Multiple Sclerosis Misdiagnosis Research Articles

Consensus-Based Guidelines for Communicating a Misdiagnosis of Multiple Sclerosis to Reduce Psychological Distress.

Multiple sclerosis (MS) misdiagnosis is common, and when discovered, frequently leads to substantial disruption to patients' lives and anxiety for clinicians. Our objective was to develop expert consensus-based guidelines about how to communicate a misdiagnosis of MS to a patient, to reduce the potential for both psychological distress and litigation. A modified Delphi method using a systematic literature review on doctor and patient experiences of the MS diagnosis communication was used to populate items for a first-round questionnaire. Our Delphi panel represented three perspectives (clinicians, people with MS, and published experts in health communication), and we recruited 18 panelists in total (6 per perspective). Consensus was defined a priori as 75% of panelists giving an item the same rating. A feedback round was undertaken with six external reviewers, naïve to the guideline development process, and the panelists. Items were reviewed by the study team and synthesized to create the finalized guidelines. Consensus was reached for 45 items rated as "very important" and presented in the feedback round. The study team synthesized the 45 items to 27 items. Ten items related specifically to the communication of the MS misdiagnosis and 17 items to generic guidelines highlighted as important in the MS misdiagnosis appointment. Seven recommendations form the guidelines presented here. Seven consensus-based recommendations offer guidance to practising neurologists in their communication with patients in a situation that has the potential to be highly distressing, for both clinician and patient.

Misdiagnosis and underdiagnosis of multiple sclerosis: A systematic review and meta-analysis

Background: Diagnostic errors in multiple sclerosis (MS) impact patients and healthcare systems. Objectives: This study aimed to determine the prevalence of MS misdiagnosis and underdiagnosis, time delay in reaching a correct diagnosis and potential impact of sex. Methods: Systematic review and meta-analysis on MS diagnostic errors. Results: Out of 3910 studies, we included 62 for a qualitative synthesis and 24 for meta-analyses. Frequency of misdiagnosis (incorrect assignment of an MS diagnosis) ranged from 5% to 41%, with a pooled proportion based on six studies of 15% (95% CI: 9%–26%, n = 1621). The delay to rectify a misdiagnosis ranged from 0.3 to 15.9 years. Conversely, underdiagnosis (unrecognized diagnosis of MS) ranged from 3% to 58%, with a pooled proportion in four studies of 36% (95% CI: 20%–55%, n = 728). Pooling seven studies comprising 2851 individuals suggested a diagnostic delay to establish a correct MS diagnosis of 17.3 months (95% CI: 11.9–22.7) in patients underdiagnosed. In a meta-analysis of five studies, women were 2.1 times more likely to be misdiagnosed with MS compared to men (odds ratio, 95% CI: 1.53–2.86). Conclusion: This study provides summary-level evidence for the high prevalence of MS misdiagnosis and underdiagnosis. Future studies are needed to understand the causes of these diagnostic challenges in MS care.

Misdiagnosis in multiple sclerosis in a Brazilian reference center: Clinical, radiological, laboratory profile and failures in the diagnostic process-Cohort study.

Multiple sclerosis misdiagnosis remains a problem despite the well-validated McDonald 2017. For proper evaluation of errors in the diagnostic process that lead to misdiagnosis, it is adequate to incorporate patients who are already under regular follow-up at reference centers of demyelinating diseases. To evaluate multiple sclerosis misdiagnosis in patients who are on follow-up at a reference center of demyelinating diseases in Brazil. We designed an observational study including patients in regular follow-up, who were diagnosed with multiple sclerosis at our specialized outpatient clinic in the Hospital of Clinics in the University of Sao Paulo, from 1996 to 2021, and were reassessed for misdiagnosis in 2022. We evaluated demographic information, clinical profile, and complementary exams and classified participants as "established multiple sclerosis," "non-multiple sclerosis, diagnosed," and "non-multiple sclerosis, undiagnosed." Failures in the diagnostic process were assessed by the modified Diagnostic Error Evaluation and Research tool. A total of 201 patients were included. After analysis, 191/201 (95.02%) participants were confirmed as "established multiple sclerosis," 5/201 (2.49%) were defined as "non-multiple sclerosis, diagnosed," and 5/201 (2.49%) were defined as "non-multiple sclerosis, undiagnosed." Multiple sclerosis misdiagnosis persists in reference centers, emphasizing the need for careful interpretation of clinical findings to prevent errors.

