Diagnosis, Differential Diagnosis, and Misdiagnosis of Multiple Sclerosis

Andrew J. Solomon, MD Multiple Sclerosis and Other CNS Inflammatory Diseases p. 611-635 June 2019, Vol.25, No.3 doi: 10.1212/CON.0000000000000728
REVIEW ARTICLES
BROWSE ARTICLES
Continuum Audio Article as PDF

PURPOSE OF REVIEW: The diagnosis of multiple sclerosis (MS) is often challenging. This article discusses approaches to the clinical assessment for MS that may improve diagnostic accuracy.

RECENT FINDINGS: Contemporary diagnostic criteria for MS continue to evolve, while knowledge about diseases that form the differential diagnosis of MS continues to expand. Recent data concerning causes of MS misdiagnosis (the incorrect assignment of a diagnosis of MS) have further informed approaches to syndromes that may mimic MS and the accurate diagnosis of MS.

SUMMARY: This article provides a practical update on MS diagnosis through a discussion of recently revised MS diagnostic criteria, a renewed consideration of MS differential diagnosis, and contemporary data concerning MS misdiagnosis.

Address correspondence to Dr Andrew J. Solomon, Larner College of Medicine at the University of Vermont, University Health Center—Arnold 2, 1 S Prospect St, Burlington, VT 05401, Andrew.Solomon@uvm.edu.

RELATIONSHIP DISCLOSURE: Dr Solomon has served as a consultant for Biogen and EMD Serono, Inc, and has received research/grant support from Biogen and personal compensation for speaking engagements from Med Learning Group, the National Multiple Sclerosis Society, and RMEI Medical Education.

UNLABELED USE OF PRODUCTS/INVESTIGATIONAL USE DISCLOSURE: Dr Solomon reports no disclosure.

INTRODUCTION

Multiple sclerosis (MS) is a complex disease, and its clinical and radiologic heterogeneity often make its diagnosis challenging. No highly specific and sensitive biomarker for MS has been identified, and many diseases can mimic its appearance. Efforts to develop MS diagnostic criteria commenced over 50 years ago, and the continued refinement of criteria, including the 2017 revisions to the McDonald criteria, have enabled earlier diagnosis of MS. However, MS misdiagnosis (the assignment of an incorrect diagnosis of MS), remains an important contemporary problem, with considerable consequences for patients. A clinical approach combining knowledgeable attention to the appropriate application of 2017 McDonald criteria, thoughtful consideration of the differential diagnosis of MS and the presence of potential red flags for alternative diagnoses, and an understanding of common contemporary causes of MS misdiagnosis will improve accuracy of MS diagnosis.

DIAGNOSIS OF RELAPSING-REMITTING MULTIPLE SCLEROSIS

Beginning with the Schumacher criteria in 1965, diagnostic criteria have relied on five principles to confirm of the diagnosis of MS: (1) the identification of a syndrome “typical” of MS-related demyelination, (2) objective evidence of central nervous system (CNS) involvement, (3) demonstration of dissemination in space, (4) demonstration of dissemination in time, and (5) “no better explanation” other than MS.

Over the past 20 years, evolving data have supported the incorporation of laboratory and radiologic assessments to complement what were previously solely clinical assessments to fulfill these principles. The revisions to the McDonald criteria have enabled earlier diagnosis of MS. Yet MS diagnosis, including the application of the 2017 McDonald criteria, continues to rely on the fulfillment of these five key principles.

Typical Syndromes

The evaluation for a diagnosis of MS begins with an assessment of whether a patient’s clinical presentation is typical for MS-related demyelination. A broad spectrum of neurologic symptoms may prompt a clinical evaluation for MS. Similarly, patients with a confirmed MS diagnosis may have an assortment of chronic and paroxysmal symptoms that are sequelae of the CNS damage associated with the disease. However, confirmation of a diagnosis of MS using the current diagnostic criteria requires first the identification of the presentation of a one of a limited number of syndromes typical for an MS-related demyelinating attack or relapse. Typical syndromes include optic neuritis, brainstem syndromes such as internuclear ophthalmoplegia and trigeminal neuralgia, cerebellar syndromes, and transverse myelitis. Clinical acumen and experience are often necessary for this first critical step in approaching the diagnosis of MS, as distinguishing a noninflammatory optic neuropathy or myelopathy from optic neuritis or myelitis may be challenging at times (refer to the section “No Better Explanation”: the Differential Diagnosis of Relapsing-Remitting Multiple Sclerosis later in this article).

Importantly, the McDonald criteria were validated only in cohorts of patients presenting with attacks or relapses consisting of these typical syndromes. Since the specificity for MS of the McDonald criteria has not been evaluated in other syndromes, their application alone for diagnosis of MS in patients with other clinical presentations is not recommended. If a patient’s clinical presentation is determined to be atypical, further clinical, laboratory, and radiologic assessments beyond the minimum requirements of the McDonald criteria are necessary to confirm a diagnosis of MS (refer to the section Atypical Syndromes, Typical Syndromes With Red Flags, and Evaluation of Long-standing Diagnoses later in this article).

