of active lesions on serial MRI scans carries a high risk of continuous
disease activity [22,23].
Gadolinium enhancement patterns may provide some clues to the underlying pathology of lesions. MS lesions typically are ring-
enhancing (closed or open ring) or nodular, and occur in the brain more often than in the spinal cord [6]. Other patterns may suggest
alternative diagnosis:
● Large or multiple closed-ring enhancement may be seen in acute disseminated encephalomyelitis (ADEM) (see 'ADEM' below),
malignancy, or infection.
● Meningeal and/or nerve root enhancement suggests neurosarcoidosis
● The trident sign (ie, spinal cord linear dorsal subpial enhancement accompanied by central cord/canal enhancement in a "trident"
pattern [24]) also suggests neurosarcoidosis
● Punctate or miliary enhancement may occur with chronic lymphocytic inflammation with pontine perivascular enhancement
responsive to steroids (CLIPPERS) (see 'CLIPPERS' below), vasculitis, progressive multifocal encephalopathy (PML), or Susac
syndrome
● Band-like enhancement is suggestive of Baló concentric sclerosis (see 'Tumefactive demyelination' below)
● Cloud-like enhancement of lesions with blurred margins in the corpus callosum [25] may be seen in neuromyelitis optica
spectrum disorder (NMOSD) (see 'NMOSD' below)
● Flat pancake-like enhancement [26] may be seen in cervical spinal cord spondylotic myelopathy
● Purely cortical enhancement is concerning for vasculitis or ischemic lesion
● Persistence of enhancement for more than three months is worrisome for malignancy
Black holes — Most MS lesions are isointense to white matter on T1-weighted MRI, but some are hypointense or appear as "black
holes" [27-30], particularly in the supratentorial region (image 3 and image 6). These hypointense lesions are nonspecific at a given
time point, as nearly half will revert to normal in a few months. The disappearance of a black hole is most likely due to remyelination
and resolution of edema [31].
Although the evidence is limited, persistent black holes are thought to be markers of severe demyelination and axonal loss [27]. The
pathological substrate for the accumulation of persisting black holes appears to be predominantly axonal damage [27,28,31], as
shown in a postmortem histopathology-MRI correlation study [27]. Such focal axonal loss most likely contributes to Wallerian
degeneration. In contrast to this evidence, another study suggested that black holes were associated with remyelination [32].
Radiologically isolated syndrome — A radiologically isolated syndrome (RIS) is defined by incidental brain (usually) or spinal cord
(rarely) MRI findings that are highly suggestive of MS, based upon location and morphology within the central nervous system, in an
asymptomatic patient lacking any history, symptoms, or signs of multiple sclerosis [33]. Typically the MRI has been obtained for a
completely unrelated condition such as headaches or trauma. (See 'For a radiologically isolated syndrome' below.)
In addition to white matter abnormalities, demyelinating cortical lesions have been identified in some patients with RIS using double
inversion recovery MRI sequences [34].
Advances in MRI techniques — It is difficult to distinguish the edema of an acute plaque from the gliosis and demyelination of a
chronic plaque with conventional MRI technology. In addition, conventional MRI techniques do not distinguish other manifestations of
MS pathology such as demyelination, remyelination, axonal loss, and gliosis [35].
Phosphorus magnetic resonance spectroscopy (MRS) can provide information on phospholipid metabolism, and proton MRS can
generate information about other metabolic components, such as N-acetyl aspartate (NAA, an exclusively neuronal marker), creatine
phosphate (Cr, an energy marker), choline containing compounds (membrane components), and lactic acid (LA). Chronic MS is
associated with a reduction of NAA in comparison with choline and Cr within the brain. A reduced NAA/Cr ratio is the common means
of expressing such reduction. This reduced ratio implies loss of neurons or axons, which is consistent with pathological studies and
appears to parallel disability in MS [36]. In addition, the whole-brain concentration of NAA may be a sensitive surrogate marker of
neuronal loss in MS [37,38].
Diffusion-weighted and diffusion tensor MRI imaging, as well as MRS, may provide insight into the axonal loss and diffuse
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abnormalities in normal appearing white matter and the evolution of normal appearing gray matter [39-41]. Quantitative MRI methods
such as magnetization transfer ratio are increasingly used to assess myelin content and axonal count [42].
Diffusion tensor imaging allows measurement of fractional anisotropy, which reflects the degree to which the diffusion of water
molecules follows one direction versus many directions. This technique is useful for assessing the integrity of white matter tracts,
which normally have a high degree of anisotropy due to their linear arrangement and the preferred diffusion of water along the long
axis of the myelinated fibers [43]. Injury to nerve axons or myelin sheaths permits increased diffusion of water across the white matter
tract and thereby decreases fractional anisotropy (image 7).
Normal appearing white matter that is immediately adjacent to plaques seen on T2 imaging may have abnormally reduced anisotropy.
As an example, a study that evaluated 36 white matter plaques in 20 patients with MS found that mean plaque size, as measured by
a 40 percent reduction in fractional anisotropy, was significantly increased (145 percent) compared with the size measured by
conventional T2-weighted imaging [44].
Although MS predominately affects white matter, involvement of cortical gray matter is common [45-48]. Conventional T2-weighted
MRI sequences may underestimate MS plaque size and thus overall plaque burden, particularly for cortical lesions [49]. Visualization
of gray matter lesions may be improved with the use of MRI techniques, including seven-Tesla MRI, two- and three-dimensional fluid-
attenuated inversion recovery imaging, double inversion recovery imaging, phase-sensitive inversion recovery T1-weighted
sequences, and diffusion tensor imaging [45,48,50-56].
ANCILLARY TESTS
Cerebrospinal fluid (CSF) analysis and determination of CSF-specific oligoclonal bands, evoked potentials, optical coherence
tomography, and autoantibody tests can be useful in the evaluation of suspected MS when clinical and magnetic resonance imaging
(MRI) evidence is insufficient to support its diagnosis, as discussed in the sections that follow.
CSF analysis and oligoclonal bands — A lumbar puncture is not a requirement for the diagnosis of MS in patients with classic MS
symptoms and brain MRI appearance, but it can be used to help increase diagnostic confidence in the following settings [2,57]:
● When patients present with a clinically isolated syndrome suggestive of MS that meets radiologic criteria for dissemination in
space but not time; the McDonald criteria accept the finding of CSF-specific oligoclonal bands as a substitute for dissemination in
time
● For patients with a clinically isolated syndrome who have MRI findings that do not meet the McDonald criteria for dissemination
in space (ie, a brain MRI that shows no or few lesions), as assessment of cerebrospinal fluid for oligoclonal immunoglobulin G
(IgG) bands can help to refine the risk estimation for progression to multiple sclerosis (see "Management of clinically and
radiologically isolated syndromes suggestive of multiple sclerosis", section on 'With oligoclonal bands')
● With presentations other than a typical clinically isolated syndrome, including a progressive course at onset (ie, suggestive of
primary progressive MS)
● When clinical, imaging, or laboratory features are atypical of MS
● In populations in which MS is less common, including children and older adults
Qualitative assessment of CSF for oligoclonal IgG bands using isoelectric focusing – accompanied by a concomitant analysis of the
serum – is the most important CSF study when determining a diagnosis of MS.
Repeating the lumbar puncture and CSF analysis is suggested if clinical suspicion for MS is high but initial CSF results are equivocal,
negative, or show only a single band on isoelectric focusing [58].
Oligoclonal bands are found in up to 95 percent of patients with clinically definite MS (table 2) [59,60]. Oligoclonal bands represent
limited classes of antibodies that are depicted as discrete bands on agarose gel. A positive CSF is based upon the finding of either
oligoclonal bands different from any such bands in serum, or by an increased IgG index. The IgG level may be expressed as a
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percentage of total protein (normal <11 percent), as a percentage of albumin (normal <27 percent), by use of the calculated IgG index
(normal value <0.66 to <0.9, depending upon the individual laboratory), or by use of a formula for intrathecal fluid synthesis of IgG.
The CSF appearance and pressure are grossly normal in MS. The total leukocyte count is normal in approximately one-third of
patients, exceeds 15 cells/microL in another third, and seldom exceeds 50 cells/microL (a finding that should raise suspicion of
another etiology) [61]. Lymphocytes are the predominant cell type, the vast majority of which are T cells. CSF protein (or albumin)
level is usually normal. Albumin is not synthesized in the central nervous system, and albumin determination therefore gives a better
indication of blood-CSF-barrier disruption than total protein, some of which may be synthesized within the central nervous system
(eg, immunoglobulin).
Up to 8 percent of CSF samples from patients without MS also contain oligoclonal bands; most are the result of chronic central
nervous system infections, viral syndromes, and neuropathies. In many such cases, the oligoclonal bands are also reflected in the
analysis of serum. Nevertheless, the presence of oligoclonal bands is not equivalent to a diagnosis of MS, given the number of false
positives that can occur and the variability in technique and interpretation in different laboratories. Elevation of the CSF
immunoglobulin level relative to other protein components is a common finding in patients with MS and suggests intrathecal
synthesis. The immunoglobulin increase is predominantly IgG, although the synthesis of immunoglobulin M (IgM) and
immunoglobulin A (IgA) is also increased.
The technique for performing a lumbar puncture in adults is discussed separately. (See "Lumbar puncture: Technique, indications,
contraindications, and complications in adults" and "Cerebrospinal fluid: Physiology and utility of an examination in disease states",
section on 'Composition of the CSF'.)
Evoked potentials — Evoked potentials are the electrical events generated in the central nervous system by peripheral stimulation
of a sensory organ. Evoked potentials are used to detect subclinical, abnormal central nervous system function. Detection of a
subclinical lesion in a site remote from the region of clinical dysfunction supports a diagnosis of multifocal MS. Evoked potentials also
may help define the anatomical site of the lesion in tracts not easily visualized by imaging (eg, optic nerves, dorsal columns).
The three most frequently employed evoked potential tests are somatosensory evoked potentials, visual evoked responses, and
brainstem auditory evoked potentials. Patients with clinically definite MS have abnormal visual evoked responses in 50 to 90 percent
of cases (table 2). The visual evoked responses test is particularly useful in patients who lack clear clinical evidence of dysfunction
above the level of the foramen magnum, such as those with a chronic progressive myelopathy. Ocular or retinal disorders must be
excluded before attributing abnormal visual evoked responses to demyelination in the optic pathways.
Optical coherence tomography — Optical coherence tomography (OCT) uses infrared light waves that reflect off the internal
microstructure of biological tissues to produce images based upon the differential optical reflectivity. OCT provides a noninvasive way
to image the retina at high resolution. It can be used to measure the thickness of the retinal nerve fiber layer, which is reduced in
most patients (85 percent) with optic neuritis. Optic nerve or optic tract demyelination leads to retrograde degeneration of
unmyelinated retinal nerve fiber layer axons. Retinal nerve fiber layer loss becomes evident with OCT approximately three months
after optic neuritis [62].
