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:
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 . 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:
●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 magnetic resonance imaging (MRI) of the brain and spinal cord without and with contrast . Dedicated optic nerve MRI can be useful for diagnosis in patients with a clinically isolated syndrome, those with atypical clinical features (eg, atypical, isolated optic neuritis), and for exclusion of alternative diagnoses such as neuromyelitis optica spectrum disorders (NMOSD) or myelin oligodendrocyte glycoprotein antibody-associated disease (MOGAD). (See "Neuromyelitis optica spectrum disorder (NMOSD): Clinical features and diagnosis" and "Myelin oligodendrocyte glycoprotein antibody-associated disease (MOGAD): Clinical features and diagnosis".)
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 . 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 . 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) . 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 . 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 .
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) . MS lesions (plaques) usually have an ovoid appearance.
Periventricular MS 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 nonspecific lesions on brain MRI, especially in patients with migraine or hypertension, there is a significant risk for false positive results . Moreover, changes to the McDonald diagnostic criteria in 2017 seem to exacerbate this problem . As such, white matter hyperintensities are not by themselves diagnostic of MS and must be interpreted in the clinical context of the patient .
Spinal cord MRI — Spinal cord MRI lesions are nearly as common as brain lesions in patients with MS [11,12], 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 , 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 [12,14-17]:
●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 . The diagnosis of MS was made by the 1982 criteria of Poser et al . 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  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 .
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 . 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 . Prolonged persistence of enhancement should caution against the diagnosis of MS .
●Longitudinal studies have demonstrated that the presence of active lesions on serial MRI scans carries a high risk of continuous disease activity [24,25].
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 . 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 ) 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)
●Flat pancake-like enhancement  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" [29-32], 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 .
Although the evidence is limited, persistent black holes are thought to be markers of severe demyelination and axonal loss . The pathological substrate for the accumulation of persisting black holes appears to be predominantly axonal damage [29,30,33], as shown in a postmortem histopathology-MRI correlation study . 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 .
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 . 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 .
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 [3,37]:
●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 .
Oligoclonal bands are found in up to 95 percent of patients with clinically definite MS (table 2) [39,40]. 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 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) . 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 5 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 .
The role of OCT for the diagnosis of MS is not well-established [44-46]. 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 . 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 . (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 suspicion for NMOSD include the following (see 'NMOSD' below):
●Optic neuritis that is simultaneously bilateral, involves the optic chiasm (image 7), 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 antibody-associated disease (MOGAD), 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 'MOGAD' below). Indications for MOG-IgG testing are listed in the table (table 3). (See "Myelin oligodendrocyte glycoprotein antibody-associated disease (MOGAD): Clinical features and diagnosis".)
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 . (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) . 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 . (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 . 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 . 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 8), 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 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 .
●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 .
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 .
●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 .
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) . 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 .
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 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 . 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 [3,48,50]:
●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)
●Meningismus and/or headache
●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
●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 . 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 antibody-associated disease (MOGAD) 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 MOGAD 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). CIS is not necessarily a different disease than MS, but rather often a precursor to it.
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 "Clinical features, evaluation, and diagnosis of X-linked adrenoleukodystrophy", section on 'Myeloneuropathy'.)
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 . These patients do not have MS. Compression of the 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 . 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 . 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 .
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 secondary 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, MOGAD, 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.
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. Overall, overdiagnosis of MS is likely a bigger problem than underdiagnosis .
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 9), especially in older patients with vascular risk factors
●Systemic lupus erythematosus, which can present as a recurrent neurologic syndrome before the systemic manifestations appear (see "Neurologic and neuropsychiatric manifestations of systemic lupus erythematosus", section on 'Inflammatory and demyelinating disease')
●Sjögren's disease (see "Neurologic manifestations of Sjögren's disease")
●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 the patient with HIV and 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 10) is an acute tumor-like MS variant in which patients present with large (>2 cm) acute lesions, often associated with edema or ring enhancement [56-59]. 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. Baló concentric sclerosis (image 11) 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 [60,61].
