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Author:Michael J Olek, DOSection Editor:Francisco Gonzalez-Scarano, MDDeputy Editor:John F Dashe, MD, PhD
Disclosures:Michael J Olek, DO Nothing to disclose. Francisco Gonzalez-Scarano, MD Employment: University of Texas Health Science Center, San Antonio; University of Pennsylvania. Equity Ownership/Stock Options: Multiple, but traded by advisors without my input [Pharmaceutical]. Other Financial Interests: NeuroLink [Venture Capital]. 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
All topics are updated as new evidence becomes available and our peer review process is complete.
Literature review current through: Aug 2015. | This topic last updated: Apr 29, 2015.
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 increasingly recognized as a prominent pathologic feature of MS. Certain clinical features are typical of MS, but the disease has a highly variable pace and many atypical forms.
The diagnosis, differential diagnosis, and unusual presentations of MS are reviewed here. Other aspects of MS are discussed separately:
?(See "Pathogenesis and epidemiology of multiple sclerosis".)
?(See "Clinical course and classification of multiple sclerosis".)
?(See "Clinical features of multiple sclerosis in adults".)
?(See "Clinically isolated syndromes suggestive of multiple sclerosis".)
?(See "Treatment of acute exacerbations of multiple sclerosis in adults".)
?(See "Treatment of relapsing-remitting multiple sclerosis in adults".)
?(See "Treatment of progressive multiple sclerosis in adults".)
DIAGNOSIS - MS is primarily diagnosed clinically. The core requirement for the diagnosis is the demonstration of central nervous system lesion dissemination in time and space, based upon either clinical findings alone or a combination of clinical and MRI findings. The history and physical examination are most important for diagnostic purposes. MRI is the test of choice to support the clinical diagnosis of MS [1]. The McDonald diagnostic criteria include specific MRI criteria for the demonstration of lesions dissemination in time and space. (See 'McDonald criteria' below.)
The diagnosis of MS is relatively straightforward for patients who present with symptoms and MRI neuroimaging findings that are typical for MS and have a relapsing-remitting course [2]. 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 not be complete. 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 (see "Clinical features of multiple sclerosis in adults", section on 'Clinical symptoms and signs'), some are highly characteristic (table 1). Common presenting symptoms of MS are listed in the table (table 2).
Diagnostic difficulties arise in patients who have atypical presentations, monophasic episodes, or progressive illness from onset (see 'Differential diagnosis' below). In these cases, investigative studies in addition to MRI such as evoked potentials and cerebrospinal fluid analysis (table 3) are often needed to confirm the diagnosis and exclude other possibilities. Additionally, some individuals have characteristic MRI lesions without symptoms, often discovered in the diagnostic workup for other conditions (ie, headaches). These cases, termed radiographically isolated syndrome, present an additional diagnostic difficulty. (See "Clinically isolated syndromes suggestive of multiple sclerosis", section on 'Radiologically isolated syndrome'.)
Diagnostic criteria for MS developed in the early 1980s (the Poser criteria) considered clinical characteristics and a number of laboratory studies including cerebrospinal fluid analysis, evoked potentials, and neuroimaging [3]. These findings were then used to place patients in categories ranging from clinically definite to laboratory supported definite to clinically probable to laboratory supported probable MS. The Poser criteria were developed primarily to ensure that only MS patients were included in research studies. They have been supplanted by the McDonald criteria, which were developed in 2001 [4] and subsequently revised in 2005 [5] and 2010 [6].
McDonald criteria - The McDonald criteria [6], first developed in 2001 [4] and revised in 2005 [5], were revised again in 2010 in order to incorporate newer evidence [7-9] and to simplify the use of neuroimaging while preserving the sensitivity and specificity of the criteria [6]. The core requirement of the diagnosis is the objective demonstration of dissemination of central nervous system lesions in both space and time, based upon either clinical findings alone or a combination of clinical and MRI findings. (See 'Magnetic resonance imaging' below.)
?Dissemination in space is demonstrated with MRI by one or more T2 lesions in at least two of four MS-typical regions of the central nervous system (periventricular, juxtacortical, infratentorial, or spinal cord) or by the development of a further clinical attack implicating a different central nervous system site. For patients with brainstem or spinal cord syndromes, symptomatic MRI lesions are excluded from the criteria and do not contribute to lesion count.