The role of OCT for the diagnosis of MS is not well-established [63-65]. However, OCT testing may be useful for demonstrating
objective evidence of retinal nerve fiber layer loss in patients who have a history consistent with optic neuritis but otherwise have a
normal examination and brain imaging [63]. In addition, some data suggest that retinal nerve fiber layer and ganglion cell layer
thinning is more severe with neuromyelitis optica spectrum disorder compared with MS, a finding that might be useful in differentiating
the two disorders [66]. (See "Optic neuritis: Pathophysiology, clinical features, and diagnosis", section on 'Optical coherence
tomography'.)
Autoantibody testing — Testing for the aquaporin-4 (AQP4) IgG serum autoantibody and the myelin oligodendrocyte glycoprotein
IgG autoantibody (MOG-IgG) are indicated for patients presenting with acute central nervous system demyelination when clinical,
imaging, or laboratory features are atypical of MS.
AQP4 antibody — The AQP4 antibody is a specific biomarker for neuromyelitis optica spectrum disorder (NMOSD). Therefore,
patients suspected of having NMOSD should be tested for serum AQP4 IgG antibodies. Clinical presentations that should raise
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suspicion for NMOSD include the following (see 'NMOSD' below):
● Optic neuritis that is simultaneously bilateral, involves the optic chiasm (image 8), causes an altitudinal visual field defect, or
causes severe residual visual loss
● A complete (rather than partial) spinal cord syndrome, especially when accompanied by paroxysmal tonic spasms; spine MRI
may reveal a longitudinally extensive spinal cord lesion spanning three or more vertebral segments
● An area postrema clinical syndrome consisting of intractable hiccups or nausea and vomiting
MOG-IgG antibody — The MOG-IgG antibody is a marker of MOG-associated encephalomyelitis (MOG-EM), a relatively
uncommon demyelinating disorder characterized by a variety of manifestations that include relapsing and bilateral optic neuritis,
transverse myelitis, brainstem encephalitis, and acute disseminated encephalomyelitis (ADEM) (see 'MOG-EM' below). Indications
for MOG-IgG testing are listed in the table (table 3).
DIAGNOSIS
MS is primarily a clinical diagnosis. The history and physical examination are most important for diagnostic purposes. Magnetic
resonance imaging (MRI) is the test of choice to support the clinical diagnosis of MS [3]. (See 'McDonald diagnostic criteria' below.)
McDonald diagnostic criteria — The McDonald criteria for the diagnosis of MS, as revised in 2017, apply primarily to patients who
have a typical clinically isolated syndrome that suggests the onset of relapsing-remitting MS (algorithm 1) [2]. The McDonald criteria
can also be applied to patients presenting with insidious neurological progression suggestive of primary progressive MS.
While useful when the diagnosis of MS is clinically suspected, the McDonald criteria are not intended for distinguishing MS from
other neurologic conditions [67]. (See 'Differential diagnosis' below.)
To confidently diagnose MS, there cannot be a better explanation for the clinical presentation, and there must be objective clinical
evidence to confirm the presence of central nervous system lesions corresponding to the current or historical attack, as described in
the sections that follow.
The application of the McDonald criteria for the diagnosis of MS in patients with an attack at onset is dependent upon the number of
clinical attacks and the number of central nervous system lesions confirmed by objective clinical evidence (table 4).
● What defines an attack? — An MS attack is defined by the McDonald criteria as a monophasic clinical episode with patient-
reported symptoms and objective findings typical of MS, reflecting a focal or multifocal inflammatory demyelinating event in the
central nervous system, developing acutely or subacutely, with a duration of at least 24 hours, with or without recovery, and in
the absence of fever or infection [2]. Attack, relapse, exacerbation, and (when it is the first episode) clinically isolated syndrome
(CIS) are synonyms. The most common initial attacks are sensory disturbances, motor weakness, and visual complaints (either
monocular visual loss or diplopia). (See "Clinical presentation, course, and prognosis of multiple sclerosis in adults".)
● What is objective clinical evidence? — The MS attack should be confirmed by objective clinical evidence, that is, an
abnormality on neurologic examination, imaging (eg, MRI or optical coherence tomography), or neurophysiologic testing (eg,
visual evoked potentials) that corresponds to the anatomic location suggested by the symptoms of the current or historical attack
[2]. As an example, a previous episode of self-limited, painful, monocular visual impairment consistent with optic neuritis should
be confirmed by a finding of optic disc pallor or a relative afferent pupillary defect (picture 1), optic nerve T2 hyperintensity on
MRI (image 9), retinal nerve fiber layer thinning on optical coherence tomography, or P100 latency prolongation on visual evoked
potentials.
For relapsing-remitting MS — Relapsing-remitting MS, which is by far the most common type of MS at disease-onset, is
characterized by clearly defined relapses (also known as attacks or exacerbations) with partial or full recovery. For patients with two
or more attacks (ie, suspected relapsing-remitting MS), the McDonald criteria apply as follows (table 4):
● For patients with a history of two or more clinical MS attacks who have objective clinical evidence of two or more lesions or
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objective clinical evidence of one lesion with reasonable historical evidence of a prior attack involving a lesion in a distinct
anatomic location, no additional data are required to make the diagnosis of MS. Nevertheless, brain MRI should be done for all
patients being evaluated for MS [2].
● For patients with a history of two or more attacks who have objective clinical evidence of only one lesion, the criteria require
additional evidence of dissemination in space (table 5), as demonstrated on MRI by hyperintense T2 lesions that are
characteristic of MS in at least two of four MS-typical regions of the central nervous system (periventricular, cortical or
juxtacortical, infratentorial, and spinal cord), or by the development of an additional clinical attack, supported by objective clinical
evidence, that implicates a different central nervous system site [2].
For a clinically isolated syndrome — For patients with a first clinical attack (ie, a CIS), the McDonald criteria apply as follows
(table 4) :
● For patients with one attack who have objective clinical evidence of two or more lesions, the criteria require additional evidence
of dissemination in time (table 6), as demonstrated by the development of an additional clinical attack supported by objective
clinical evidence, or demonstrated with MRI by the simultaneous presence of gadolinium-enhancing and nonenhancing lesions
at any time, or by a new hyperintense T2 and/or gadolinium-enhancing lesion(s) on follow-up MRI, irrespective of its timing with
reference to a baseline scan, or (as a substitute for dissemination in time) by the presence of cerebrospinal fluid (CSF)-specific
oligoclonal bands [2].
● For patients with one attack who have objective clinical evidence of one lesion, the criteria require additional evidence of
dissemination in both space (table 5) and time (table 6), as described above.
Thus, the diagnosis of MS can be made for some patients at the time they present with a first clinical attack (ie, a CIS) if a single MRI
obtained at any time shows dissemination in space and, as evidence for dissemination in time, the simultaneous presence of
gadolinium-enhancing and nonenhancing lesions or the presence of CSF-specific oligoclonal bands.
An MRI that shows dissemination in space but either lacks any enhancing lesions or shows all lesions enhancing would fail to confirm
dissemination in time. In the absence of CSF-specific oligoclonal bands, a follow-up MRI would be required in order to demonstrate
new T2 or gadolinium-enhancing lesions as evidence of dissemination in time. (See "Management of clinically and radiologically
isolated syndromes suggestive of multiple sclerosis", section on 'Monitoring'.)
For a radiologically isolated syndrome — A radiologically isolated syndrome (RIS) is defined by incidental brain or spinal cord
MRI findings that are highly suggestive of MS, based upon location and morphology within the central nervous system, in an
asymptomatic patient. That is, the patient with an RIS has not had clinical attacks suggestive of MS.
The diagnosis of RIS is based entirely on the interpretation of MRI findings, after a meticulous history and examination have excluded
any history, symptoms, or signs of MS and excluded other conditions that could account for the MRI findings [68].
Proposed diagnostic criteria for a RIS require demonstration of lesion dissemination in space by one or more T2-hyperintense lesions
in at least two of four MS-typical regions of the central nervous system (periventricular, cortical or juxtacortical, infratentorial, and
spinal cord) [68]. RIS is excluded if there is clinical evidence of neurologic dysfunction suggestive of MS based on historical
symptoms and/or objective signs. It is also excluded if there are MRI abnormalities explained by any other disease process, with
particular attention to aging or vascular-related abnormalities, and those due to exposure to toxins or drugs.
For an individual with an RIS, who by definition fulfill McDonald criteria for dissemination in space, the diagnosis of MS can be made
if an MRI shows evidence of dissemination in time (ie, gadolinium-enhancing lesions and/or new T2 lesions) and there is subsequent
development of a neurologic event, confirmed by objective clinical evidence, which is consistent with central nervous system
demyelination [68].
Surveillance of individuals with an RIS is reviewed separately. (See "Management of clinically and radiologically isolated syndromes
suggestive of multiple sclerosis", section on 'Monitoring'.)
For primary progressive MS — For patients who present with insidious neurological progression suggestive of primary
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progressive MS, and no better explanation for the clinical presentation, the McDonald criteria require evidence of one year of disease
progression (retrospectively or prospectively determined), independent of clinical relapse, plus two of the three following criteria:
● One or more hyperintense T2 lesions characteristic of MS in one or more of the periventricular, cortical or juxtacortical, or
infratentorial areas
● Two or more hyperintense T2 lesions in the spinal cord
● Presence of CSF-specific oligoclonal bands
Diagnostic confidence — The McDonald criteria can only be applied after careful clinical evaluation of the patient [2]. The criteria
assign diagnostic confidence as follows:
● The diagnosis of MS is given if the McDonald criteria are fulfilled and there is no better explanation for the clinical presentation
● The diagnosis of possible MS is given if MS is suspected by virtue of a CIS but the McDonald criteria are not completely met
● The diagnosis is not MS if another diagnosis better explains the clinical presentation
DIFFERENTIAL DIAGNOSIS
The differential diagnosis of MS includes a number of inflammatory, vascular, infectious, genetic, granulomatous, and other
demyelinating disorders (table 7), but depends on the clinical setting. The differential is limited in the setting of a young adult who has
had two or more clinically distinct episodes of central nervous system dysfunction with at least partial resolution and typical magnetic
resonance imaging (MRI) findings. Diagnostic difficulties arise in patients who have atypical presentations, monophasic episodes,
progressive illness, who are either younger or older, and lack specific MRI findings. A monophasic illness with symptoms attributable
to one site in the central nervous system creates a large differential that includes neoplasms, vascular events, or infections. The
unusual nature of some sensory symptoms and the difficulty patients experience in describing such symptoms may result in a
misdiagnosis of somatic syndrome disorder.
Red flags — Features that should alert the clinician to the possibility of diseases other than MS (ie, red flags) include the following
[2,67,69]:
● Family history of neurologic disease other than MS