Objective Evidence

Objective clinical evidence of at least one CNS lesion corresponding to the presentation of an attack typical for MS-related demyelination is also necessary to fulfill MS diagnostic criteria. Objective evidence may include a relative afferent pupillary defect in a patient presenting with visual symptoms suggestive of optic neuritis, internuclear ophthalmoplegia in a patient presenting with diplopia, or detection of a hemisensory level in a patient with sensory or motor symptoms suggestive of myelitis.

The authors of the 2017 revisions to the McDonald criteria also affirm that paraclinical or radiographic evidence of a CNS abnormality that corresponds to the anatomic location suggested by symptoms may substitute for clinical objective evidence for diagnosis of MS. For example, P100 latency prolongation on a visual evoked potential or a T2 hyperintensity on MRI in the optic nerve might provide objective evidence of an episode of optic neuritis, or a T2 hyperintensity in the spinal cord might provide objective evidence of an episode of myelitis.

In patients presenting with symptoms concerning for a syndrome typical for MS but without objective clinical, paraclinical, or radiographic evidence of a corroborating CNS lesion, caution is especially warranted before making a diagnosis of MS. For example, patients often present for MS evaluation with neurologic symptoms accompanied by a normal neurologic examination and a brain MRI with abnormalities that would not explain the presenting symptoms. The McDonald criteria have not been tested in such patients, and their application without objective evidence would likely diminish specificity for MS. Further clinical evaluation and radiographic monitoring is often necessary in such patients to avoid misdiagnosis and to accurately confirm a diagnosis of MS.

Dissemination in Space and Time

Confirmation of objective evidence for a single attack typical for MS-related demyelination is the first step in an evaluation for a diagnosis of MS. Such a patient has a clinically isolated syndrome if the patient has no further fulfillment of MS diagnostic criteria. Subsequent assessment for evidence of both dissemination in space and dissemination in time of CNS involvement characteristic of MS is the next step toward the confirmation of a MS diagnosis. Evidence of dissemination in space is defined as detection of lesions in more than one distinct anatomic location within the CNS. Multifocal CNS involvement is characteristic of MS. Fulfillment of dissemination in time requires confirmation of new CNS lesions over time, suggesting an ongoing disease process typical of MS rather than a monophasic disease.

Objective evidence of a second attack typical for MS in a different location than the first would fulfill dissemination in space and dissemination in time criteria. The authors of the 2017 revisions to the McDonald criteria reaffirm that prospective confirmation of objective clinical findings for two attacks disseminated in both space and time typical for an MS diagnosis remains most secure. However, in a patient with objective evidence of a single typical attack, evolving data have suggested that the results of CSF and MRI assessments may substitute for clinical evidence to demonstrate dissemination in space and dissemination in time without diminishing specificity and sensitivity for the diagnosis of MS.

MRI Demonstration of Dissemination in Space

Recent studies continue to support the 2017 McDonald criteria recommendations for MRI demonstration of dissemination in space by detection of the presence of T2-hyperintense MRI lesions in four areas of the CNS, including (1) periventricular, (2) cortical or juxtacortical, and (3) infratentorial brain regions and (4) the spinal cord. The presence of at least one T2-hyperintense MRI lesion in two of these regions demonstrates dissemination in space.

As a result of new data, the 2017 revisions to the McDonald criteria now include symptomatic lesions for demonstration of dissemination in space. For example, in a patient presenting with myelitis and MRI evidence of a corresponding spinal cord lesion (objective evidence of a “symptomatic lesion”), a single additional T2-hyperintense MRI lesion in the periventricular, cortical or juxtacortical, or infratentorial region would demonstrate MRI dissemination in space. Of note, although MRI may provide paraclinical objective evidence of an attack of optic neuritis, the anterior visual system was not included as a region for demonstration of MRI dissemination in space in the 2017 criteria. In a patient presenting with optic neuritis, evidence of lesions in two of the four aforementioned regions remains necessary to demonstrate MRI dissemination in space.

The 2017 McDonald criteria also for the first time include cortical lesions (considered equivalent to juxtacortical lesions) as a region that may provide MRI demonstration of dissemination in space. The detection of cortical lesions remains challenging, particularly using MRI scanners and sequences typically employed in clinical practice. Recent studies and consensus guidelines recommend the use of advanced imaging techniques available at specialized centers for cortical lesion detection. MRI evaluation for cortical lesions to meet dissemination in space may be best limited to physicians experienced in using such techniques.

MRI and CSF Demonstration of Dissemination in Time

Similar to previous revisions, the 2017 McDonald criteria specify that MRI dissemination in time can be demonstrated on a single MRI scan by the presence of any gadolinium-enhancing and nonenhancing lesions or by the appearance of a new T2-hyperintense or gadolinium-enhancing lesion on a follow-up MRI compared to a baseline scan, irrespective of the timing of either scan. In a change from the 2010 criteria, previously excluded gadolinium-enhancing symptomatic lesions often responsible for the syndrome prompting evaluation (eg, a gadolinium-enhancing brainstem lesion in a patient with internuclear ophthalmoplegia) may now be included for consideration of fulfillment of MRI dissemination in time.