?Dissemination in time is demonstrated with MRI by the simultaneous presence of asymptomatic gadolinium-enhancing and nonenhancing lesions at any time, or a new T2 and/or gadolinium-enhancing lesion(s) on follow-up MRI, irrespective of its timing with reference to a baseline scan, or by the development of a second clinical attack.
The McDonald criteria can only be applied after careful clinical evaluation of the patient [6]. Additional data needed to confirm the diagnosis of MS depend upon the clinical presentation:
?For patients with two or more 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, generally no additional data are required. However, it is desirable to confirm the diagnosis of MS through imaging or laboratory testing. If MRI and other tests (eg, cerebrospinal fluid) are negative, alternative diagnoses must be considered. To be comfortable with the diagnosis of MS, there cannot be a better explanation for the clinical presentation, and there must be supportive objective clinical evidence (ie, on physical examination).
?For patients with two or more attacks who have objective clinical evidence of one lesion, the criteria require evidence of dissemination in space.
?For patients with one attack who have objective clinical evidence of two or more lesions, the criteria require evidence of dissemination in time.
?For patients with one attack who have objective clinical evidence of one lesion (ie, a clinically isolated syndrome [CIS]), the criteria require evidence of dissemination in space and time.
?For patients who present with insidious neurological progression suggestive of primary progressive MS, the criteria require evidence of the one year of disease progression (retrospectively or prospectively determined) plus two of the three following criteria (for patients with brainstem or spinal cord syndromes, symptomatic MRI lesions are excluded from the criteria and do not contribute to lesion count):
.Dissemination in space in the brain based upon one or more T2 lesions in at least one area characteristic for MS (periventricular, juxtacortical, or infratentorial)
.Dissemination in space in the spinal cord based upon two or more T2 lesions in the cord
.Positive cerebrospinal fluid findings with isoelectric focusing evidence of oligoclonal bands and/or elevated IgG index
An MS attack (also called a relapse or exacerbation) is defined by the McDonald criteria as a patient-reported or objectively observed event typical of an acute inflammatory demyelinating event in the central nervous system, and can be either current or historical, with duration of at least 24 hours, in the absence of fever or infection [6]. The most common initial attacks are sensory disturbances, motor weakness, and visual complaints (either monocular visual loss or diplopia). (See "Clinical features of multiple sclerosis in adults", section on 'Clinical symptoms and signs'.)
The attack should be confirmed by a neurologic examination, but some historical events with symptoms and evolution characteristic for MS, for which no objective neurologic findings are documented, can provide reasonable evidence of a prior demyelinating event. Paroxysmal symptoms should consist of multiple episodes occurring over a minimum of 24 hours. Before a definite diagnosis of MS can be made, at least one attack must be confirmed by findings on either neurologic examination, visual evoked potential response in patients with prior visual disturbance, or MRI consistent with demyelination in central nervous system region associated with the prior neurologic symptoms.
The McDonald criteria assign diagnostic confidence as follows [6]:
?The diagnosis of "MS" is given if the criteria are fulfilled and there is no better explanation for the clinical presentation
?The diagnosis of "possible MS" is given if MS is suspected but the criteria are not completely met
?The diagnosis of "not MS" is given if another diagnosis better explains the clinical presentation
It is not clear whether the McDonald criteria are sufficiently accurate in patients with a clinically isolated syndrome to make decisions regarding disease modifying therapy. This issue is discussed separately. (See "Clinically isolated syndromes suggestive of multiple sclerosis", section on 'McDonald diagnostic criteria'.)
Magnetic resonance imaging - MRI is the test of choice to support the clinical diagnosis of MS [1]. The McDonald diagnostic criteria for MS include specific MRI criteria for the demonstration of lesion dissemination in time and space as discussed above [6].