● Nonspecific neurologic symptoms and/or neurologic exam findings not easily localized to the central nervous system (eg,
isolated fatigue)
● Hyperacute presentation (ie, maximal deficit in minutes to hours)
● Short-lasting symptoms (ie, minutes to hours)
● Leptomeningeal disease
● Meningismus and/or headache
● Encephalopathy
● Prominent cortical features such as aphasia or neglect syndrome
● Progressive ataxia or cognitive dysfunction
● Severe optic neuritis with poor recovery
● Simultaneous or near simultaneous bilateral optic neuritis
● Complete or fluctuating ophthalmoplegia
● Multiple cranial neuropathies or hearing loss
● Complete transverse myelitis, and/or longitudinally extensive spinal cord lesion on MRI
● A well demarcated spinal level in the absence of disease above the foramen magnum
● Prominent back pain that persists
● Recurrent symptoms and signs that can be attributed to one anatomic site
● Rapidly progressive disease
● Failure to remit
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● Symptoms of systemic disease such as weight loss, fever, and night sweats
The diagnostic considerations associated with atypical and red flag presentations are listed in the table (table 8).
None of these features completely excludes the diagnosis of MS. However, one should explore the possibility of other etiologies
before accepting the diagnosis of MS in patients who have atypical clinical syndromes or red flags. This point is illustrated by the
findings from a study of 281 new patient referrals to an outpatient university-based MS center for a first or second opinion as to
whether the patient had MS [70]. Probable or possible MS was confirmed in only 33 percent of the patients, and none of those with
confirmed MS had atypical manifestations. A wide variety of alternative diagnoses were made, including other neurologic diseases,
possible psychiatric disease, and no clear diagnosis (32, 23, and 13 percent, respectively). The retrospective nature of this study
limits the strength of its findings.
Optic neuritis — In addition to MS, the differential diagnosis of optic neuritis includes neuromyelitis optica spectrum disorder
(NMOSD), and MOG-associated encephalomyelitis (MOG-EM) discussed below. Optic neuritis related to an MS attack or a clinically
isolated syndrome (CIS) suggestive of MS is typically unilateral. In contrast, optic neuritis related to NMOSD or MOG-EM is more
likely to be bilateral in onset and/or more severe compared with optic neuritis related to MS. Sarcoidosis is also a diagnostic
consideration in patients with bilateral optic neuritis.
Other potential causes of recurrent optic neuritis in the differential include systemic lupus erythematosus, chronic relapsing
inflammatory optic neuropathy (CRION), and paraneoplastic optic neuropathy. (See "Optic neuritis: Pathophysiology, clinical features,
and diagnosis" and "Pathogenesis, clinical features, and diagnosis of pediatric multiple sclerosis", section on 'Clinical features and
diagnosis' and "Optic neuropathies", section on 'Inflammatory optic neuropathies'.)
Some patients have their entire clinical illness confined to the optic nerves. One optic nerve may be affected sequentially after
another, or there can be simultaneous bilateral visual loss, a state that is uncommon in classic MS. In some instances, brain MRI will
show scattered intracerebral lesions in addition to lesions of the optic nerves, or cerebrospinal fluid examination (CSF) will show
oligoclonal bands, attesting to some degree of dissemination of the lesions. Children and preadolescent patients are more likely than
adults to have recurrent or simultaneous optic neuropathy. The distinction from an MS variant can be challenging. Patients with
repetitive, isolated optic neuritis have a condition known as CRION, which is highly-responsive to glucocorticoids. (See "Optic
neuropathies", section on 'Chronic relapsing inflammatory optic neuropathy'.)
Clinically isolated syndromes — A CIS is a single, monosymptomatic attack compatible with MS (eg, optic neuritis, a brainstem
syndrome, or a spinal cord syndrome) that does not fulfill diagnostic criteria for MS but may be the first attack of MS. The differential
diagnosis of a CIS and a radiologically isolated syndrome (RIS) suggestive of MS is essentially the same as the differential of MS and
includes a number of inflammatory, vascular, infectious, genetic, granulomatous, and other disorders (table 7).
Myelopathy — The differential diagnosis for myelopathy differs for patients presenting with a chronic or progressive myelopathy
versus patients with presenting with acute or subacute spinal cord dysfunction suggesting inflammatory disease.
Progressive myelopathy — In addition to primary progressive MS, the differential diagnosis of progressive myelopathy includes
inflammatory, infectious, paraneoplastic, metabolic, and genetic disorders. Motor neuron disease may be the cause if there are no
sensory signs or symptoms (primary lateral sclerosis). Human T-lymphotropic virus type I (HTLV-I) infection, B12 deficiency, and HIV
infection can all be excluded by appropriate testing. Spinal dural arteriovenous malformation can cause a steadily or stepwise
progressive myelopathy, usually in the lower spinal segments, and usually in older patients. Adrenomyeloneuropathy also should be
considered. (See "Disorders affecting the spinal cord" and "Diagnosis of amyotrophic lateral sclerosis and other forms of motor
neuron disease" and "Human T-lymphotropic virus type I: Disease associations, diagnosis, and treatment" and "Clinical
manifestations and diagnosis of vitamin B12 and folate deficiency" and "Acute and early HIV infection: Treatment" and "Disorders
affecting the spinal cord", section on 'Vascular malformations' and "Adrenoleukodystrophy", section on 'Adrenomyeloneuropathy
(AMN)'.)
Eventually, there remains a group of patients who do not fit into these categories and whose spinal MRI scans are repeatedly
negative. Visual evoked responses, cerebrospinal fluid oligoclonal bands, and brain MRI scan show no sign of demyelination
elsewhere, though MRI may show nonspecific white matter abnormalities [71]. These patients do not have MS. Compression of the
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cervical cord by intervertebral disc disease is often an issue in middle-aged patients, since a majority has some degree of disc
disease. There is little doubt that some laminectomies have been carried out for cervical spondylosis where MS was the final correct
diagnosis. Alternatively, there are patients who have been diagnosed with MS when cervical spondylosis was the cause of their
symptoms.
Progressive solitary sclerosis — Progressive myelopathy due to MS is the most common presentation of primary progressive
MS (see "Clinical presentation, course, and prognosis of multiple sclerosis in adults", section on 'Primary progressive MS').
Nevertheless, a single demyelinating lesion can produce a progressive myelopathy similar to primary progressive MS, a condition
termed progressive solitary sclerosis. A case series described 30 patients who developed progressive motor impairment attributable
to a single demyelinating lesion on MRI [72]. The progressive impairments in this group were hemiparesis/monoparesis (n = 24),
quadriparesis (n = 5), and paraparesis (n = 1). These deficits were attributed to solitary demyelinating lesions identified by MRI in the
cervical spinal cord (n = 18), cervicomedullary junction and brainstem region (n = 6), thoracic spinal cord (n = 4), and subcortical
white matter (n = 2). With a median follow-up from symptom onset of 100 months, none had clinical symptoms suggestive of relapses
affecting other portions of the central nervous system, and no new lesions were found in the patients who had repeat MRI scans of
the brain and spinal cord. Oligoclonal bands or an elevated immunoglobulin G (IgG) index were present in 13 of 26 (50 percent)
patients. There was no evidence suggesting another etiology for progressive myelopathy, such as NMO. However, these patients do
not fulfill the McDonald criteria for MS because they lack evidence of dissemination in space [2]. Importantly, some patients may have
demyelination only in the spinal cord and cerebral cortex, but not the white matter, a type of MS termed myelocortical MS [73].
The treatment of progressive solitary sclerosis is not well-studied but can be approached in the same manner as primary progressive
MS. (See "Treatment of progressive multiple sclerosis in adults".)
Acute and subacute transverse myelitis — Transverse myelitis is an inflammatory disorder that presents with acute or subacute
spinal cord dysfunction resulting in weakness, sensory alterations, and autonomic impairment (eg, bowel, bladder, and sexual
dysfunction) below the level of the lesion. Transverse myelitis can occur as an independent entity, usually as a postinfectious
complication, but transverse myelitis also exists on a continuum of neuro-inflammatory disorders:
● Transverse myelitis can occur as part of the spectrum of MS. In some cases, transverse myelitis is the initial demyelinating event
(and therefore represents a clinically isolated syndrome) that precedes clinically definite MS. (See "Manifestations of multiple
sclerosis in adults" and "Management of clinically and radiologically isolated syndromes suggestive of multiple sclerosis".)
● Transverse myelitis manifesting as a longitudinally extensive spinal cord lesion spanning three or more vertebral segments is
one of the characteristic manifestations, along with bilateral optic neuritis, of NMOSD. However, NMOSD can also cause
transverse myelitis involving fewer segments. (See 'NMOSD' below.)
● Transverse myelitis may be seen in patients with acute disseminated encephalomyelitis. (See "Acute disseminated
encephalomyelitis (ADEM) in adults".)
Clinical and imaging evidence of multifocal involvement within the central nervous system, when present, suggest that transverse
myelitis is not idiopathic, but rather is associated with MS, NMOSD, MOG-EM, or acute disseminated encephalomyelitis.
Of note, patients presenting with acute complete idiopathic transverse myelitis (complete or near complete clinical deficits below the