In a change from previous revisions and based on recent data suggesting CSF-specific oligoclonal bands are an independent predictor of a second clinical attack, the 2017 McDonald criteria recommend that demonstration of two or more oligoclonal bands may substitute for demonstration of clinical or MRI dissemination in time. This notable revision enables earlier diagnosis of MS in a patient with objective evidence of a single clinical attack typical for MS with an MRI that only demonstrates dissemination in space. The authors of the 2017 McDonald criteria emphasize that the accuracy of oligoclonal band testing depends on the methodology employed, and a laboratory that performs agarose gel electrophoresis with isoelectric focusing and immunoblotting or immunofixation for IgG is recommended.

Patients presenting for evaluation for MS often report a history of prior neurologic symptoms that may, at times, aid in diagnosis. When objective evidence exists of a single clinical attack typical for MS, the description of historical symptoms compatible with an additional prior syndrome typical for MS may support demonstration of dissemination in time. In such instances, evaluation for objective evidence of a CNS lesion to confirm a suspected prior syndrome by neurologic examination or paraclinical testing such as evoked potentials or by MRI identification of a lesion is highly recommended. Consideration of prior symptoms alone for the demonstration of dissemination in time may increase the risk of MS misdiagnosis. The authors of the 2017 criteria recommend caution when considering historical symptoms for the demonstration of dissemination in time in the absence of supportive objective evidence of a CNS lesion.table 2-1 summarizes the 2017 McDonald criteria for the diagnosis of relapsing-remitting MS, including requirements of demonstration of dissemination in space and dissemination in time. case 2-1 and case 2-2 demonstrate application of the revised criteria.

“No Better Explanation”: the Differential Diagnosis of Relapsing-Remitting Multiple Sclerosis

Objective evidence of a demyelinating syndrome typical for MS demonstrating dissemination in space and dissemination in time is insufficient for the diagnosis of MS. As no single biomarker for MS exists, each revision of MS diagnostic criteria has also specified that there must be a determination of “no better explanation” for the clinical presentation under consideration. This final key element of MS diagnosis requires an astute consideration of the differential diagnosis of MS, with particular attention to the presence of red flags, before the confirmation of MS diagnosis.

Better Explanation for Typical Syndromes

A variety of disorders may present with objective evidence of a syndrome typical for MS and demonstrate clinical or radiographic dissemination in space and dissemination in time, thus appearing to fulfill MS diagnostic criteria. Disorders such as neuromyelitis optica spectrum disorder (NMOSD), syndromes associated with myelin oligodendrocyte glycoprotein (MOG) antibody (anti-MOG), neurosarcoidosis, and CNS manifestations of systemic rheumatologic and oncologic disease may present with optic neuritis or transverse myelitis. Yet in many instances, these disorders are accompanied by a red flag, that is, clinical, laboratory, or radiographic findings atypical for MS and suggestive of an alternative diagnosis that may offer a better explanation than MS for the clinical presentation. Thoughtful assessment for such red flags may avoid a misdiagnosis of MS.

Although optic neuritis or transverse myelitis may be typical for MS, specific characteristics atypical for MS may alert the astute clinician that an alternative diagnosis should be investigated. For example, severe or bilateral optic neuritis may suggest NMOSD. Longitudinally extensive transverse myelitis may suggest NMOSD, neurosarcoidosis, anti-MOG–associated myelitis, systemic rheumatologic disease, or a paraneoplastic disorder. Complete spinal cord lesions or a history of intractable vomiting may also suggest NMOSD. Transverse myelitis associated with prodromal symptoms or MRI T2 signal abnormality confined to spinal cord gray matter may suggest anti-MOG–associated myelitis. Multiple cranial nerve involvement might suggest neurosarcoidosis. Transverse myelitis or optic neuritis accompanied by high CSF pleocytosis should also prompt investigation into infectious or inflammatory disorders other than MS. Systemic symptoms such as joint pain, skin changes, and weight loss might suggest either rheumatologic or paraneoplastic disease. A variety of additional non-neurologic red flags accompanying a typical syndrome might also suggest specific alternative diagnoses.

A comprehensive review of red flags suggesting alternative diagnoses in patients presenting with syndromes otherwise typical for MS is beyond the scope of this article. Several excellent review articles expand further on the differential diagnosis that should be considered in such patients before determining that a typical syndrome has no better explanation other than MS.

Validation of the 2017 McDonald Criteria

Knowledge of the characteristics of patients included in the studies on which the 2017 revisions to the McDonald criteria relied is also important for the consideration of “no better explanation” in an evaluation for MS. These studies included predominantly white patients from Europe, the United States, and Canada who were younger than 50 years old. The authors of the 2017 McDonald criteria also recommend application with caution in diverse populations and patients younger than 11 years of age, in whom the 2017 McDonald criteria have not been evaluated.