Lesion characteristics - The characteristic lesion demonstrated on MRI is the cerebral or spinal plaque. Pathologically, plaques consist of a discrete region of demyelination with relative preservation of axons. However, mounting evidence suggests that axonal injury is a prominent pathologic feature of MS, and that axonal loss may occur either as part of the demyelinating process [10], or as an independent process [11]. Histological examination of active plaques reveals perivascular infiltration of lymphocytes (predominantly T cells) and macrophages with occasional plasma cells. Perivascular and interstitial edema may be prominent.
Plaques suggestive of MS are typically found on MRI in the periventricular region, corpus callosum, centrum semiovale, and, to a lesser extent, deep white matter structures and basal ganglia (image 1 and image 2). MS plaques usually have an ovoid appearance, and lesions are 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. The plaques appear hyperintense on proton density and T2-weighted studies, and they are hypointense (if visible at all) on T1-weighted images.
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. (See 'Advances in MRI techniques' below.)
Diagnostic utility - MRI detects many more MS lesions than CT, and it is able to detect plaques in regions that are rarely abnormal on CT such as the brainstem, cerebellum, and spinal cord (image 2). Most lesions seen on MRI correlate with pathologic lesions [12]. However, some lesions that are extensive on MRI show only small plaques on pathological examination, suggesting that much of the abnormal MRI signal may be a result of increased water content of the brain around such plaques, due to presumed disruption of the blood-brain barrier.
Patients with clinically definite MS have typical white matter lesions on MRI in nearly all cases. However, central nervous system lesions due to other disorders (eg, ischemia, systemic lupus erythematosus, Beh?et's syndrome, other vasculitides, HTLV-I, sarcoidosis) may appear similar to MS lesions on MRI. This is particularly true for ischemic lesions, which make MRI criteria less reliable for the diagnosis of MS in patients over the age of 50 [13].
The sensitivity and specificity of MRI for the diagnosis of MS varies widely in different studies, and the variation is probably due to differences among the studies in MRI criteria and patient populations [14]. In one early study of 1500 brain MRI scans that included 134 scans of patients with a clinical diagnosis of MS, using the criteria of three or four areas of increased signal intensity resulted in a high sensitivity for the diagnosis of MS (90 and 87 percent, respectively), but a low specificity (71 and 74 percent, respectively) [13]. Accuracy was improved by using criteria that included at least three areas of increased signal intensity plus two of the following features: lesions abutting body of lateral ventricles; infratentorial lesion location; and size >5 mm. Using these criteria, sensitivity decreased slightly to 81 percent while specificity improved to 96 percent. In a later study evaluating MRI diagnostic criteria that were eventually incorporated into the revised 2010 McDonald criteria, the sensitivity and specificity were approximately 53 and 87 percent, respectively [8].
MRI scanning is more sensitive and specific for predicting evolution to clinically definite MS than other studies such as CT scans, cerebrospinal fluid parameters, or evoked potentials [15]. This was illustrated in a two-year follow-up of 200 patients referred for suspected MS that found 30 percent (50 percent of those under age 50 years) had developed clinically definite MS, of whom 84 percent had initial MRI scans that were strongly suggestive of MS [16]. In contrast, the proportion of patients who had cerebrospinal fluid oligoclonal bands, abnormal visual evoked potentials, or an abnormal CT when initially studied was 69, 69, and 38 percent, respectively. In a second, five-year study of 89 patients, progression to clinically definite MS occurred in 37 out of 57 (65 percent) with an initially abnormal MRI, and only 1 of 32 (3 percent) with a normal MRI [17]. Again, MRI was a better predictor of progression to clinically definite MS than cerebrospinal fluid analysis.
Spinal cord MRI - Spinal cord MRI lesions are nearly as common as brain lesions in patients with MS [18,19], 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 3 percent, since the non-MS-related hyperintense signal seen in older patients on cranial MRI does not occur in the spinal cord. Furthermore, spinal cord atrophy in patients with MS correlates with clinical disability [20-22].
Spinal cord MRI may increase the likelihood of finding dissemination of MS 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 [19]. The diagnosis of MS was made by the 1982 criteria of Poser et al [3]. 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 [4] from 66 to 85 percent.
Spinal cord lesions typical of MS are associated with the following MRI characteristics [5,19,23,24]:
?Little or no cord swelling
?Unequivocal hyperintensity on T2-weighted sequences and 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 cord in cross-section
?Focal (ie, clearly delineated and circumscribed on T2-weighted sequences)
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 [6]. (See 'Neuromyelitis optica' below.)