lesion) have a low risk of developing MS. However, partial or incomplete myelitis with mild or grossly asymmetric spinal cord
dysfunction is a more common clinical entity with a higher risk of progression to MS, as discussed separately. (See "Transverse
myelitis", section on 'Progression to multiple sclerosis'.)
Multiple central nervous system lesions — A common error is to over-interpret multiple hyperintense lesions on brain MRI as
equivalent to MS in the absence of clinical symptoms consistent with the diagnosis. Unfortunately, it is not uncommon for
misdiagnosed patients to be treated with disease-modifying therapies.
Some central nervous system inflammatory or infectious diseases may produce multifocal lesions with or without a relapsing-remitting
course, but these conditions generally do not present as a characteristic MS attack. The list includes the following:
● Microvascular disease (image 10), especially in older patients with vascular risk factors
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● Migraine (see "Headache, migraine, and stroke", section on 'Subclinical brain lesions')
● Systemic lupus erythematosus, which can present as a recurrent neurologic syndrome before the systemic manifestations
appear (see "Neurologic manifestations of systemic lupus erythematosus")
● Sjögren syndrome (see "Neurologic manifestations of Sjögren's syndrome")
● Polyarteritis nodosa (see "Clinical manifestations and diagnosis of polyarteritis nodosa in adults", section on 'Neurologic
disease')
● Behçet syndrome (see "Clinical manifestations and diagnosis of Behçet syndrome", section on 'Neurologic disease')
● Syphilis (see "Neurosyphilis")
● Retroviral diseases (see "Approach to HIV-infected patients with central nervous system lesions" and "Human T-lymphotropic
virus type I: Disease associations, diagnosis, and treatment", section on 'HTLV-I-associated myelopathy/tropical spastic
paraparesis')
● Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (see "Cerebral autosomal dominant
arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL)")
● Susac syndrome, a rare microangiopathy characterized by the triad of encephalopathy, branch retinal artery occlusions and
hearing loss (see "Primary angiitis of the central nervous system in adults", section on 'Alternative diagnoses')
Tumefactive demyelination — Tumefactive demyelination (image 11) is an acute tumor-like MS variant in which patients present
with large (>2 cm) acute lesions, often associated with edema or ring enhancement [74-77]. There may be mass effect, with
compression of the lateral ventricle and midline shift.
Although there is no consensus regarding nomenclature, this type of inflammatory demyelinating disease has been termed
tumefactive MS or Marburg disease or variant. Balo concentric sclerosis (image 12) is the term preferred by some to describe
concentrically layered lesions in the cerebral white matter that have a whorled appearance similar to an onion ring [78].
The clinical abnormalities in such patients are variable; they may be very slight even in a patient with a massive lesion, while
confusion, hemiparesis, or neglect syndrome can be seen in another patient with a lesion that appears no different. Typically, much of
the T2-bright lesion volume on brain MRI is due to edema and may be rapidly responsive to glucocorticoid treatment. However,
radiologic improvement with glucocorticoids can also occur with glioma or with central nervous system lymphoma and is therefore not
a useful diagnostic criterion. Biopsy is often required.
In one of the largest series, 168 patients with biopsy-confirmed, tumor-like inflammatory demyelinating disease were analyzed
retrospectively [74]. The following observations were reported:
● The median age at onset was 37 years (range 8 to 69).
● Clinical presentations were typically polysymptomatic. Motor, cognitive, sensory, and cerebellar symptoms were the most
frequent.
● Lesions on brain MRI were often multifocal, and the median size of the largest T2 lesion was 4 cm. Gadolinium enhancement on
brain MRI was observed in more than half of the lesions; ring, heterogeneous, and homogeneous patterns were the most
common.
● The clinical course at last follow-up was relapsing-remitting in approximately one-half of the patients and monophasic in about
one-quarter. The final diagnosis was definite or probable multiple sclerosis in 79 percent and an isolated demyelinating syndrome
in 14 percent.
Specific disorders — A number of inflammatory disorders must be considered in the differential diagnosis of MS, including acute
disseminated encephalomyelitis (ADEM), NMOSD, myelin oligodendrocyte glycoprotein IgG-associated encephalomyelitis (MOG-
EM), and chronic lymphocytic inflammation with pontine perivascular enhancement responsive to steroids (CLIPPERS).
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ADEM — ADEM is autoimmune demyelinating disease of the central nervous system that typically follows a systemic viral
infection (parainfectious encephalomyelitis) or, less commonly, a vaccination. Pathologically, there is perivascular inflammation,
edema, and demyelination within the central nervous system. Clinically, patients with ADEM present with the rapid development of
focal or multifocal neurologic dysfunction, including motor, sensory, cranial nerve, and brainstem deficits as well as nonspecific
symptoms such as headache, malaise, and altered mental status. (See "Acute disseminated encephalomyelitis (ADEM) in adults".)
Certain clinical features may be helpful in supporting the diagnosis of ADEM or MS. However, there is substantial overlap (see "Acute
disseminated encephalomyelitis (ADEM) in adults", section on 'Clinical features'):
● ADEM typically follows a prodromal viral illness, while MS may or may not
● ADEM may present with fever and stiff neck, which is unusual in MS
● ADEM usually produces a widespread central nervous system disturbance, often with impaired consciousness and/or
encephalopathy, while MS typically is monosymptomatic (eg, optic neuritis or a subacute myelopathy) and has a relapsing-
remitting course
Brain MRI features may also be helpful in distinguishing ADEM from MS, although complete differentiation is not possible on the
basis of a single study (see "Acute disseminated encephalomyelitis (ADEM) in adults", section on 'Neuroimaging'):
● ADEM usually has more MRI lesions than MS, with larger bilateral but asymmetric white matter abnormalities
● ADEM lesions tend to have poorly defined margins, while MS lesions tend to have better defined margins
● The presence of brain lesions of about the same age on MRI is most consistent with ADEM, while the presence of brain lesions
of different ages and/or the presence of black holes (hypointense T1-weighted lesions) suggests MS
● Thalamic lesions are common in ADEM and rare in MS
● Periventricular lesions are less common in ADEM than MS
In addition, oligoclonal bands are less common in ADEM than MS [79]. (See "Acute disseminated encephalomyelitis (ADEM) in
adults", section on 'CSF analysis'.)
NMOSD — NMOSD is reviewed here briefly and discussed in detail elsewhere. (See "Neuromyelitis optica spectrum disorders".)
NMOSD is an inflammatory disorder of the central nervous system characterized by severe, immune-mediated demyelination and
axonal damage predominantly targeting the optic nerves and spinal cord, but also the brain and brainstem. Once considered a variant
of multiple sclerosis, NMOSD is now recognized as a distinct clinical entity based upon the presence of the disease-specific
aquaporin-4 (AQP4) antibody, which plays a direct role in the pathogenesis of NMOSD. (See "Neuromyelitis optica spectrum
disorders", section on 'Background' and "Neuromyelitis optica spectrum disorders", section on 'Pathogenesis'.)
The incidence of NMOSD in women is up to 10 times higher than in men. NMOSD, unlike MS, is more common in people of Asian,
Hispanic, and African descent. Hallmark features of NMOSD include acute attacks of bilateral or rapidly sequential optic neuritis
(leading to visual loss) and transverse myelitis (often causing limb weakness and bladder dysfunction) with a typically relapsing
course. Central nervous system involvement outside of the optic nerves and spinal cord is also recognized in NMOSD. Other
suggestive symptoms include episodes of intractable vomiting or hiccoughs, excessive daytime somnolence or narcolepsy due to
hypothalamic lesions, reversible posterior leukoencephalopathy syndrome, neuroendocrine disorders, and (in children) seizures.
While no clinical features are disease-specific, some are highly characteristic. NMOSD has a relapsing course in 90 percent or more
of cases. Unlike MS, patients with NMOSD commonly have other autoimmune disorders. (See "Neuromyelitis optica spectrum
disorders", section on 'Epidemiology' and "Neuromyelitis optica spectrum disorders", section on 'Clinical features'.)
The diagnosis of NMOSD is based on clinical, imaging, and laboratory data. Severe attacks of myelitis or optic neuritis should raise
suspicion for NMOSD. Diagnostic criteria for NMOSD require the presence of optic neuritis, myelitis, and at least two of three
supportive criteria (see "Neuromyelitis optica spectrum disorders", section on 'Evaluation and diagnosis'):
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● A contiguous spinal cord lesion on MRI extending three or more segments (image 13)
● Initial brain MRI not meeting usual diagnostic criteria for MS
● Seropositivity for NMO-IgG (ie, anti-AQP4 antibody)
Several features appear to distinguish NMOSD from classical relapsing-remitting MS (see "Neuromyelitis optica spectrum disorders",
section on 'Differential diagnosis'):
● Brain MRI may be normal in patients with NMOSD, particularly at onset, and spinal cord MRI, by definition, exhibits extensive
lesions spanning three or more vertebral segments. However, clinical or MRI evidence of brain involvement, particularly in the
brainstem, occurs in a substantial proportion of patients with NMOSD. Findings on brain MRI that suggest the diagnosis of MS
rather than NMOSD include T2-weighted lesions in one or more of the following locations:
• Lesion adjacent to lateral ventricle