Thus, a presentation of optic neuritis, a brainstem or cerebellar syndrome, or transverse myelitis in a very young, older, or nonwhite patient would be a potential red flag that should prompt further evaluation before a diagnosis of MS. Alternative diagnoses may be more common in patients with this demographic profile. For instance, MS is less common in nonwhites, whereas NMOSD and neurosarcoidosis are comparatively more common in such populations. Although children may present with MS, evaluation for other pediatric demyelinating syndromes, particularly acute disseminated encephalomyelitis (ADEM), is essential in young children. A first clinical attack typical of MS demyelination is less common after the age of 50. In an older patient, vascular disease or a neoplasm might prove a better explanation than MS for neurologic syndromes or MRI abnormalities that appear to fulfill MS diagnostic criteria.

Expanding the Differential Diagnosis and Red Flags to Noninflammatory Disorders

Some disorders often included in the broad differential diagnosis of MS do not usually present with syndromes typical for demyelination. The explanation for this is that the symptoms caused by these syndromes (eg, visual or sensory symptoms) may be mistaken for symptoms typical of MS. The determination that objective evidence exists of a syndrome typical for MS, a clinical assessment reliant on the expertise of the examining neurologist, can often be challenging. Nondemyelinating and noninflammatory syndromes are frequently mistaken for a presentation typical of MS.

Knowledge of the specific disorders frequently mistaken for optic neuritis and myelitis and the skills to facilitate their diagnosis are critical in the evaluation for MS. Nonarteritic anterior ischemic optic neuropathy may frequently be mistaken for optic neuritis; other optic neuropathies, migrainous visual symptoms, functional vision loss, retinal or macular disorders, and neoplasms must also often be differentiated from optic neuritis. Patients with myelopathies with vascular, spondylotic, or compressive etiology frequently present for evaluation of myelitis, and infectious, metabolic, or neoplastic myelopathies may also mimic transverse myelitis. Several recent large cohort studies have provided guidance on a number of clinical, paraclinical, or radiographic red flags that may help identify a noninflammatory diagnosis in patients with ophthalmic or spinal cord syndromes. figure 2-1, figure 2-2, and table 2-2 present approaches and the differential diagnosis of clinical presentations that may mimic syndromes typical for MS.

Studies spanning 30 years that evaluated the characteristics of patients referred to MS subspecialty centers and data concerning MS misdiagnosis have identified migraine and functional neurologic disorders as diagnoses frequently prompting MS evaluation. Diagnosis requires special attention to history and clinical examination, as MRI abnormalities accompanying nonspecific neurologic symptoms often prompt an initial evaluation for MS in such patients. White matter abnormalities associated with migraine or small vessel ischemia may demonstrate MRI dissemination in space, and interval symptoms may appear to demonstrate dissemination in time if attention to an initial confirmation of an MS-specific typical syndrome is neglected. The presence of migraine or risk factors for small vessel ischemia in any patient seen for an evaluation for MS should prompt caution for the interpretation of MRI abnormalities. Important initial red flags that should prompt further evaluation for common noninflammatory diagnoses that may result in brain MRI abnormalities and neurologic symptoms include the absence of clinical or radiographic spinal cord involvement or of CSF-restricted oligoclonal bands.

Comprehensive knowledge of every red flag for the disorders that may mimic MS is not easy, and misdiagnosis of a rare syndrome presenting with an infrequently seen red flag may be difficult to avoid. table 2-3 presents a list of important red flags that may suggest diagnoses other than MS, including a number of rare syndromes. A stepwise clinical approach to MS differential diagnosis, such as that suggested by figure 2-1, figure 2-2, and table 2-2 and recent authors, may aid in the initial identification of alternative broad categories of disease other than MS before ultimately leading to the confirmation of a specific diagnosis. case 2-3 demonstrates an approach to the evaluation for MS incorporating the consideration of red flags.

Atypical Syndromes, Typical Syndromes With Red Flags, and Evaluation of Long-Standing Diagnoses

The authors of the 2017 McDonald criteria reaffirmed that the criteria “were not developed to differentiate MS from other conditions” but to confirm the diagnosis of MS in patients presenting with typical demyelinating syndromes. Application of the McDonald criteria in patients presenting with atypical syndromes (presentations other than optic neuritis, brainstem/cerebellar syndromes, or myelitis) likely diminishes their accuracy. The criteria were not validated in patients with atypical syndromes or in patients presenting with typical syndromes accompanied by red flags. However, a small proportion of patients eventually diagnosed with MS do present with such atypical syndromes or a clinical, paraclinical, or radiographic red flag. In such patients, further data complementing fulfillment of the McDonald criteria are advised to confirm a diagnosis of MS. Monitoring for new radiographic changes suggestive of MS, repeating CSF evaluation to confirm the subsequent appearance of CSF-restricted oligoclonal bands, or waiting for an additional attack typical for MS-related demyelination may be necessary to confirm a diagnosis of MS in patients presenting with atypical syndromes or red flags.