Active versus chronic lesions - Acute MS lesions tend to be larger than chronic lesions on MRI with somewhat ill-defined margins. As resolution occurs, 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 [25].
Gadolinium-DTPA, a paramagnetic contrast agent that can cross only disrupted blood-brain barriers, has been used to assess plaque activity [26]. Gadolinium increases signal intensity on T1-weighted images. 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 (Gd) 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 1). The importance of Gd-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 Gd-enhancing plaques are clinically asymptomatic, although the presence of ongoing enhancement suggests continuing disease activity that likely contributes to cumulative pathophysiology.
?Approximately 10 to 20 percent of lesions on T2-weighted MRI will show contrast enhancement at some point if followed over time.
?Gadolinium enhancement is a transient phenomenon in MS and usually disappears after 30 to 40 days, but it may rarely persist for up to eight weeks in acute plaques. Prolonged persistence of enhancement should caution against the diagnosis of MS [27].
?Longitudinal studies have demonstrated that the presence of active lesions on serial MRI scans carries a high risk of continuous disease activity [28,29].
?A meta-analysis demonstrated that Gd enhancement predicts the occurrence of relapses, but it is not a strong predictor of the development of cumulative impairment or disability [30].
There are several methods that can be used to increase the sensitivity of Gd-enhanced MRI for the detection of active MS lesions [31], such as using higher doses of Gd [32,33]. In particular, triple-dose Gd is more sensitive than single-dose Gd (0.1 mmol/kg) in detecting MS lesions [34]. Other useful techniques for increasing sensitivity include thinner slices or delayed imaging. Newer methods such as magnetization transfer contrast imaging (MTI) also increase sensitivity of Gd [35].
Gadolinium enhancement patterns may provide some clues to the underlying pathology of lesions. Concentric ring-enhancing lesions with central contrast pallor arise in previously damaged areas or in areas of accelerated local inflammation [36-43]. They are larger and of longer duration than homogeneously-enhancing lesions [37,38,40]. Moreover, ring-enhancing lesions weakly predict the development of persisting hypointense lesions on T1 MRI [44]. (See 'Black holes' below.)
Therefore, ring-enhancing lesions are thought to be related to accelerated disease activity and extensive tissue damage [37,43,44] and may mark a type of inflammation characteristic of more aggressive forms of disease. Ring enhancement may also occur in an incomplete (open) ring pattern, which is somewhat more specific for MS than infections or neoplastic diseases.
Black holes - Most MS lesions are isointense to white matter on T1-weighted MRI, but some are hypointense or appear as "black holes" [45-48], particularly in the supratentorial region (image 1). 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 [49].
Although the evidence is limited, persistent black holes are thought to be markers of severe demyelination and axonal loss [45]. The pathological substrate for the accumulation of persisting black holes appears to be predominantly axonal damage [45,46,49], as shown in a postmortem histopathology-MRI correlation study [45]. 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 [50].
The correlation between black hole volume and clinical disability, as measured by the Expanded Disability Status Scale (EDSS), suggests that these black holes may be clinically relevant for measuring disease progression [46-48].
Atrophy - Brain atrophy can be a feature of early MS and atrophy of specific areas, such as the thalamus, can predict progression to clinically definite MS in patients who have had a single attack [51,52].
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 [53].
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 [54]. In addition, the whole-brain concentration of NAA may be a sensitive surrogate marker of neuronal loss in MS [55,56].
Diffusion-weighted and diffusion tensor MRI imaging as well as MRS may provide insight into the axonal loss and diffuse abnormalities in normal appearing white matter and the evolution of normal appearing gray matter that can occur in MS [57-59]. Quantitative MRI methods such as magnetization transfer ratio are increasingly used to assess myelin content and axonal count [60].
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 [61]. Injury to nerve axons or myelin sheaths permits increased diffusion of water across the white matter tract and thereby decreases fractional anisotropy (image 3).
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 [62].