• Inferior temporal lobe white matter lesion
• Ovoid (ie, "Dawson finger") periventricular lesion
• U-fiber juxtacortical lesion
● During acute attacks of NMOSD, the CSF may exhibit a neutrophilic pleocytosis, but it is usually negative for oligoclonal bands.
● The detection of AQP4 antibody positivity is specific for NMOSD. (See "Neuromyelitis optica spectrum disorders", section on
'AQP4 autoantibody'.)
● The myelopathy with NMOSD tends to be more severe than with MS, with less likelihood of recovery. Unlike MS, there does not
appear to be a progressive phase independent from relapses.
MOG-EM — IgG serum antibodies to myelin oligodendrocyte glycoprotein, once considered to be markers of MS disease activity,
are now recognized to denote a separate disease entity termed MOG-EM. The disorder is characterized by a variety of
manifestations related to central nervous system demyelination that include relapsing and bilateral optic neuritis, transverse myelitis,
brainstem encephalitis, and ADEM [80-83].
There is substantial overlap of the clinical and radiologic features of MOG-EM with MS and with NMOSD [84,85]. MOG-EM typically
follows a relapsing course, is less often monophasic, and rarely follows a chronic progressive course. Clinical findings may involve a
high frequency and/or severity of optic neuritis, severe or frequent episodes of brainstem encephalitis or acute transverse myelitis,
persistent sphincter and/or erectile dysfunction after transverse myelitis, and area postrema syndrome (intractable nausea and
vomiting). In some cases, MOG-EM initially presents as an acute flaccid myelitis [83]. Other clinical manifestations may include acute
respiratory insufficiency, disturbance of consciousness, behavioral changes, or epileptic seizures.
Frequent MRI findings include longitudinally extensive spinal cord lesions (three or more contiguous vertebral segments), conus
medullaris lesions, and longitudinally extensive optic nerve lesions (eg, more than half the length of the pre-chiasmal optic nerve).
Spinal cord lesions generally show an H-shaped pattern of T2 hyperintensity confined to the gray matter on axial MRI and lack of
contrast enhancement [83]. Unlike MS, ovoid or round lesions on brain MRI adjacent to the lateral ventricles or radially oriented
lesions in the sagittal plane (Dawson's finger-type lesions) are generally not found in MOG-EM.
Most patients with MOG-EM do not have CSF-specific oligoclonal bands, unlike MS [83]. The CSF findings in MOG-EM can include a
neutrophilic pleocytosis and/or a white count >50 cells/microL [84], both of which are rarely associated with MS.
Proposed diagnostic criteria for MOG antibody–associated disorders, derived from a series of 51 patients, require serum positivity for
MOG-IgG by cell-based assay and a clinical presentation consistent with central nervous system demyelination (ie, ADEM, optic
neuritis, transverse myelitis, a brain or brainstem demyelinating syndrome, or any combination of these), and exclusion of an
alternative diagnosis [86]. In the absence of serum, positivity for MOG-IgG in the CSF allow fulfillment of the criteria. A transient
seropositivity favors a lower risk of relapse.
CLIPPERS — CLIPPERS is a type of encephalomyelitis that predominantly involves the pons [87,88]. The clinical features include
a relapsing-remitting pattern of diplopia, gait ataxia, dysarthria, and facial paresthesia along with characteristic radiologic appearance
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of punctate, curvilinear gadolinium-enhancing lesions on MRI scattered throughout the pons with variable involvement of the medulla,
brachium pontis, cerebellum, midbrain, and spinal cord (image 14) [87,89,90]. Neuropathology of the brainstem and cerebellar
lesions demonstrates a predominantly T cell lymphocytic infiltrate in the perivascular white matter. Some patients have oligoclonal
bands in the cerebrospinal fluid. CLIPPERS is generally responsive to long-term glucocorticoid therapy; a few reports describe
transitioning to glucocorticoid-sparing immunosuppressive agents [91].
SOCIETY GUIDELINE LINKS
Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately.
(See "Society guideline links: Multiple sclerosis and related disorders".)
SUMMARY AND RECOMMENDATIONS
● The most common presentation of multiple sclerosis (MS) consists a single, monosymptomatic attack compatible with
demyelination (eg, optic neuritis, a brainstem syndrome, or a spinal cord syndrome). In some patients, the diagnosis of MS can
be established at that point based on clinical, magnetic resonance imaging (MRI), and cerebrospinal fluid criteria. Clinically
isolated syndrome refers to a monosymptomatic attack that does not fulfill diagnostic criteria for MS but may predispose to
clinically definite MS. Approximately 10 to 15 percent of patients with MS present with insidious neurologic worsening and
accumulation of disability from spastic paraparesis or cerebellar ataxia, a pattern known as primary progressive MS. (See 'When
to suspect MS' above.)
● The evaluation of suspected MS begins with a detailed clinical history and examination. All patients should also have a brain MRI
without and with contrast. For patients with a typical presentation who have insufficient clinical and MRI evidence to confirm the
diagnosis of MS by the McDonald criteria, additional testing with lumbar puncture for cerebrospinal fluid-specific oligoclonal
bands, visual evoked potentials, and/or optical coherence tomography can be used to support the diagnosis. For patients with a
presentation other than a typical clinically isolated syndrome or patients with atypical findings in any aspect of the clinical history,
examination, or brain imaging, additional testing with spine MRI, lumbar puncture, and/or autoantibody determination for
aquaporin-4 (AQP4) and myelin-oligodendrocyte glycoprotein (MOG) antibodies is warranted to investigate alternatives in the
differential diagnosis. (See 'Evaluation' above.)
● MRI lesions suggestive of MS are typically found in the periventricular region, corpus callosum, centrum semiovale, and, to a
lesser extent, deep white matter structures and basal ganglia (image 3 and image 2). MS lesions typically have an ovoid
appearance. The lesions are characteristically arranged at right angles to the corpus callosum; when viewed on sagittal images,
they are referred to as Dawson fingers. The MS brain lesions appear hyperintense on proton density and T2-weighted studies,
and they are hypointense (if visible at all) on T1-weighted images. Spinal cord MRI lesions are nearly as common as brain
lesions in patients with MS. Gadolinium-enhancing lesions on T1-weighted MRI are associated with new or newly active plaques.
(See 'Magnetic resonance imaging' above.)
● Oligoclonal bands are found in cerebrospinal fluid in up to 95 percent of patients with clinically definite MS. A positive
cerebrospinal fluid is based upon the finding of either oligoclonal bands different from any such bands in serum, or by an
increased immunoglobulin G (IgG) index. (See 'CSF analysis and oligoclonal bands' above.)
● MS is primarily a clinical diagnosis. The history and physical examination are most important for diagnostic purposes. The
McDonald criteria for the diagnosis of MS (table 4) apply primarily to patients who have a typical clinically isolated syndrome at
presentation suggestive of relapsing-remitting MS, and can also be applied to patients presenting with insidious neurologic
progression suggestive of primary progressive MS. While useful when the diagnosis of MS is clinically suspected, the McDonald
criteria are not intended for distinguishing MS from other neurologic conditions. The core requirement of the diagnosis of MS is
the objective demonstration of dissemination of central nervous system lesions in both space (table 5) and time (table 6), based
upon clinical findings alone, a combination of clinical and MRI findings, or in some instances an appropriate clinical syndrome
and highly supportive MRI data. (See 'Diagnosis' above.)
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● The differential diagnosis of MS includes a number of inflammatory, vascular, infectious, genetic, granulomatous, and other
demyelinating disorders (table 7), but depends on the clinical setting. (See 'Differential diagnosis' above.)
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51. Calabrese M, Rinaldi F, Seppi D, et al. Cortical diffusion-tensor imaging abnormalities in multiple sclerosis: a 3-year longitudinal
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52. Seewann A, Kooi EJ, Roosendaal SD, et al. Postmortem verification of MS cortical lesion detection with 3D DIR. Neurology
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53. Nelson F, Poonawalla AH, Hou P, et al. Improved identification of intracortical lesions in multiple sclerosis with phase-sensitive
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54. Sethi V, Yousry TA, Muhlert N, et al. Improved detection of cortical MS lesions with phase-sensitive inversion recovery MRI. J
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55. Filippi M, Rocca MA, Horsfield MA, et al. Imaging cortical damage and dysfunction in multiple sclerosis. JAMA Neurol 2013;
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58. Freedman MS, Thompson EJ, Deisenhammer F, et al. Recommended standard of cerebrospinal fluid analysis in the diagnosis
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59. Dobson R, Ramagopalan S, Davis A, Giovannoni G. Cerebrospinal fluid oligoclonal bands in multiple sclerosis and clinically
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60. Giesser BS. Diagnosis of multiple sclerosis. Neurol Clin 2011; 29:381.
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75. Nagappa M, Taly AB, Sinha S, et al. Tumefactive demyelination: clinical, imaging and follow-up observations in thirty-nine
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78. Hardy TA, Miller DH. Baló's concentric sclerosis. Lancet Neurol 2014; 13:740.
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80. Jarius S, Paul F, Aktas O, et al. MOG encephalomyelitis: international recommendations on diagnosis and antibody testing. J
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81. Ramanathan S, Dale RC, Brilot F. Anti-MOG antibody: The history, clinical phenotype, and pathogenicity of a serum biomarker
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82. Cobo-Calvo A, Ruiz A, Maillart E, et al. Clinical spectrum and prognostic value of CNS MOG autoimmunity in adults: The
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84. Jarius S, Ruprecht K, Kleiter I, et al. MOG-IgG in NMO and related disorders: a multicenter study of 50 patients. Part 2:
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85. Spadaro M, Gerdes LA, Krumbholz M, et al. Autoantibodies to MOG in a distinct subgroup of adult multiple sclerosis. Neurol
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86. López-Chiriboga AS, Majed M, Fryer J, et al. Association of MOG-IgG Serostatus With Relapse After Acute Disseminated
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87. Pittock SJ, Debruyne J, Krecke KN, et al. Chronic lymphocytic inflammation with pontine perivascular enhancement responsive
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88. Dudesek A, Rimmele F, Tesar S, et al. CLIPPERS: chronic lymphocytic inflammation with pontine perivascular enhancement
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89. Simon NG, Parratt JD, Barnett MH, et al. Expanding the clinical, radiological and neuropathological phenotype of chronic
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Topic 1688 Version 44.0
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GRAPHICS
Suggestive and atypical features of multiple sclerosis
Features suggestive of multiple sclerosis