Clinicians also often encounter patients presenting for evaluation with a previous diagnosis of MS made by another provider. Evidence of a remote attack typical for MS can be difficult to confirm as symptom history may be challenging to recall, and symptoms, neurologic examination findings, and radiologic abnormalities may change, evolve, or even resolve over time. The McDonald criteria have not been evaluated in patients with a prior long-standing diagnosis of MS. Yet some proportion of such patients presenting to establish care for a preexisting diagnosis of MS may not have MS. The hindsight potentially provided by a duration of time since initial diagnosis in such patients may reveal red flags for alternative diagnoses. Although clinicians may be reluctant to reevaluate a preexisting MS diagnosis, particularly if it is long-standing, confirmation is necessary before proceeding with care. If objective evidence of a prior attack is no longer present, radiographic or paraclinical (eg, visual evoked potential) confirmation of a historical episode is an important first step in evaluation. Records and prior imaging confirming the presence of spinal cord lesions and CSF-specific oligoclonal bands also make a diagnosis of MS more likely but require consideration of alternative inflammatory disorders. table 2-4 summarizes an approach to the diagnosis of MS in patients with atypical and challenging clinical presentations.

DIAGNOSIS AND DIFFERENTIAL DIAGNOSIS OF PRIMARY PROGRESSIVE MULTIPLE SCLEROSIS

Approximately 10% to 15% of patients with MS have a progressive course from the onset of symptoms. The diagnostic criteria for primary progressive MS differ from the criteria for relapsing-remitting MS. A small proportion of patients with primary progressive MS may have infrequent attacks or relapses. The diagnosis of primary progressive MS first requires confirmation of at least 1 year of gradual disability progression, independent of any disability associated with a clinical relapse, determined either retrospectively or prospectively. In addition to 1 year of progression, primary progressive MS diagnostic criteria require fulfillment of two of the following: (1) at least one T2-hyperintense MRI lesion in the periventricular, cortical or juxtacortical, or infratentorial brain regions; (2) two or more T2-hyperintense spinal cord lesions; or (3) detection of CSF-specific oligoclonal bands. The criteria for the diagnosis of primary progressive MS remain the same in the 2017 McDonald criteria as in the previous criteria, with the exception of the incorporation of cortical and symptomatic lesions as discussed for the criteria for relapsing MS. table 2-5 presents the updated criteria for primary progressive MS.

The differential diagnosis for primary progressive MS is considerably shorter than that of relapsing-remitting MS and includes compressive myelopathy and a limited number of hereditary, metabolic, inflammatory, infectious, neuromuscular, vascular, paraneoplastic, and toxic disorders (table 2-6). In many cases, completion of laboratory, radiographic, and CSF evaluation may provide red flags suggesting these alternative diagnoses.

MISDIAGNOSIS OF MULTIPLE SCLEROSIS

Misdiagnosis of MS (the incorrect assignment of a MS diagnosis) remains a contemporary problem. MS misdiagnosis is associated with unnecessary long-term risk and morbidity for patients and considerable costs to health care systems. Although the prevalence of MS misdiagnosis is unknown, neurologists endorse having frequently evaluated patients who had been previously misdiagnosed with MS. Recent data concerning the characteristics of misdiagnosed patients provide important guidance on its prevention.

Accurate diagnosis of MS relies on an initial clinical assessment to determine if a presentation is typical for MS in order to proceed with the diagnostic process described above. If objective evidence of a syndrome typical for MS is not seen, the 2017 McDonald criteria do not apply. However, many of the clinical diagnoses mistaken for MS are diagnoses that do not usually present with such typical syndromes. These include migraine, functional neurologic disorders, fibromyalgia, and nonspecific symptoms that do not localize to the CNS. This suggests either that, in some cases, the evaluating providers are either unaware that MS diagnostic criteria require objective confirmation of a limited number of specific syndromes for their application or that patient syndromes are often incorrectly identified as typical of MS-related demyelination. Thus, the first step in the prevention of MS misdiagnosis may be broader education surrounding the diagnosis of presentations typical for MS.

Abnormal brain MRI findings prompt an evaluation for MS in many patients. Overreliance on such MRI abnormalities, particularly in patients with atypical, nonspecific, or non–CNS-localizing clinical presentations, is an important contributor to MS misdiagnosis. Demonstration of MRI dissemination in space is possible in a number of common disorders, such as migraine and small vessel ischemic disease, and lack of attention to the presence of atypical syndromes in patients with these diagnoses leads to misdiagnosis. Furthermore, studies have suggested that some providers either misunderstand or have difficulty correctly applying MRI dissemination in space criteria to juxtacortical and periventricular lesions. Careful and correct application of MRI dissemination in space criteria, now further specified in 2017 McDonald criteria, would likely also prevent many cases of MS misdiagnosis.