The pathologic correlate of the decreased fractional anisotropy in white matter that appears normal on T2-weighted MRI is uncertain. One possibility is that demyelination and axonal disruption at the periphery of a centrifugally expanding plaque is less severe than at the center; the peripheral injury is sufficient to cause reduced anisotropy but not sufficient to cause increased T2 signal. Another possibility is that the periphery is undergoing regression and repair.
Although MS predominately affects white matter, involvement of cortical gray matter is common [63-66]. Conventional T2-weighted MRI sequences may underestimate MS plaque size and thus overall plaque burden, particularly for cortical lesions [67]. Visualization of gray matter lesions may be improved with the use of MRI techniques, including two and three-dimensional fluid-attenuated inversion recovery imaging, double inversion recovery imaging, phase-sensitive inversion recovery T1-weighted sequences, and diffusion tensor imaging [63,66,68-73].
Cerebrospinal fluid analysis - 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 rule out the diagnosis in equivocal cases. Qualitative assessment of cerebrospinal fluid (CSF) for oligoclonal IgG bands (OCBs) using isoelectric focusing is the most important diagnostic CSF study when determining a diagnosis of MS in such cases. 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 IgM and IgA is also increased.
The 2010 McDonald criteria note that positive CSF findings can provide supportive evidence that the underlying disorder is inflammatory demyelinating, and incorporate them into the criteria for primary progressive MS. However, in contrast to the earlier 2001 and 2005 McDonald criteria, the CSF findings are not incorporated into the 2010 criteria for dissemination in space [4,5].
A positive CSF is based upon the finding of either OCBs different from any such bands in serum, or by an increased IgG index. (See 'Oligoclonal bands' below.)
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 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. An abnormality of CSF IgG production as measured by the IgG index or IgG synthesis rate is found in 90 percent of clinically definite MS patients [74].
The CSF appearance and pressure are grossly normal in MS. The total leukocyte count is normal in two-thirds of patients, exceeds 15 cells/microL in <5 percent, and only rarely exceeds 50 cells/microL (a finding that should raise suspicion of another etiology) [75]. 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).
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'.)
Oligoclonal bands - OCBs are found in up to 95 percent of patients with clinically definite MS (table 3) [76,77]. OCBs represent limited classes of antibodies that are depicted as discrete bands on agarose gel. Up to 8 percent of CSF samples from patients without MS also contain OCBs; most are the result of chronic central nervous system infections, viral syndromes, and neuropathies.
The presence of OCBs in monosymptomatic patients predicts a significantly higher rate of progression to MS than the absence of bands: 25 versus 9 percent at three years follow-up in one report [74]. However, quantification of OCBs is an insensitive prognostic indicator [78]. In addition, the presence of OCBs 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.
Repeating the lumbar puncture and CSF analysis is suggested if clinical suspicion for MS is high but results are equivocal, negative, or show only a single band on isoelectric focusing [79].
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 used evoked potentials are somatosensory evoked potentials (SSEP), visual evoked responses (VER), and brainstem auditory evoked potentials (BAEP). Patients with clinically definite MS have abnormal VERs in 50 to 90 percent of cases (table 3). The VER 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 VERs to demyelination in the optic pathways.
Antimyelin antibodies - Initial studies suggested that antibodies to myelin oligodendrocyte glycoprotein (MOG) and myelin basic protein (MBP) were potential markers of MS disease activity and predictors of progression from a clinically isolated syndrome to MS [80,81]. However, subsequent evidence suggests that these antibodies are not associated with an increased risk of progression to MS [82-84] or with MS disease activity [85].
Several factors may contribute to the discrepant findings, such as differences in technique used in MOG preparation [81,85,86]. In addition, autoantibodies to many myelin constituents in patients with MS, including anti-MOG, may simply represent part of a generalized "nonsense" antibody response [87], reflecting an increased immune response due to MS rather than to a specific root cause of MS [86].
UNUSUAL CLINICAL PRESENTATIONS - Several inflammatory demyelinating disorders may be variants of MS, though their precise relationship to MS is uncertain. These include isolated optic neuritis, progressive myelopathy associated with a single demyelinating lesion, and tumefactive MS.