Relapses and remissions
Onset between ages 15 and 50 years
Optic neuritis
Lhermitte sign
Internuclear ophthalmoplegia
Fatigue
Heat sensitivity (Uhthoff phenomenon)
Features atypical for multiple sclerosis

Steady progression
Onset before age 10 or after age 50 years
Cortical deficits such as aphasia, apraxia, alexia, or neglect
Rigidity or sustained dystonia
Convulsions
Early dementia
Deficit developing within minutes
Graphic 63940 Version 6.0
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Brain MRI showing plaque in the pons of a patient with multiple sclerosis
Axial FLAIR (A) image demonstrate a large demyelinating lesion in the left pons. The lesion shows peripheral enhancement on
axial post-contrast T1-weighted image (B).
MRI: magnetic resonance imaging; FLAIR: fluid-attenuated inversion recovery.
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Spinal cord MRI demonstrating transverse myelitis in a

37-year-old man with multiple sclerosis
T2-weighted sagittal (A) and axial (B) images show a focus of hyperintensity in
the posterior columns of the cervical spinal cord at the C2 level. Post-gadolinium
T1-weighted sagittal (C) and axial (D) images demonstrate enhancement
consistent with an active plaque.
MRI: magnetic resonance imaging.
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Brain MRI of a 42-year-old woman with multiple sclerosis
Axial T2-weighted (A) and axial fluid attenuated inversion recovery (FLAIR) (B) images show
multiple, ovoid shaped, hyperintense foci consistent with multiple sclerosis plaques. Sagittal FLAIR
(C) image also shows these lesions to be radiating out from the corpus callosum. Axial precontrast
T1-weighted (D) image shows that many of these lesions are hypointense, consistent with black
holes. Axial postgadolinium fat saturated T1-weighted (E) image shows that some of these plaques
enhance in a ring-like fashion consistent with active plaques.
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Brain MRI of patient with multiple sclerosis demonstrating Dawson fingers
Axial (A) and sagittal (B) MRI FLAIR images of the brain demonstrate multiple, ovoid periventricular lesions (Dawson fingers) in a
patient with multiple sclerosis.
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Brain MRI showing multiple enhancing lesions in a patient with multiple sclerosis
On brain MRI, axial (A) and sagittal (B) post-contrast T1-weighted images demonstrate multiple solid and ring-enhancing lesions
indicative of active demyelinating disease.
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Brain MRI showing multiple black holes in a patient with chronic multiple sclerosis
Axial T1-weighted images (A and B) demonstrate multiple hypointense areas (black holes) in a patient with longstanding MS.
MRI: magnetic resonance imaging; MS: multiple sclerosis.
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Brain MRI of a 38-year-old woman with multiple sclerosis
Axial flair image (A) show two plaques in the internal capsule, one in the anterior limb and
one in the posterior limb. Diffusion tensor fractional anisotropy map (B) shows asymmetric
hypointensity (decreased anisotropy) in these regions (arrows), consistent with loss of
axonal integrity.
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Ancillary testing in multiple sclerosis
Test Percent abnormal in patients with multiple sclerosis
Visual evoked responses 50 to 90
Brainstem auditory evoked responses 20 to 55
Somatosensory evoked potentials 50
Cerebrospinal fluid oligoclonal banding 85 to 95
Cerebrospinal fluid IgG index 75
Brain MRI 70 to 95
Data from:
1. Giesser BS. Diagnosis of multiple sclerosis. Neurol Clin 2011; 29:381.
2. 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.
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Brain MRI with optic chiasm lesion in a patient with NMO
MRI of the brain. Axial (A) and sagittal (B) post-contrast T1-weighted images demonstrate enhancement of the optic chiasm.
MRI: magnetic resonance imaging; NMO: neuromyelitis optic.
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Recommended indications for MOG-IgG testing in patients presenting with acute CNS demyelination of putative
autoimmune etiology
1. Monophasic or relapsing acute optic neuritis, myelitis, brainstem encephalitis, encephalitis, or any combination thereof, and
2. Radiologic or, only in patients with a history of optic neuritis, electrophysiologic (VEP) findings compatible with CNS demyelination, and
3. At least one of the following findings:
MRI
a. Longitudinally extensive spinal cord lesion (≥3 VS, contiguous, so-called LETM)
b. Longitudinally extensive spinal cord atrophy (≥3 VS, contiguous) in patients with a history compatible with acute myelitis
c. Conus medullaris lesions, especially if present at onset
d. Longitudinally extensive optic nerve lesion (eg, >1/2 of the length of the pre-chiasmal optic nerve, T2 or T1/Gd)
e. Perioptic Gd enhancement during acute ON
f. Normal supratentorial MRI in patients with acute ON, myelitis and/or brainstem encephalitis
g. Brain MRI abnormal but no lesion adjacent to a lateral ventricle that is ovoid/round or associated with an inferior temporal lobe lesion and no Dawson
finger-type or juxtacortical U fiber lesion
h. Large, confluent T2 brain lesions suggestive of ADEM
Funduscopy
i. Prominent papilledema/papillitis/optic disc swelling during acute ON
CSF
j. Neutrophilic CSF pleocytosis or CSF white cell count >50/microL
k. No CSF-restricted OCB as detected by IEF at first or any follow-up examination (applies to continental European patients only)
Histopathology
l. Primary demyelination with intralesional complement and IgG deposits
m. Previous diagnosis of "pattern II MS"
Clinical findings
n. Simultaneous bilateral acute ON
o. Unusually high ON frequency or disease mainly characterized by recurrent ON
p. Particularly severe visual deficit/blindness in one or both eyes during or after acute ON
q. Particularly severe or frequent episodes of acute myelitis or brainstem encephalitis
r. Permanent sphincter and/or erectile disorder after myelitis
s. Patients diagnosed with "ADEM," "recurrent ADEM," "multiphasic ADEM," or "ADEM-ON"
t. Acute respiratory insufficiency, disturbance of consciousness, behavioral changes, or epileptic seizures (radiological signs of demyelination required)
u. Disease started within four days to approximately four weeks after vaccination
v. Otherwise unexplained intractable nausea and vomiting or intractable hiccups (compatible with area postrema syndrome)
w. Coexisting teratoma or NMDAR encephalitis (low evidence)
Treatment response
x. Frequent flare-ups after intravenous methylprednisolone, or steroid-dependent symptoms (including CRION)
y. Clear increase in relapse rate following treatment with interferon-beta or natalizumab in patients diagnosed with MS (low evidence)
MOG-IgG: myelin oligodendrocyte glycoprotein immunoglobulin G autoantibody; CNS: central nervous system; VEP: visual evoked potentials; MRI: magnetic
resonance imaging; VS: vertebral segment; LETM: longitudinally extensive transverse myelitis; Gd: gadolinium; ON: optic neuritis; ADEM: acute disseminated
encephalomyelitis; CSF: cerebrospinal fluid; OCB: oligoclonal bands; IEF: isoelectric focusing; IgG: immunoglobulin G; MS: multiple sclerosis; NMDAR: N-methyl-
D-aspartate receptor; CRION: chronic relapsing inflammatory optic neuropathy.
Adapted from: Jarius S, Paul F, Aktas O, et al. MOG encephalomyelitis: international recommendations on diagnosis and antibody testing. J Neuroinflammation 2018;
15:134. DOI: 10.1186/s12974-018-1144-2. Copyright © 2018 Jarius S, Paul F, Aktas O, et al. Reproduced under the terms of the Creative Commons Attribution
License 4.0.
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Diagnosis of typical relapsing-remitting multiple sclerosis
CIS: clinically isolated syndrome; CNS: central nervous system; CSF: cerebrospinal fluid; DIS: dissemination in space; DIT: dissemination in time; DMT: disease-
modifying therapy; MRI: magnetic resonance imaging; MS: multiple sclerosis; OCBs: oligoclonal bands; OCT: optical coherence tomography; VEPs: visual evoked
potentials.
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The 2017 McDonald criteria for the diagnosis of multiple sclerosis in patients with an attack at onset
Number of lesions with objective clinical Additional data needed for a diagnosis of
evidence multiple sclerosis
≥2 clinical attacks ≥2 None*
1 (as well as clear-cut historical evidence of a previous attack None*