Clinical and radiologic characteristics associated with multiple sclerosis misdiagnosis at a tertiary referral center in the United States

Background: Misdiagnosis of multiple sclerosis (MS) is common and can have harmful effects on patients and healthcare systems. Identification of factors associated with misdiagnosis may aid development of prevention strategies. Objective: To identify clinical and radiological predictors of MS misdiagnosis. Methods: We retrospectively reviewed medical records of all patients who were referred to Johns Hopkins MS Center from January 2018 to June 2019. Patients who carried a diagnosis of MS were classified as correctly diagnosed or misdiagnosed with MS by the Johns Hopkins clinician. Demographics, clinical, laboratory, and radiologic data were collected. Differences between the two groups were evaluated, and a regression model was constructed to identify predictors of misdiagnosis. Results: Out of 338 patients who were previously diagnosed with MS, 41 (12%) had been misdiagnosed. An alternative diagnosis was confirmed in 28 (68%) of the misdiagnosed patients; cerebrovascular disease was the most common alternate diagnosis. Characteristics associated with misdiagnosis were female sex (odds ratio (OR): 5.81 (95% confidence interval (CI): 1.60, 21.05)) and non-specific brain magnetic resonance imaging (MRI) lesions (OR: 7.66 (3.42, 17.16)). Conclusion: Misdiagnosis is a frequent problem in MS care. Non-specific brain lesions were the most significant predictor of misdiagnosis. Interventions aimed to reduce over-reliance on imaging findings and misapplication of the McDonald criteria may prevent MS misdiagnosis.

The frequency and characteristics of multiple sclerosis misdiagnosis in Latin America: A referral center study in Buenos Aires, Argentina

Objective: Most contemporary data concerning the frequency and causes of multiple sclerosis (MS) misdiagnosis are from North America and Europe with different healthcare system structure and resources than countries in Latin America. We sought to determine the frequency, and potential contributors to MS misdiagnosis in patients evaluated at an MS referral center in Argentina. Methods: The study was a retrospective medical record review. We included patients evaluated at the MS Clinic at Fleni between April 2013 and March 2021. Diagnoses prior to consultation, final diagnoses after consultation, demographic, clinical and paraclinical data, and treatment were extracted and classified. Results: Seven hundred thirty-six patients were identified. Five hundred seventy-two presented with an established diagnosis of MS and after evaluation, misdiagnosis was identified in 89 (16%). Women were at 83% greater risk of misdiagnosis (p = 0.034). The most frequent alternative diagnoses were cerebrovascular disease, radiological isolated syndrome (RIS), and headache. Seventy-four (83%) of misdiagnosed patients presented with a syndrome atypical for demyelination, 62 (70%) had an atypical brain magnetic resonance imaging (MRI), and 54 (61%) were prescribed disease-modifying therapy. Conclusion: Sixteen percent of patients with established MS were subsequently found to have been misdiagnosed. Women were at higher risk for misdiagnosis. Expert application of the McDonald criteria may prevent misdiagnosis and its associated morbidity and healthcare system cost.

REVISION OF MULTIPLE SCLEROSIS CASES ACCORDING TO NEW 2017 MCDONALD CRITERIA AMONG DIAGNOSED PATIENTS IN SULAIMANI CITY

Background 
 Multiple sclerosis (MS) is a chronic, immune-mediated inflammatory disorder of the central nervous system. The diagnosis of Multiple sclerosis is challenging, owing to having a comprehensive list of differentials and mimickers.
 Objectives 
 To determine the frequency of misdiagnosed Multiple Sclerosis cases diagnosed among those patients in Sulaimani city.
 Patients and and Methods
 This retrospective observational study was conducted within a period between December 24th. 2019 and June 10th, 2020, on 106 already diagnosed patients. The study included patients diagnosed with the relapse-remitting form of multiple sclerosis. We excluded those patients with progressive forms of multiple sclerosis. We re-evaluated each patient in-depth and stratified the cases according to the diagnosis certainty based on the fulfillment of the 2017 McDonald Criteria. Finally, we returned those suspicious cases to the multiple sclerosis committee of Shar hospital to verify their final diagnosis. 
 Results
 Sixteen (16.9%) out of 106 patients, there was diagnostic uncertainty in which 6 (5.7%) of them received the confirmatory diagnosis of relapse-remitting multiple sclerosis by the committee, and 1(0.9%) patient considered secondary progressive multiple sclerosis. In the remaining 9 (8.4%) patients, we found the clinically isolated syndrome in 5 (4.7%) patients, solitary sclerosis in 1 (0.9%) patient, stroke with polycythemia rubra vera (PRV) in 1 (0.9%) patient, possible cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy in 1 (0.9%) patient, and 1 (0.9 %) patient was undiagnosed. 
 Conclusion
 To sum up, the frequency of multiple sclerosis misdiagnosis was 8.4% in Sulaimani city, slightly lower than the other reporting centers.