Although the identification of prior episodes of demyelination may aid in the demonstration of dissemination in time and confirm a diagnosis of MS, the assessment of historical episodes of neurologic symptoms without objective evidence of a lesion has been noted to be a frequent contributor to MS misdiagnosis. Authors of the 2017 criteria state that if such historical events include “symptoms and evolution characteristic for a previous inflammatory demyelinating attack,” they may be considered for demonstration of dissemination in time in the absence of objective evidence. Determining if remote and subsequently resolved symptoms (eg, a history of visual disturbance, vertigo or diplopia, or sensory and motor impairment in an extremity) are indeed typical of MS-related demyelination can be especially difficult. Without corroborating objective CNS findings on neurologic examination, visual evoked potentials, or MRI, consideration of such historical symptoms for the demonstration of dissemination in time warrants caution given its association with misdiagnosis. In some cases, waiting to confirm a diagnosis of MS until interval imaging demonstrates MRI dissemination in time may be prudent. In the majority of patients who do not demonstrate clinical or MRI dissemination in time but have a high likelihood of developing MS, evaluation for the presence of CSF-restricted oligoclonal bands may now provide fulfillment of dissemination in time according to the 2017 criteria.

In the absence of a highly specific biomarker for MS, misdiagnosis may not always be avoidable. In some cases, the passage of time after an initial diagnosis may be necessary to reveal subsequent red flags for clinical features atypical for MS and raise suspicion for alternative diagnoses. For this reason, it is necessary to continue to reassess any diagnosis of MS. Yet, as detailed above, many causes of MS misdiagnosis reflect inappropriate application of MS diagnostic criteria. Although the McDonald criteria necessitate clinical assessments that, by definition, may be susceptible to error, a detailed knowledge of the criteria and their various caveats and strict adherence to their application would likely prevent many cases of MS misdiagnosis. The 2017 McDonald criteria now provide detailed discussion of MS misdiagnosis and its avoidance and a helpful glossary defining the fundamental clinical, paraclinical, and radiologic terms necessary for its correct application.table 2-7 summarizes recommendations for the prevention of MS misdiagnosis in the application of 2017 McDonald criteria.

CONCLUSION

The skilled confirmation of a syndrome typical for MS demyelination is required to maintain accuracy for the initial clinical assessment for a diagnosis of MS. Meticulous knowledge of MS diagnostic criteria and their careful application is necessary to confirm demonstration of dissemination in space and time suggestive of MS. Vigilance for clinical, paraclinical, and radiographic red flags and an understanding of the causes of MS misdiagnosis ensures that no better explanation exists other than a diagnosis MS.

KEY POINTS

  • Diagnosis of relapsing-remitting multiple sclerosis begins with confirmation of objective evidence of a syndrome typical for multiple sclerosis.
  • Knowledge of the recent revisions to the 2017 McDonald criteria is essential for the proper use of paraclinical (ie, visual evoked potentials, CSF examination) and radiographic data to substitute for a second clinical attack for the demonstration of dissemination in space and dissemination in time for the diagnosis of multiple sclerosis.
  • Objective evidence of a demyelinating syndrome typical for multiple sclerosis demonstrating both dissemination in space and dissemination in time must be accompanied by a search for “no better explanation” to confirm a diagnosis of multiple sclerosis.
  • A syndrome typical for multiple sclerosis may also exhibit characteristics atypical for multiple sclerosis, suggesting a specific alternative diagnosis.
  • The demographic profile of patients presenting with syndromes typical for multiple sclerosis may provide an important red flag prompting evaluation for alternative diagnoses.
  • Noninflammatory conditions may also be mistaken for a typical presentation of multiple sclerosis. Knowledge of broad red flags suggesting a structural, functional, metabolic, infectious, neoplastic, or other disease may lead to a specific alternative diagnosis.
  • The McDonald criteria have not been evaluated in patients presenting with atypical syndromes or typical syndromes with red flags, and additional clinical, paraclinical, or radiographic evaluation and monitoring is necessary to confirm a diagnosis of multiple sclerosis.
  • In patients presenting to establish care with a preexisting diagnosis of multiple sclerosis, reassessment of the accuracy of multiple sclerosis diagnosis is prudent.
  • The diagnosis of primary progressive multiple sclerosis and its mimics differs from that of relapsing-remitting multiple sclerosis and requires a thorough understanding of the assessment of clinical progression.
  • Misdiagnosis of multiple sclerosis is often caused by misapplication of the McDonald criteria in patients with atypical syndromes, overreliance on or misunderstanding of MRI dissemination in space, or consideration of historical episodes of symptoms without objective evidence of a central nervous system lesion for demonstration of dissemination in time.

