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.
The practicing neurologist frequently encounters patients for whom a diagnosis of multiple sclerosis (MS) is considered. At times, diagnosis might be straightforward, but making a rapid and accurate diagnosis of MS can also be challenging, particularly because no highly specific biomarker for MS has been identified. The formal diagnostic criteria for MS have evolved substantially over time1,2,3,4 but remain centred on the principle of identifying episodes of CNS dysfunction separated in space and time, in the context of a specific clinical history and an abnormal neurological examination, for which other potential causes are ruled out4.
Charcot defined the clinicopathological basis of MS in the 19th century, but MRI of the brain, spine and orbits has transformed diagnosis of MS and improved our understanding of the disease5,6,7,8. Over the past 30 years, the sensitivity of MRI has enabled identification of individuals with clinically isolated syndrome (CIS) and a high risk of developing additional clinical or radiographic features that fulfil the formal diagnostic criteria for MS9,10. Furthermore, individuals who undergo MRI for symptoms that are seemingly unrelated to MS can be identified as exhibiting MRI abnormalities that suggest presymptomatic MS — a phenomenon termed radiologically isolated syndrome (RIS)11,12. The ability to diagnose MS early in the disease course has evolved and improved over time with the use of MRI, but accurate diagnosis remains tightly linked to clinical features, and over-reliance on imaging in the absence of these features increases the likelihood of misdiagnosis.
Alongside developments that have enabled earlier diagnosis of MS, the introduction of disease-modifying therapies (DMTs) for MS has provided increasing evidence that earlier treatment is associated with better long-term outcomes13,14. This evidence creates pressure for the physician to make a diagnosis of MS as early as possible so that treatment can be initiated. This pressure, in turn, creates a tension between the benefits of an early diagnosis of MS and the risk of an inaccurate diagnosis that can have serious health and financial consequences.
In this Perspectives article, we first consider the extent of the problem of misdiagnosis of MS and the reasons that are likely to underlie many cases of misdiagnosis. We then discuss the need for an early diagnosis for the successful treatment of MS, and the tension that this need creates owing to the consequences of misdiagnosis.
The problem of MS misdiagnosis
Medical error has been identified as the third leading cause of death in the USA15. Determining the incidence of diagnostic error for any disease is methodologically challenging16,17 and, as is the case for many other disorders, the incidence of misdiagnosis of MS (that is, a diagnosis of MS given incorrectly) has not been studied rigorously. Historical estimates indicate that 5–10% of all patients who are initially diagnosed with MS are misdiagnosed18. These estimates originate from studies19,20,21 conducted in the 1980s and earlier, which used now outdated versions of MS diagnostic criteria, did not specify MS phenotype, often included patients with a diagnoses of possible or probable MS (thereby making a true misdiagnosis in such patients questionable), were conducted before standard clinical use of MRI, were frequently case reports, which are prone to over-represent rare or unusual clinical presentations, and were limited by a number of biases, including referral and selection bias. These limitations make the findings of these studies unreliable for application to current practice. Although misdiagnosis of MS is frequently acknowledged by MS specialists22,23, further study is needed to determine the contemporary incidence of the problem.
Beyond individual case reports, few studies have reported on the characteristics of cohorts of patients who are misdiagnosed with MS; the most recent study to do so was published 20 years ago19,21,24,25. However, two studies have provided contemporary data about the characteristics of patients who were incorrectly diagnosed with MS. In our study published in 2012, 122 MS specialists were surveyed about clinical encounters with patients whom they identified to have been incorrectly diagnosed with MS22. The responses revealed that 95% of participating physicians recalled having assessed one or more patients over the preceding year who they felt had been misdiagnosed with MS for 1 year or longer. One-third of participants recalled seeing six or more such patients during the year before the survey. This study provided initial contemporary data on the misdiagnosis of MS, but the conclusions that can be drawn from survey data are limited. In another study from our group published in 2016 (Ref. 26), we collected demographic and clinical data from four academic MS centres concerning 110 patients who, in the opinion of participating MS specialists, had previously been misdiagnosed with MS. This study confirmed earlier findings21 that misdiagnosis typically persisted for a long time — one-third of the participants had lived with an incorrect diagnosis of MS for 10 years or longer.