The frequency and characteristics of MS misdiagnosis in patients referred to the multiple sclerosis centre of Catalonia

Background: Multiple sclerosis (MS) misdiagnosis may cause physical and emotional damage to patients. Objectives: The objective of this study is to determine the frequency and characteristics of MS misdiagnosis in patients referred to the Multiple Sclerosis Centre of Catalonia. Methods: We designed a prospective study including all new consecutive patients referred to our centre between July 2017 and June 2018. Instances of misdiagnosis were identified, and referral diagnosis and final diagnosis were compared after 1 year of follow-up. Association of misdiagnosis with magnetic resonance imaging (MRI) findings, presence of comorbidities and family history of autoimmunity were assessed. Results: A total of 354 patients were referred to our centre within the study period, 112 (31.8%) with ‘established MS’. Misdiagnosis was identified in eight out of 112 cases (7.1%). MRI identified multifocal white matter lesions, deemed non-specific or not suggestive of MS in all misdiagnosed cases. Patients with MS misdiagnosis had more comorbidities in general than patients with MS (p = 0.026) as well as a personal history of autoimmunity (p < 0.001). Conclusion: A low frequency of MS misdiagnosis was found in our clinical setting. Multifocal non-specific white matter lesions in referral MRI examinations and the presence of comorbidities, including a personal history of autoimmunity, seem to be contributing factors to misdiagnosis.

Central vein sign: A diagnostic biomarker in multiple sclerosis (CAVS-MS) study protocol for a prospective multicenter trial

The specificity and implementation of current MRI-based diagnostic criteria for multiple sclerosis (MS) are imperfect. Approximately 1 in 5 of individuals diagnosed with MS are eventually determined not to have the disease, with overreliance on MRI findings a major cause of MS misdiagnosis. The central vein sign (CVS), a proposed MRI biomarker for MS lesions, has been extensively studied in numerous cross sectional studies and may increase diagnostic specificity for MS. CVS has desirable analytical, measurement, and scalability properties. “Central Vein Sign: A Diagnostic Biomarker in Multiple Sclerosis (CAVS-MS)” is an NIH-supported, 2-year, prospective, international, multicenter study conducted by the North American Imaging in MS Cooperative (NAIMS) to evaluate CVS as a diagnostic biomarker for immediate translation into clinical care. Study objectives include determining the concordance of CVS and McDonald Criteria to diagnose MS, the sensitivity of CVS to detect MS in those with typical presentations, and the specificity of CVS among those with atypical presentations. The study will recruit a total of 400 participants (200 with typical and 200 with atypical presentations) across 11 sites. T2*-weighted, high-isotropic-resolution, segmented echo-planar MRI will be acquired at baseline and 24 months on 3-tesla scanners, and FLAIR* images (combination of FLAIR and T2*) will be generated for evaluating CVS. Data will be processed on a cloud-based platform that contains clinical and CVS rating modules. Imaging quality control will be conducted by automated methods and neuroradiologist review. CVS will be determined by Select6* and Select3* lesion methods following published criteria at each site and by central readers, including neurologists and neuroradiologists. Automated CVS detection and algorithms for incorporation of CVS into McDonald Criteria will be tested. Diagnosis will be adjudicated by three neurologists who served on the 2017 International Panel on the Diagnosis of MS. The CAVS-MS study aims to definitively establish CVS as a diagnostic biomarker that can be applied broadly to individuals presenting for evaluation of the diagnosis of MS.