involving a lesion in a distinct anatomical location ¶ )
1 Dissemination in space demonstrated by an additional clinical

attack implicating a different CNS site or by MRI Δ
1 clinical attack ≥2 Dissemination in time demonstrated by an additional clinical

attack or by MRI ◊ OR demonstration of CSF-specific
oligoclonal bands §
1 Dissemination in space demonstrated by an additional clinical

attack implicating a different CNS site or by MRI Δ
AND
Dissemination in time demonstrated by an additional clinical
attack or by MRI ◊ OR demonstration of CSF-specific
oligoclonal bands §
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. An attack is
defined as a monophasic clinical episode with patient-reported symptoms and objective findings typical of multiple sclerosis, reflecting a focal or multifocal
inflammatory demyelinating event in the CNS, developing acutely or subacutely, with a duration of at least 24 hours, with or without recovery, and in the
absence of fever or infection. Attack, relapse, exacerbation, and (when it is the first episode) clinically isolated syndrome are synonyms.
CNS: central nervous system; MRI: magnetic resonance imaging; CSF: cerebrospinal fluid.
* 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. In addition, spinal cord MRI or CSF examination should be considered in patients with insufficient clinical
and MRI evidence supporting multiple sclerosis, with a presentation other than a typical clinically isolated syndrome, or with atypical features. If imaging or other tests
(eg, CSF) are undertaken and are negative, caution needs to be taken before making a diagnosis of multiple sclerosis, and alternative diagnoses should be considered.
¶ 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 neurological findings, can include historical events with symptoms and evolution characteristic for 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.
Δ The MRI criteria for dissemination in space are described in the text of the UpToDate topic on the diagnosis of multiple sclerosis in adults.
◊ The MRI criteria for dissemination in time are described in the text of the UpToDate topic on the diagnosis of multiple sclerosis in adults.
§ The presence of CSF-specific oligoclonal bands does not demonstrate dissemination in time per se but can substitute for the requirement for demonstration of this
measure.
Reproduced from: Thompson AJ, Banwell BL, Barkhof F, et al. Diagnosis of multiple sclerosis: 2017 revisions of the McDonald criteria. Lancet Neurol 2018; 17:162.
Table used with the permission of Elsevier Inc. All rights reserved.
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Afferent pupillary defect of the right eye, demonstrated by

the swinging flashlight test
An afferent pupillary defect occurs in optic neuritis if the other eye is uninvolved and
otherwise healthy. This is demonstrated by shining a light alternately in one eye and
then the other and finding that the direct response to light is more sluggish in the
affected eye. Alternate swinging of the light between the two eyes therefore
produces dilation each time the light is directed to the affected eye.
(Image A) With both eyes exposed to the same amount of light, the pupils are equal
because the efferent pathways are intact.
(Image B) When the light is directed to the unaffected (left) eye, both eyes constrict
normally because light is detected normally by the left eye.
(Image C) When the light is directed to the right eye, it perceives little or no light
because the afferent pathway on that side is damaged, and both pupils dilate.
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Brain MRI of a patient with optic neuritis
Coronal STIR (A) image demonstrates hyperintensity of the right optic nerve (arrows), which shows enhancement on post-contrast
T1-weighted image (B).
MRI: magnetic resonance imaging; STIR: short tau inversion recovery.
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McDonald criteria for dissemination in space
Dissemination in space is defined as the development of lesions in distinct anatomic locations within the central nervous system, indicating a multifocal process.
The McDonald criteria for dissemination in space are fulfilled if one of the following is present in a patient with a clinically isolated syndrome or typical MS attack:
An MRI with one or more hyperintense T2 lesions that are characteristic of multiple sclerosis in at least two of four MS-typical regions of the central nervous
system:
Periventricular
Cortical or juxtacortical
Infratentorial
Spinal cord
Development of an additional clinical attack characteristic of multiple sclerosis, supported by objective clinical evidence, that implicates a different central
nervous system site
Adapted from: Thompson AJ, Banwell BL, Barkhof F, et al. Diagnosis of multiple sclerosis: 2017 revisions of the McDonald criteria. Lancet Neurol 2018; 17:162.
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McDonald criteria for dissemination in time
Dissemination in time requires the development or appearance of new central nervous system lesions over time.
The McDonald criteria for dissemination in time are fulfilled if one of the following is present in a patient with a clinically isolated syndrome or a characteristic MS
attack:
The development of an additional clinical attack, supported by objective clinical evidence, that is characteristic of multiple sclerosis
An MRI of the brain and/or spinal cord with the simultaneous presence of gadolinium-enhancing and nonenhancing lesions at any time, or by a new
hyperintense T2 and/or gadolinium-enhancing lesion(s) on follow-up MRI, irrespective of its timing with reference to a baseline scan
Finding of cerebrospinal fluid-specific oligoclonal bands (as a substitute for dissemination in time)
Adapted from: Thompson AJ, Banwell BL, Barkhof F, et al. Diagnosis of multiple sclerosis: 2017 revisions of the McDonald criteria. Lancet Neurol 2018; 17:162.
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Differential diagnosis of multiple sclerosis
Inflammatory disease
Acute disseminated encephalomyelitis
Behçet disease
Chronic lymphocytic inflammation with pontine perivascular enhancement responsive to steroids
Clinically isolated syndromes suggestive of multiple sclerosis
Myelin oligodendrocyte glycoprotein IgG-associated encephalomyelitis
Neuromyelitis optica spectrum disorder
Paraneoplastic encephalomyelopathies
Polyarteritis nodosa
Primary angiitis of the central nervous system
Sjögren syndrome
Systemic lupus erythematosus
Infectious disease
Human immunodeficiency virus
Lyme neuroborreliosis
Neurosyphilis
Progressive multifocal leukoencephalopathy
HTLV-1-associated myelopathy/Tropical spastic paraparesis
Genetic disease
Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy
Granulomatous disease
Lymphomatoid granulomatosis
Sarcoidosis
Granulomatosis with polyangiitis (Wegener's)
Disease of myelin
Adrenoleukodystrophy
Adult metachromatic leukodystrophy
Other
Arnold-Chiari malformation
Compressive spinal cord lesions
Vascular malformations
Vitamin B12 deficiency
Spinocerebellar disorders
Human T-lymphotropic virus, type I; IgG: Immunoglobulin G.
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Atypical or red flag presentations for multiple sclerosis
Atypical or red flag presentations Diagnostic considerations
General
Deficit developing within minutes Ischemic stroke; seizure
Fevers, weight loss, night sweats, alopecia, and synovitis Infection; systemic vasculitis; SLE
Livedo reticularis, early trimester abortions, and thrombotic events Antiphospholipid syndrome
Headache or meningismus ADEM, cerebral venous thrombosis; chronic meningitis; lymphoma; glioma;
vasculitis; SLE
Gradually progressive course from onset HTLV-1; adrenomyeloneuropathy; adrenoleukodystrophy; metachromatic