Isolated optic neuritis - 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 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. Sarcoidosis is commonly a diagnostic consideration in patients with bilateral optic neuritis. Other potential causes of recurrent optic neuritis in the differential include lupus, chronic relapsing inflammatory optic neuropathy (CRION), and paraneoplastic optic neuropathy (serum CRMP-5/CV2 antibody). (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'.)
Progressive spinal cord syndrome - Progressive myelopathy due to MS is the most common presentation of primary progressive MS (see "Clinical features of multiple sclerosis in adults", section on 'Presentation'). Minor clues suggestive of MS include the presence of a Lhermitte sign (a term for electric shock-like sensations that run down the back and/or limbs upon flexion of the neck) or an undue sensitivity to elevated temperature. Nevertheless, a syndrome of slowly progressive spinal cord dysfunction can present a major diagnostic challenge, since a single demyelinating lesion can produce a progressive myelopathy similar to primary progressive MS. As an example, one case series described seven patients who developed a progressive myelopathy with motor impairment attributable to a single demyelinating lesion on MRI in the upper cervical spinal cord or brainstem [88]. None had clinical symptoms suggestive of relapses affecting other portions of the central nervous system, and no new lesions were found in the three patients who had serial MRI scans of the brain and spinal cord. Oligoclonal bands were present in four of the six patients tested. There was no evidence suggesting another etiology for progressive myelopathy, such as neuromyelitis optica.
In addition to 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). 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 "Diagnosis and treatment 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'.)
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 [89]. 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.
Tumefactive MS - Tumefactive MS is an acute tumor-like MS variant in which some patients with demyelinating disease present with large (>2 cm) acute lesions, often associated with edema or ring enhancement [90-93]. There may be mass effect, with compression of the lateral ventricle and shift across the midline. Although there is no consensus regarding nomenclature, this type of inflammatory demyelinating disease has been termed tumefactive multiple sclerosis, Marburg disease or variant, and Balo concentric sclerosis.
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 the largest series, 168 patients with biopsy-confirmed, tumor-like inflammatory demyelinating disease were analyzed retrospectively [91]. 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.
DIFFERENTIAL DIAGNOSIS - The differential diagnosis of MS includes a number of inflammatory, vascular, infectious, genetic, granulomatous, and other demyelinating disorders (table 4), 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. Diagnostic difficulties arise in patients who have atypical presentations, monophasic episodes, or progressive illness.
?The unusual nature of some sensory symptoms and the difficulty patients experience in describing such symptoms may result in a misdiagnosis of hysteria.
?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 largest diagnostic difficulty arises with progressive central nervous system dysfunction; great care must be taken in these patients to exclude other treatable etiologies, such as compressive myelopathies, arteriovenous malformation, cavernous angioma, Arnold-Chiari malformation, and human immunodeficiency virus. Other potential causes have no proven treatment, such as human T-lymphotropic virus type I and a number of hereditary conditions including adult metachromatic leukodystrophy, adrenoleukodystrophy, and spinocerebellar disorders.
A common error is to over-interpret multiple hyperintense lesions on MRI as equivalent to MS in the absence of clinical symptoms consistent with the diagnosis (table 2). Some central nervous system inflammatory or infectious diseases may produce multifocal lesions with or without a relapsing-remitting course, including the following:
?Systemic lupus erythematosus, which can present as a recurrent neurologic syndrome before the systemic manifestations appear (see "Neurologic manifestations of systemic lupus erythematosus")
?Sj?gren's syndrome (see "Clinical manifestations of Sj?gren's syndrome: Extraglandular disease", section on 'Central nervous system')
?Polyarteritis nodosa (see "Clinical manifestations and diagnosis of polyarteritis nodosa in adults", section on 'Neurologic disease')
?Beh?et's syndrome (see "Clinical manifestations and diagnosis of Beh?et's 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')
Many physicians fail to pursue further diagnostic steps when a patient is labeled as MS. Features that should alert the clinician to the possibility of other diseases include:
?Family history of neurologic disease other than MS
?A well demarcated spinal level in the absence of disease above the foramen magnum
?Prominent back pain that persists
?Symptoms and signs that can be attributed to one anatomical site
?Patients who are over 60 years of age or less than 15 years at the onset of disease
?Rapidly progressive disease
?Symptoms of systemic disease such as weight loss, fever, etc
None of these features excludes the diagnosis of MS. However, one should explore the possibility of other etiologies before accepting the diagnosis of MS, particularly in patients who have atypical clinical syndromes. 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 [94]. Probable or possible MS was confirmed in only 33 percent of the patients, and none of those with confirmed MS had atypical manifestations of demyelination. 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.