Preventing multiple sclerosis misdiagnosis using the “central vein sign”: A real-world study

Background: Misdiagnosis of multiple sclerosis (MS) is common and often occurs due to misattribution of non-MS magnetic resonance imaging (MRI) lesions to MS demyelination. A recently developed MRI biomarker, the central vein sign (CVS), has demonstrated high specificity for MS lesions and may thus help prevent misdiagnosis.Objective: This study explores the potential “real world” diagnostic value of CVS by comparing CVS in patients with MS and patients previously misdiagnosed with MS.Methods: Fifteen patients with MS and 15 misdiagnosed with MS were prospectively recruited to undergo 3T brain MRI. T2-weighted fluid-attenuated inversion recovery (FLAIR) and T2*-weighted segmented echo-planar-imaging (T2*-EPI) were acquired. The generated FLAIR* images were analyzed by two independent raters. The percentage of lesions with CVS was calculated for each patient.Results: A CVS lesion threshold of 29% or higher resulted in high sensitivity (0.79) and specificity (0.88) for MS and correctly identified 87% of patients previously misdiagnosed with MS. Interrater reliability for CVS was high with a Cohen's kappa coefficient of 0.86.Conclusion: This study demonstrates the ability of CVS to differentiate between patients with MS and patients with an MS misdiagnosis resulting from standard MRI and clinical evaluation. Clinical application of CVS may reduce MS misdiagnosis.

Magnetic Resonance Imaging of Multiple Sclerosis

Magnetic resonance imaging (MRI) is the imaging modality of choice for patients with multiple sclerosis (MS). The roles of MRI in MS include diagnosis, imaging biomarkers, and safety monitoring for patients receiving disease-modifying drugs (DMDs). In terms of diagnosis, MRI plays a pivotal role in the international diagnosis criteria (McDonald criteria). MRI is also useful for differential diagnosis. The rate of MS misdiagnosis might be as high as 10%, and careful interpretation of MRI may reduce rates of misdiagnosis. Quantified MRI data have been widely used as primary and secondary outcomes in clinical trials of DMDs. MRI is also a powerful tool for monitoring the efficacy of DMDs in individual patients (i.e., determination of responder status for each drug). MRI assists with early detection of the side effects of DMDs. MRI can detect lesions of natalizumab-induced progressive multifocal leukoencephalopathy (PML) before symptoms occur. This review summarizes our current understanding of the utility of MRI in the diagnosis and treatment of patients with MS.

Challenges in multiple sclerosis diagnosis: Misunderstanding and misapplication of the McDonald criteria

Objective: To assess comprehension and application of the McDonald criteria. Background: Studies suggest that knowledge gaps for specific core elements of the McDonald criteria may contribute to multiple sclerosis (MS) misdiagnosis. Methods: Neurology residents (NR) and multiple sclerosis specialists (MSS) in North America completed a web-based survey. Results: A total of 160 participants were included: 72 NR and 88 MSS. Syndromes incorrectly identified as typical of MS included: complete transverse myelopathy (35% NR and 15% MSS), intractable vomiting/nausea/hiccoughs (20% NR and 5% MSS), and bilateral optic neuritis/unilateral optic neuritis with poor visual recovery (17% NR and 10% MSS). Periventricular magnetic resonance imaging (MRI) lesions were correctly identified by 39% NR and 52% MSS, and juxtacortical lesions were correctly identified by 28% NR and 53% MSS. The correct definition of “periventricular” was chosen by 38% NR and 61% MSS, and that of “juxtacortical” was chosen by 19% NR and 54% MSS. Regions incorrectly identified for MRI dissemination in space fulfillment included the optic nerve (31% NR and 26% MSS) and the subcortical white matter (11% NR and 18% MSS). The majority of participants assessed previous non-specific neurological symptoms without objective evidence of a central nervous system (CNS) lesion as sufficient for clinical dissemination in time. Conclusion: The McDonald criteria are often misunderstood and misapplied. Concerted educational efforts may prevent MS misdiagnosis.

Diagnosis, Differential Diagnosis, and Misdiagnosis of Multiple Sclerosis.

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

Incidence of multiple sclerosis misdiagnosis in referrals to two academic centers