REFERENCES

1. Reich DS, Lucchinetti CF, Calabresi PA. Multiple sclerosis. N Engl J Med 2018;378(2):169–180. doi:10.1056/NEJMra1401483.
2. Solomon AJ. Instead of tweaking the diagnostic criteria for MS in those with CIS, we should develop diagnostic criteria that distinguish MS from other conditions—yes [published online ahead of print January 11, 2019]. Mult Scler. doi:10.1177/1352458518813107.
3. Schumacher GA, Beebe G, Kibler RF, et al. Problems of experimental trials of therapy in multiple sclerosis: report by the panel on the evaluation of experimental trials of therapy in multiple sclerosis. Ann N Y Acad Sci 1965;122:552–568. doi:10.1111/j.1749-6632.1965.tb20235.x.
4. Thompson AJ, Banwell BL, Barkhof F, et al. Diagnosis of multiple sclerosis: 2017 revisions of the McDonald criteria. Lancet Neurol 2018;17(2):162–173. doi:10.1016/S1474-4422(17)30470-2.
5. Solomon AJ, Bourdette DN, Cross AH, et al. The contemporary spectrum of multiple sclerosis misdiagnosis: a multicenter study. Neurology 2016;87(13):1393–1399. doi:10.1212/WNL.0000000000003152.
6. Solomon AJ, Corboy JR. The tension between early diagnosis and misdiagnosis of multiple sclerosis. Nat Rev Neurol 2017;13(9):567–572. doi:10.1038/nrneurol.2017.106.
7. McNicholas N, Lockhart A, Yap SM, et al. New versus old: implications of evolving diagnostic criteria for relapsing-remitting multiple sclerosis [published online ahead of print April 1, 2018]. Mult Scler. doi:10.1177/1352458518770088.
8. Brownlee WJ, Hardy TA, Fazekas F, Miller DH. Diagnosis of multiple sclerosis: progress and challenges. Lancet 2017;389(10076):1336–1346. doi:10.1016/S0140-6736(16)30959-X.
9. Lublin FD, Reingold SC, Cohen JA, et al. Defining the clinical course of multiple sclerosis: the 2013 revisions. Neurology 2014;83(3):278–286. doi:10.1212/WNL.0000000000000560.
10. Arrambide G, Tintore M, Espejo C, et al. The value of oligoclonal bands in the multiple sclerosis diagnostic criteria. Mult Scler 2018;141(4):8–84. doi:10.1093/brain/awy006.
11. Filippi M, Preziosa P, Meani A, et al. Prediction of a multiple sclerosis diagnosis in patients with clinically isolated syndrome using the 2016 MAGNIMS and 2010 McDonald criteria: a retrospective study. Lancet Neurol 2018;17(2):133–142. doi:10.1016/S1474-4422(17)30469-6.
12. Arrambide G, Tintore M, Auger C, et al. Lesion topographies in multiple sclerosis diagnosis: a reappraisal. Neurology 2017;89(23):2351–2356. doi:10.1212/WNL.0000000000004715.
13. McNicholas N, Hutchinson M, McGuigan C, Chataway J. 2017 McDonald diagnostic criteria: a review of the evidence. Mult Scler Relat Disord 2018;24:48–54. doi:10.1016/j.msard.2018.05.011.
14. Filippi M, Rocca MA, Ciccarelli O, et al. MRI criteria for the diagnosis of multiple sclerosis: MAGNIMS consensus guidelines. Lancet Neurol 2016;15(3):292–303. doi:10.1016/S1474-4422(15)00393-2.
15. Zalewski NL, Flanagan EP. Autoimmune and paraneoplastic myelopathies. Semin Neurol 2018;38(3):278–289. doi:10.1055/s-0038-1660856.
16. Jacob A, Weinshenker BG. An approach to the diagnosis of acute transverse myelitis. Semin Neurol 2008;28(1):105–120. doi:10.1055/s-2007-1019132.
17. Toosy AT, Mason DF, Miller DH. Optic neuritis. Lancet Neurol 2014;13(1):83–99. doi:10.1016/S1474-4422(13)70259-X.
18. Hickman SJ, Dalton CM, Miller DH, Plant GT. Management of acute optic neuritis. Lancet 2002;360(9349):1953–1962. doi:10.1016/S0140-6736(02)11919-2.
19. Miller DH, Weinshenker BG, Filippi M, et al. Differential diagnosis of suspected multiple sclerosis: a consensus approach. Mult Scler 2008;14(9):1157–1174. doi:10.1177/1352458508096878.
20. Charil A, Yousry TA, Rovaris M, et al. MRI and the diagnosis of multiple sclerosis: expanding the concept of “no better explanation.” Lancet Neurol 2006;5(10):841–852. doi:10.1016/S1474-4422(06)70572-5.
21. Dubey D, Pittock SJ, Krecke KN, et al. Clinical, radiologic, and prognostic features of myelitis associated with myelin oligodendrocyte glycoprotein autoantibody [published online ahead of print December 21, 2018] . JAMA Neurol. doi:10.1001/jamaneurol.2018.4053.