Clinically isolated syndromes - Clinically isolated syndromes are single, monosymptomatic attacks compatible with MS (eg, optic neuritis, brainstem syndromes, spinal cord syndromes) that do not fulfill diagnostic criteria for MS but may be the first attack of MS. For patients with one attack who have objective clinical evidence of one lesion (ie, a clinically isolated syndrome), MS criteria require evidence of lesion dissemination in space and time (see 'McDonald criteria' above). This topic is discussed separately. (See "Clinically isolated syndromes suggestive of multiple sclerosis".)
Acute disseminated encephalomyelitis - Acute disseminated encephalomyelitis (ADEM) is autoimmune demyelinating disease of the central nervous system that typically follows an immunization or vaccination (postvaccination encephalomyelitis) or systemic viral infection (parainfectious encephalomyelitis). 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 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 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 in adults", section on 'Neuroimaging'):
?ADEM usually has more MRI lesions than MS, with larger bilateral but asymmetric white matter abnormalities
?Lesions tend to be poorly defined in ADEM and have better defined margins in MS
?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 [95]. (See "Acute disseminated encephalomyelitis in adults", section on 'Lumbar puncture'.)
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 "Clinical features of multiple sclerosis in adults" and "Clinically 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 neuromyelitis optica. However, neuromyelitis optica can also cause transverse myelitis involving fewer segments. (See 'Neuromyelitis optica' below.)
?Transverse myelitis may be seen in patients with acute disseminated encephalomyelitis. (See "Acute disseminated encephalomyelitis in adults".)
Clinical and imaging evidence of multifocal involvement within the central nervous system suggest that transverse myelitis not idiopathic, but rather is associated with MS, neuromyelitis optica, 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'.)
Neuromyelitis optica - Neuromyelitis optica (NMO, sometimes called Devic disease) is reviewed here briefly and discussed in detail elsewhere. (See "Neuromyelitis optica spectrum disorders".)
NMO 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. Once considered a variant of multiple sclerosis, NMO is now recognized as a distinct clinical entity based upon the presence of the disease-specific anti-aquaporin-4 (AQP4) antibody, which plays a direct role in the pathogenesis of NMO. (See "Neuromyelitis optica spectrum disorders", section on 'Background' and "Neuromyelitis optica spectrum disorders", section on 'Pathogenesis'.)
The incidence of NMO in women is up to 10 times higher than in men. NMO is much more common in people of Asian, Hispanic, and African descent, which is not the case with MS. Hallmark features of NMO 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 NMO and NMO spectrum disorders. Other suggestive symptoms include episodes of intractable vomiting or hiccoughs, excessive daytime somnolence or narcolepsy, reversible posterior leukoencephalopathy syndrome, neuroendocrine disorders, and (in children) seizures. While no clinical features are disease-specific, some are highly characteristic. NMO has a relapsing course in 90 percent or more of cases. (See "Neuromyelitis optica spectrum disorders", section on 'Epidemiology' and "Neuromyelitis optica spectrum disorders", section on 'Clinical features'.)
The diagnosis of NMO is based on clinical, imaging, and laboratory data. Severe attacks of myelitis or optic neuritis should raise suspicion for NMO. Diagnostic criteria for NMO 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'):
?A contiguous spinal cord lesion on MRI extending three or more segments
?Initial brain MRI not meeting usual diagnostic criteria for MS
?Seropositivity for NMO-IgG (ie, anti-aquaporin-4 antibody)
Several features appear to distinguish NMO from classical relapsing-remitting MS (see "Neuromyelitis optica spectrum disorders", section on 'Differential diagnosis'):
?Brain MRI is often normal in patients with NMO, 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 NMO. Findings on brain MRI that suggest the diagnosis of multiple sclerosis rather than NMO 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 NMO, the cerebrospinal fluid may exhibit a neutrophilic pleocytosis, but it is usually negative for oligoclonal bands.