leukodystrophy; vitamin B12 deficiency
Onset before age 20 years Mitochondrial encephalomyopathy; leukodystrophy; Friedrich ataxia
Onset after age 50 years Cerebral infarction; cerebral amyloid angiopathy; lymphoma
Supratentorial
Encephalopathy (alterations in awareness and coma) ADEM; PRES; MOG-EM; infectious/autoimmune encephalitis
Hemianopsia and cortical blindness Ischemic stroke; PRES; neoplasm; PML
Insidious cognitive decline Neurodegenerative disorders; genetic leukoencephalopathy and leukodystrophy
Seizures Whipple disease; vasculitis; metastases
Cranial nerves
Progressive optic neuritis Neoplasm; neurosarcoidosis; LHON
Altitudinal deficit and monocular blindness Ischemic optic neuropathy
Clinically severe or simultaneous bilateral optic neuritis NMOSD; MOG-EM
Neuroretinitis and uveitis NMOSD
Multiple cranial neuropathies or polyradiculopathy Chronic meningitis; including neurosarcoidosis and tuberculosis; Lyme disease
Brainstem
Insidiously progressive brainstem symptoms, especially with persistent Neurosarcoidosis; histiocytosis; Behçet syndrome; malignancy; Whipple
enhancement on MRI disease; tuberculosis; CLIPPERS
Intractable nausea and vomiting or intractable hiccups (compatible with area NMOSD; MOG-EM
postrema syndrome)
Cerebellum
Progressive cerebellar symptoms Spinocerebellar ataxia; autoimmune/paraneoplastic syndromes
Spinal cord
Anterior spinal syndrome Ischemia
Complete transverse myelitis NMOSD; idiopathic myelitis; ADEM
Radiculitis Infection; neurosarcoidosis; carcinomatosis/lymphomatosis
Progressive spastic paraparesis HTLV-1; HIV; cobalamin deficiency; PLS; cervical spondylotic myelopathy;
dAVF; adrenomyeloneuropathy; progressive solitary sclerosis
Longitudinally extensive spinal cord lesion NMOSD; MOG-EM
SLE: systemic lupus erythematosus; ADEM: acute disseminated encephalomyelitis; HTLV-1: human T-lymphotropic virus type 1; PRES: posterior reversible
encephalopathy syndrome; MOG-EM: myelin oligodendrocyte glycoprotein immunoglobulin G autoantibody-associated encephalomyelitis; PML: progressive multifocal
leukoencephalopathy; LHON: Leber hereditary optic atrophy; NMOSD: neuromyelitis optica spectrum disorder; MRI: magnetic resonance imaging; CLIPPERS: chronic
lymphocytic inflammation with pontine perivascular enhancement responsive to steroids; PLS: primary lateral sclerosis; dAVF: dural arteriovenous fistula.
Adapted from: Toledano M, Weinshenker BG, Solomon AJ. A Clinical Approach to the Differential Diagnosis of Multiple Sclerosis. Curr Neurol Neurosci Rep 2015; 15:57.
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Brain MRI vascular white matter disease
Axial (A) and sagittal (B) FLAIR images demonstrate multiple, confluent hyperintense white matter lesions in an older patient with
vascular risk factors. In contrast to the lesions of multiple sclerosis, the lesions associated with vascular disease are more symmetric
and less discrete. They do not have the characteristic ovoid appearance of multiple sclerosis demyelinating lesions.
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Brain MRI tumefactive demyelination
Axial FLAIR image (A) demonstrates a large demyelinating lesion in the left frontal lobe with mass effect that shows peripheral
enhancement on post-contrast T1-weighted image (B).
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Brain MRI showing demyelinating lesion consistent with Balo concentric sclerosis
Axial (A) and coronal (B) T2-weighted images demonstrate a Balo lesion in the left frontal lobe.
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Cervical spine MRI of LETM
MRI of the cervical spine in a patient with NMO. A sagittal T2-weighted image (A) demonstrates a long area of hyperintensity in
the cervical spinal cord, which demonstrates enhancement on a post-contrast T1-weighted image (B).
LETM: longitudinally extensive transverse myelitis; MRI: magnetic resonance imaging; NMO: neuromyelitis optic.
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Brain MRI of chronic lymphocytic inflammation with

pontine perivascular enhancement responsive to
steroids (CLIPPERS)
Initial T1-weighted postgadolinium brain MRI of a 48-year-old man with

progressive vertigo, ataxia, and dysarthria.
(A) Symmetric enhancement of the pons and both cerebellar peduncles, with
pattern highly suggestive of a perivascular distribution.
(B) Near complete resolution with corticosteroids.
(C) Recurrence of the same lesions without corticosteroids.
Reproduced with permission from: Lefaucheur R, Bouwyn JP, Ahtoy P, Gérardin E,

Derrey S, Maltête D. Teaching neuroimages: punctuate and curvilinear enhancement
peppering the pons responsive to steroids. Neurology 2011; 77:e57. Copyright ©
2011 Lippincott Williams & Wilkins.
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Contributor Disclosures
Michael J Olek, DO Nothing to disclose Jonathan Howard, MD Speaker's Bureau: MCE Conferences. Other Financial Interest: Demos-Spring
Publishing; Springer Publishing. Francisco González-Scarano, MD Consultant/Advisory Boards: DeLoitte [Physician Leadership Academy]. Equity
Ownership/Stock Options: Multiple, but traded by advisors without personal input [Pharmaceutical]. John F Dashe, MD, PhD Nothing to disclose
Contributor disclosures are reviewed for conflicts of interest by the editorial group. When found, these are addressed by vetting through a multi-level
review process, and through requirements for references to be provided to support the content. Appropriately referenced content is required of all
authors and must conform to UpToDate standards of evidence.
Conflict of interest policy
45 of 45 12/30/2019, 7:23 PM

Evaluation and Diagnosis of Multiple Sclerosis in Adults - UpToDate

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Evaluation and diagnosis of multiple sclerosis in adults - UpToDate https://www-uptodate-com.offcampus.lib.washington.edu/contents/evalu...

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Pathogenesis and epidemiology of multiple sclerosis

Clinical presentation, course, and prognosis of multiple sclerosis in adults

Manifestations of multiple sclerosis in adults

Management of clinically and radiologically isolated syndromes suggestive of multiple sclerosis

Treatment of acute exacerbations of multiple sclerosis in adults

Disease-modifying treatment of relapsing-remitting multiple sclerosis in adults

Treatment of progressive multiple sclerosis in adults

MAGNETIC RESONANCE IMAGING

● Little or no cord swelling

● When clinical, imaging, or laboratory features are atypical of MS

● In populations in which MS is less common, including children and older adults

suspicion for NMOSD include the following (see 'NMOSD' below):

● Two or more hyperintense T2 lesions in the spinal cord

● Presence of CSF-specific oligoclonal bands

● Family history of neurologic disease other than MS

● Sjögren syndrome (see "Neurologic manifestations of Sjögren's syndrome")

● Syphilis (see "Neurosyphilis")

● The median age at onset was 37 years (range 8 to 69).

● Thalamic lesions are common in ADEM and rare in MS

● Periventricular lesions are less common in ADEM than MS

• Lesion adjacent to lateral ventricle

SOCIETY GUIDELINE LINKS

SUMMARY AND RECOMMENDATIONS

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3. Filippi M, Rocca MA. MR imaging of multiple sclerosis. Radiology 2011; 259:659.

multiple sclerosis. Neurology 2012; 78:1383.

Topic 1688 Version 44.0

Suggestive and atypical features of multiple sclerosis

Features suggestive of multiple sclerosis

Onset between ages 15 and 50 years

Heat sensitivity (Uhthoff phenomenon)

Features atypical for multiple sclerosis

Onset before age 10 or after age 50 years

Cortical deficits such as aphasia, apraxia, alexia, or neglect

Rigidity or sustained dystonia

Deficit developing within minutes

Graphic 63940 Version 6.0

MRI: magnetic resonance imaging; FLAIR: fluid-attenuated inversion recovery.

Graphic 119486 Version 1.0

Spinal cord MRI demonstrating transverse myelitis in a

MRI: magnetic resonance imaging.

Graphic 73197 Version 7.0

Brain MRI of a 42-year-old woman with multiple sclerosis

Graphic 61864 Version 4.0

Brain MRI of patient with multiple sclerosis demonstrating Dawson fingers

MRI: magnetic resonance imaging; FLAIR: fluid-attenuated inversion recovery.

Graphic 119485 Version 1.0

MRI: magnetic resonance imaging.

Graphic 119487 Version 1.0

MRI: magnetic resonance imaging; MS: multiple sclerosis.

Graphic 119488 Version 1.0

Brain MRI of a 38-year-old woman with multiple sclerosis

Graphic 52184 Version 4.0

Ancillary testing in multiple sclerosis

Test Percent abnormal in patients with multiple sclerosis

Visual evoked responses 50 to 90

Brainstem auditory evoked responses 20 to 55

Somatosensory evoked potentials 50

Cerebrospinal fluid oligoclonal banding 85 to 95

Cerebrospinal fluid IgG index 75