22. Wingerchuk DM, Lennon VA, Lucchinetti CF, et al. The spectrum of neuromyelitis optica. Lancet Neurol 2007;6(9):805–815. doi:10.1016/S1474-4422(07)70216-8.
23. Segal BM. Neurosarcoidosis: diagnostic approaches and therapeutic strategies. Curr Opin Neurol 2013;26(3):307–313. doi:10.1097/WCO.0b013e3283608459.
24. Neuteboom R, Wilbur C, Van Pelt D, et al. The spectrum of inflammatory acquired demyelinating syndromes in children. Semin Pediatr Neurol 2017;24(3):189–200. doi:10.1016/j.spen.2017.08.007.
25. Tardieu M, Banwell B, Wolinsky JS, et al. Consensus definitions for pediatric MS and other demyelinating disorders in childhood. Neurology 2016;87(9 suppl 2):S8–S11. doi:10.1212/WNL.0000000000002877.
26. Siuko M, Kivelä TT, Setälä K, Tienari PJ. Incidence and mimickers of acute idiopathic optic neuritis: analysis of 291 consecutive patients from Southern Finland. Ophthalmic Epidemiol 2018;25(5-6):386–391. doi:10.1080/09286586.2018.1500614.
27. Stunkel L, Kung NH, Wilson B, et al. Incidence and causes of overdiagnosis of optic neuritis. JAMA Ophthalmol 2018;136(1):76–81. doi:10.1001/jamaophthalmol.2017.5470.
28. Barreras P, Fitzgerald KC, Mealy MA, et al. Clinical biomarkers differentiate myelitis from vascular and other causes of myelopathy. Neurology 2018;90(1):e12–e21. doi:10.1212/WNL.0000000000004765.
29. Zalewski NL, Flanagan EP, Keegan BM. Evaluation of idiopathic transverse myelitis revealing specific myelopathy diagnoses. Neurology 2018;90(2):e96–e102. doi:10.1212/WNL.0000000000004796.
30. Penman MF. When neurological symptoms are not what they appear: the challenge of caring for patients with conversion disorders. Axone 1993;15(1):19–22.
31. Carmosino MJ, Brousseau KM, Arciniegas DB, Corboy JR. Initial evaluations for multiple sclerosis in a university multiple sclerosis center: outcomes and role of magnetic resonance imaging in referral. Arch Neurol 2005;62(4):585–590. doi:10.1001/archneur.62.4.585.
32. Yamout BI, Khoury SJ, Ayyoubi N, et al. Alternative diagnoses in patients referred to specialized centers for suspected MS. Mult Scler Relat Disord 2017;18:85–89. doi:10.1016/j.msard.2017.09.016.
33. Solomon AJ, Klein EP, Bourdette D. “Undiagnosing” multiple sclerosis: the challenge of misdiagnosis in MS. Neurology 2012;78(24):1986–1991. doi:10.1212/WNL.0b013e318259e1b2.
34. Liu S, Kullnat J, Bourdette D, et al. Prevalence of brain magnetic resonance imaging meeting Barkhof and McDonald criteria for dissemination in space among headache patients. Multiple Scler 2013;19(8):1101–1105. doi:10.1177/1352458512471874.
35. Toledano M, Weinshenker BG, Solomon AJ. A clinical approach to the differential diagnosis of multiple sclerosis. Curr Neurol Neurosci Rep 2015;15(8):57. doi:10.1007/s11910-015-0576-7.
36. Brownlee WJ. Use (and misuse) of the McDonald criteria to diagnose multiple sclerosis. Eur J Neurol 2018;25(2):209–210. doi:10.1111/ene.13501.
37. Kelly SB, Chaila E, Kinsella K, et al. Using atypical symptoms and red flags to identify non-demyelinating disease. J Neurol Neurosurg Psychiatry 2012;83(1):44–48. doi:10.1136/jnnp-2011-300679.
38. Kaisey M, Solomon AJ, Luu M, et al. Incidence of multiple sclerosis misdiagnosis in referrals to two academic centers. Mult Scler Relat Disord 2019;30:51–56. doi:10.1016/j.msard.2019.01.048.
39. Solomon AJ, Klein E. Disclosing a misdiagnosis of multiple sclerosis: do no harm? Continuum (Minneap Minn) 2013;19(4 Multiple Sclerosis):1087–1091. doi:10.1212/01.CON.0000433281.18146.5b.
40. Solomon AJ, Naismith RT, Cross AH. Misdiagnosis of multiple sclerosis: impact of the 2017 McDonald criteria on clinical practice. Neurology 2019;92(1):26–33. doi:10.1212/WNL.0000000000006583.
41. Miller DH, Leary SM. Primary-progressive multiple sclerosis. Lancet Neurol 2007;6(10):903–912. doi:10.1016/S1474-4422(07)70243-0.
42. Solomon AJ, Weinshenker BG. Misdiagnosis of multiple sclerosis: frequency, causes, effects, and prevention. Curr Neurol Neurosci Rep 2013;13(12):403. doi:10.1007/s11910-013-0403-y.
© 2019 American Academy of Neurology.