?The detection of AQP4 antibody positivity is specific for NMO and NMO spectrum disorders. (See "Neuromyelitis optica spectrum disorders", section on 'AQP4 autoantibody'.)
?The myelopathy with NMO 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.
Chronic lymphocytic inflammation with pontine perivascular enhancement responsive to steroids - Chronic lymphocytic inflammation with pontine perivascular enhancement responsive to steroids (CLIPPERS) is a type of encephalomyelitis that predominantly involves the pons [96,97]. 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 4) [96,98,99]. 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.
SUMMARY AND RECOMMENDATIONS
?Multiple sclerosis (MS) is a clinical diagnosis. The core requirement for the diagnosis is the demonstration of central nervous system lesion dissemination in time and space, based upon either clinical findings alone or a combination of clinical and MRI findings. There are no clinical findings that are unique to this disorder, but some are highly characteristic (table 1). Common symptoms of MS are listed in the table (table 2). (See 'Diagnosis' above.)
?MRI is the test of choice to support the clinical diagnosis of MS. The McDonald diagnostic criteria include specific clinical and MRI findings needed for the demonstration of lesion dissemination in time and space (see 'McDonald criteria' above and 'Magnetic resonance imaging' above):
.Dissemination in space is demonstrated on MRI by one or more T2 lesions in at least two of four MS-typical regions of the central nervous system (periventricular, juxtacortical, infratentorial, or spinal cord) or by the development of a further clinical attack implicating a different central nervous system site. For patients with brainstem or spinal cord syndromes, symptomatic MRI lesions are excluded from the criteria and do not contribute to lesion count. (See 'McDonald criteria' above.)
.Dissemination in time is demonstrated on MRI by the simultaneous presence of asymptomatic gadolinium-enhancing and nonenhancing lesions at any time, or a new T2 and/or gadolinium-enhancing lesion(s) on follow-up MRI, irrespective of its timing with reference to a baseline scan, or by the development of a second clinical attack. (See 'McDonald criteria' above.)
?The amount of additional data needed to confirm the diagnosis of MS in patients with acute attacks varies with the clinical presentation (see 'McDonald criteria' above):
.For patients with two or more 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, no additional data are required
.For patients with two or more attacks who have objective clinical evidence of one lesion, the criteria require evidence of dissemination in space
.For patients with one attack who have objective clinical evidence of two or more lesions, the criteria require evidence of dissemination in time
.For patients with one attack who have objective clinical evidence of one lesion (ie, a clinically isolated syndrome [CIS]), the criteria require evidence of dissemination in space and time
?For patients who present with insidious neurological progression suggestive of primary progressive MS, the McDonald criteria require evidence of the one year of disease progression plus two of the three following criteria (note that symptomatic MRI lesions are excluded from the criteria and do not contribute to lesion count for patients with brainstem or spinal cord syndromes) (see 'McDonald criteria' above):
.Dissemination in space in the brain based upon one or more T2 lesions in at least two of four MS-typical regions of the central nervous system (periventricular, juxtacortical, infratentorial, or spinal cord)
.Dissemination in space in the spinal cord based upon two or more T2 lesions in the cord
.Positive cerebrospinal fluid findings with isoelectric focusing evidence of oligoclonal bands and/or elevated IgG index
?Qualitative assessment of cerebrospinal fluid (CSF) for oligoclonal IgG bands using isoelectric focusing is the most important diagnostic CSF study when determining a diagnosis of MS. Elevation of the CSF immunoglobulin level relative to other protein components is a common finding in patients with MS. 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. (See 'Cerebrospinal fluid analysis' above.)
?Several inflammatory demyelinating disorders may be variants of MS, though their precise relationship to MS is uncertain. These include isolated optic neuritis, progressive myelopathy associated with a single demyelinating lesion, and tumefactive MS. (See 'Unusual clinical presentations' above.)
?The differential diagnosis of MS 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. Diagnostic difficulties arise in patients who have atypical presentations, monophasic episodes, or progressive illness (table 4). (See 'Differential diagnosis' above.)
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