BackgroundMultiple Sclerosis (MS) specialists routinely evaluate misdiagnosed patients, or patients incorrectly assigned a diagnosis of MS. Misdiagnosis has significant implications for patient morbidity and healthcare costs, yet its contemporary incidence is unknown. We examined the incidence of MS misdiagnosis in new patients referred to two academic MS referral centers, their most common alternate diagnoses, and factors associated with misdiagnosis. MethodsDemographic data, comorbidities, neurological examination findings, radiographic and laboratory results, a determination of 2010 McDonald Criteria fulfillment, and final diagnoses were collected from all new patient evaluations completed at the Cedars-Sinai Medical Center and the University of California, Los Angeles MS clinics over twelve months. ResultsOf the 241 new patients referred with an established diagnosis of MS, 17% at Cedars-Sinai and 19% at UCLA were identified as having been misdiagnosed. The most common alternative diagnoses were migraine (16%), radiologically isolated syndrome (9%), spondylopathy (7%), and neuropathy (7%). Clinical syndromes and radiographic findings atypical for MS were both associated with misdiagnosis. The misdiagnosed group received approximately 110 patient-years of unnecessary MS disease modifying therapy. ConclusionMS misdiagnosis is common; in our combined cohort, almost 1 in 5 patients who carried an established diagnosis of MS did not fulfill contemporary McDonald Criteria and had a more likely alternate diagnosis.

Misdiagnosis of multiple sclerosis

Misdiagnosis of multiple sclerosis (MS) (the incorrect assignment of a diagnosis of MS) remains a problem in contemporary clinical practice. Studies indicate that misdiagnosed patients are often exposed to prolonged unnecessary health care risks and morbidity. The recently published 2017 revision of the McDonald criteria for the diagnosis of MS provides an opportunity to consider the effect of these revisions on the problem of MS misdiagnosis. The 2017 McDonald criteria include several new recommendations to reduce potential for misdiagnoses. The criteria should be used for the types of patients in which validation studies were performed, specifically those patients who present with typical demyelinating syndromes. MRI lesion characteristics were defined for which McDonald criteria would be expected to perform with accuracy. However, 2017 revisions, which now include assessment for cortical lesions, and the inclusion of symptomatic lesions and positive oligoclonal bands for the fulfillment of diagnostic criteria, may have the potential to lead to misdiagnosis of MS if not applied appropriately. While the 2017 McDonald criteria integrate issues relating to MS misdiagnosis and incorporate specific recommendations for its prevention more prominently than prior criteria, the interpretation of clinical and radiologic assessments upon which these criteria depend will continue to allow misdiagnoses. In patients with atypical clinical presentations, the revised McDonald criteria may not be readily applied. In those situations, further evaluation or monitoring rather than immediate diagnosis of MS is prudent.

Fabry disease and multiple sclerosis misdiagnosis: the role of family history and neurological signs.

Fabry disease (FD) is an X-linked inherited lysosomal storage disorder caused by α galactosidase A (α-gal A) deficiency. Central nervous system involvement and chronic white matter lesions are observed in both FD and multiple sclerosis (MS), which can confound the differential diagnosis. We analyzed the GLA gene, which encodes α-gal A, in 86 patients with clinical and neuroradiological findings consistent with MS to determine whether they had FD. We identified four women initially diagnosed with MS who had GLA mutations associated with FD. Our results indicate that family history besides neurological findings should be evaluated in patients with an uncertain diagnosis of MS. Also the involvement of organs outside the central nervous system can support the FD diagnosis.

The tension between early diagnosis and misdiagnosis of multiple sclerosis.

The benefits of early treatment for multiple sclerosis (MS) place pressure on physicians to make the diagnosis early, thereby increasing the risk of misdiagnosis, which can have considerable consequences for patients and health-care systems. Solomon and Corboy examine the problem of MS misdiagnosis, including the probable causes and associated risks, and discuss how the tension between early diagnosis and misdiagnosis might be addressed. Diagnosis of multiple sclerosis (MS) can be challenging, and misdiagnosis remains a persistent problem with considerable consequences for patients and health-care systems. Common syndromes are frequently mistaken for MS. Misapplication of MS diagnostic criteria in patients with abnormal radiographic findings and clinical presentations that are atypical for MS is a frequent cause of misdiagnosis. Delays in diagnosis of MS and initiation of disease-modifying therapy (DMT) are associated with an increased risk of disability, putting pressure on physicians to make therapeutic decisions for patients whose diagnosis remains uncertain. DMT is associated with unnecessary risks and morbidity in misdiagnosed patients. This tension between the benefits of an early diagnosis and the risk of misdiagnosis is a pressing problem. For patients who present with brain MRI abnormalities and clinical syndromes that are atypical for MS, strict adherence to MS diagnostic criteria and further clinical, laboratory and radiographic evaluation is prudent and likely to clarify a diagnosis.

Author response: The contemporary spectrum of multiple sclerosis misdiagnosis: A multicenter study.