The clinical abnormalities in such patients are variable; they may be very slight even in a patient with a massive lesion, while confusion, visual field deficits, hemiparesis, aphasia, 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 . 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 antibody-associated disease (MOGAD), and chronic lymphocytic inflammation with pontine perivascular enhancement responsive to steroids (CLIPPERS).
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 . (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 disorder (NMOSD): Clinical features and diagnosis".)
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 disorder (NMOSD): Clinical features and diagnosis", section on 'History' and "Neuromyelitis optica spectrum disorder (NMOSD): Clinical features and diagnosis", 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 East 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 disorder (NMOSD): Clinical features and diagnosis", section on 'Epidemiology' and "Neuromyelitis optica spectrum disorder (NMOSD): Clinical features and diagnosis", 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:
●A contiguous spinal cord lesion on MRI extending three or more segments (image 12)
●Initial brain MRI not meeting usual diagnostic criteria for MS
●Seropositivity for NMO-IgG (ie, anti-AQP4 antibody)
These issues are reviewed in detail separately. (See "Neuromyelitis optica spectrum disorder (NMOSD): Clinical features and diagnosis", section on 'Evaluation and diagnosis'.)
Several features appear to distinguish NMOSD from classical relapsing-remitting MS (see "Neuromyelitis optica spectrum disorder (NMOSD): Clinical features and diagnosis", 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 disorder (NMOSD): Clinical features and diagnosis", 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.
MOGAD — 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 myelin oligodendrocyte glycoprotein antibody-associated disease (MOGAD). The clinical features and diagnosis of MOGAD are reviewed here briefly and discussed in detail separately. (See "Myelin oligodendrocyte glycoprotein antibody-associated disease (MOGAD): Clinical features and diagnosis".)
MOGAD is characterized by a variety of manifestations related to central nervous system demyelination. There is substantial overlap of the clinical and radiologic features of MOGAD with MS and with NMOSD [63,64]. Characteristic clinical features of MOGAD include attacks of:
●Optic neuritis, unilateral or bilateral, causing visual loss, often with optic disc edema
●Acute disseminated encephalomyelitis (ADEM), leading to altered mental status in conjunction with features of transverse myelitis
●Transverse myelitis, often causing limb weakness or numbness with bowel, bladder, and sexual dysfunction
●Cerebral cortical encephalitis, with headache, seizures, and focal neurologic deficits
MOGAD may have a monophasic or relapsing course, and rarely follows a chronic progressive course.
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 . 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 MOGAD.
Most patients with MOGAD do not have CSF-specific oligoclonal bands, unlike MS . The CSF findings in MOGAD can include a neutrophilic pleocytosis and/or a white count >50 cells/microL , both of which are rarely associated with MS. (See "Myelin oligodendrocyte glycoprotein antibody-associated disease (MOGAD): Clinical features and diagnosis", section on 'Cerebrospinal fluid'.)
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 . 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. (See "Myelin oligodendrocyte glycoprotein antibody-associated disease (MOGAD): Clinical features and diagnosis", section on 'Evaluation'.)
CLIPPERS — CLIPPERS is a type of encephalomyelitis that predominantly involves the pons [67,68]. The clinical features include a relapsing-remitting pattern of diplopia, gait ataxia, dysarthria, and facial paresthesia along with characteristic radiologic appearance 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 13) [67,69,70]. 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 .
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
●When to suspect MS – The most common presentation of multiple sclerosis (MS) consists of 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.)
●Evaluation for MS – 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.)
●Typical MRI lesions – MRI lesions suggestive of MS are typically found in the periventricular region, corpus callosum, centrum semiovale, brainstem, cerebellum, spinal cord, 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.)
●Spinal fluid and oligoclonal bands – 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 (two to four or more), or by an increased immunoglobulin G (IgG) index. (See 'CSF analysis and oligoclonal bands' above.)
●Making the diagnosis – MS is primarily a clinical diagnosis (algorithm 1). 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.)
●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. (See 'Differential diagnosis' above.)
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