We appreciate the comments of Dalla Costa et al. on our Contemporary Issues article.1 As discussed, this study was not designed to assess the frequency of multiple sclerosis (MS) misdiagnosis or its specific causes.1 We catalogued the diagnoses ultimately assigned to patients mistaken as having MS and reported the evaluation of the MS specialists who determined that a misdiagnosis had occurred according to their analysis of what led to misdiagnosis. Accepting this limitation, application of MS diagnostic criteria to a neurologic syndrome not typical for MS contributed to misdiagnosis in 65% of cases.1 MS diagnostic criteria fail in this situation, but are often applied in clinical practice. In 60% of cases, declaring MRI criteria for dissemination in space satisfied in a patient with nonspecific symptoms contributed to misdiagnosis.1 Ultimately, these 2 errors perpetuate one another. Nonspecific symptoms acquire additional and unwarranted attention when nonspecific MRI lesions are present, and nonspecific MRI lesions are accorded undue attention in the presence of symptoms of common conditions such as migraine. Further studies should establish the frequency of misdiagnosis, but the combination of nonspecific symptoms and nonspecific MRI abnormalities is likely a common contemporary source of MS misdiagnosis.

Editors' Note

Editors' Note: Regarding “The contemporary spectrum of multiple sclerosis misdiagnosis: A multicenter study,” Dalla Costa et al. express concerns about the interpretation of results because of the number of patients screened, the clinical and paraclinical characteristics of the misdiagnosed patients, and the lack of specification of fulfilled multiple sclerosis (MS) criteria through which the diagnosis was made. Solomon et al., authors of the study, explain that the study was not designed to assess the frequency of MS misdiagnosis or its specific causes. They add that application of MS diagnostic criteria to a neurologic syndrome not typical for MS contributed to misdiagnosis in 65% of cases, and that in 60% of cases, using MRI criteria for dissemination in space in a patient with nonspecific symptoms contributed to misdiagnosis. Commenting on “Early start of DOAC after ischemic stroke: Risk of intracranial hemorrhage and recurrent events,” Prof. Kawada argues that larger patient cohorts more accurately estimate the risk of intracranial hemorrhage (ICH) from direct, non–vitamin K antagonist oral anticoagulants (DOACs). Seiffge et al., authors of the study, agree but point out that they looked at symptomatic ICH only and a well-designed randomized clinical trial is necessary to address timing of DOAC after ischemic stroke due to nonvalvular atrial fibrillation. —Chafic Karam, MD, and Robert C. Griggs, MD Editors' Note: Regarding “The contemporary spectrum of multiple sclerosis misdiagnosis: A multicenter study,” Dalla Costa et al. express concerns about the interpretation of results because of the number of patients screened, the clinical and paraclinical characteristics of the misdiagnosed patients, and the lack of specification of fulfilled multiple sclerosis (MS) criteria through which the diagnosis was made. Solomon et al., authors of the study, explain that the study was not designed to assess the frequency of MS misdiagnosis or its specific causes.

The contemporary spectrum of multiple sclerosis misdiagnosis

To characterize patients misdiagnosed with multiple sclerosis (MS). Neurologists at 4 academic MS centers submitted data on patients determined to have been misdiagnosed with MS. Of 110 misdiagnosed patients, 51 (46%) were classified as "definite" and 59 (54%) "probable" misdiagnoses according to study definitions. Alternate diagnoses included migraine alone or in combination with other diagnoses 24 (22%), fibromyalgia 16 (15%), nonspecific or nonlocalizing neurologic symptoms with abnormal MRI 13 (12%), conversion or psychogenic disorders 12 (11%), and neuromyelitis optica spectrum disorder 7 (6%). Duration of misdiagnosis was 10 years or longer in 36 (33%) and an earlier opportunity to make a correct diagnosis was identified for 79 patients (72%). Seventy-seven (70%) received disease-modifying therapy and 34 (31%) experienced unnecessary morbidity because of misdiagnosis. Four (4%) participated in a research study of an MS therapy. Leading factors contributing to misdiagnosis were consideration of symptoms atypical for demyelinating disease, lack of corroborative objective evidence of a CNS lesion as satisfying criteria for MS attacks, and overreliance on MRI abnormalities in patients with nonspecific neurologic symptoms. Misdiagnosis of MS leads to unnecessary and potentially harmful risks to patients. Misinterpretation and misapplication of MS clinical and radiographic diagnostic criteria are important contemporary contributors to misdiagnosis.