The diseases and syndromes most frequently misdiagnosed as MS have probably changed along with the evolution of MS diagnostic criteria and the incorporation of MRI into these criteria in 2001 (Ref. 2). In our study published in 2012, we identified a number of conditions that were frequently misdiagnosed as MS, including migraine, fibromyalgia, psychiatric disease, nonspecific white matter abnormalities, small vessel ischaemic disease and neuromyelitis optica spectrum disorder (NMOSD)22. Studies of patients who were referred to MS subspecialty centres for possible MS have revealed a similar spectrum of alternative final diagnoses, especially psychiatric disease and migraine27,28. Findings of our study published in 2016 (Table 1) were congruent with these previous studies: migraine, fibromyalgia, nonspecific neurological symptoms with abnormal MRI, psychiatric disease and NMOSD were the final diagnoses for two-thirds of the patients who were misdiagnosed with MS26. The differential diagnosis of MS is well known to be lengthy and to comprise many rare and diagnostically challenging disorders, making an initial misdiagnosis difficult to avoid at times29,30. Indeed, several such diagnoses — including Behçet disease, moyamoya disease and mitochondrial and paraneoplastic disorders — were identified in our study26. However, these contemporary data also suggest that several common disorders — rather than those that are rare and difficult to diagnose — account for the majority of cases of MS misdiagnosis22,26.
Causes of misdiagnosis
MS can be particularly challenging to diagnose owing to its clinical and radiographic heterogeneity31,32 and the considerable number of syndromes and diseases that can mimic its characteristics29,33. With the exception of anti-aquaporin-4 antibody-positive NMOSD, the conditions that seem to be most frequently mistaken for MS lack a specific biomarker, and their recognition relies on clinical acumen and an accurate understanding of the MS diagnostic criteria to facilitate correct interpretation of clinical and radiographic data.
Misdiagnosis of MS is often caused by an over-reliance on the presence of MRI abnormalities in the context of clinical syndromes with nonspecific symptoms and/or symptoms that are atypical for MS18. MRI has high sensitivity for lesions that might be related to MS, but in many other conditions that mimic MS, such as migraine and small vessel ischaemic disease, MRI lesions can be visible in regions and have morphological characteristics that are typically associated with MS33,34,35. As a result, neurologists are frequently faced with a brain MRI scan that includes nonspecific findings that are compatible with MS as well as several common disorders (Fig. 1). Similarly, detection of intrathecal synthesis of immunoglobulins that are unique to the CNS, which has been used as a diagnostic aid in MS for over 50 years, has high sensitivity, but specificity for MS remains inadequate36,37,38.
The chance of MS misdiagnosis remains high, especially when symptoms are vague and/or do not logically localize to the CNS, neurological examination is normal, and MRI abnormalities are nonspecific. The diagnostic criteria for MS were not validated in patients with such symptoms, and MRI criteria were not developed to differentiate MS from other disorders in the absence of clinical syndromes that are typical for demyelination, such as optic neuritis, brainstem syndromes, and transverse myelitis34,35,39,40,41,42. Reliance on the MS diagnostic criteria alone when assessing patients with clinically atypical presentations diminishes specificity for MS and is an important cause of misdiagnosis.
A history that suggests demyelination is critical for accurate diagnosis of MS, but confirmatory objective findings on neurological examination43 are required to meet the MS diagnostic criteria — an aspect that might often be neglected or misinterpreted44, particularly when historical episodes of symptoms suggestive of demyelination are considered26. Application of historical symptoms to MS diagnostic criteria without objective evidence of a CNS lesion contributed to misdiagnosis in many patients in our 2016 study26. Our study also suggests that erroneous determination of MRI lesion location for application to diagnostic criteria can contribute to misdiagnosis26. In this respect, our 2016 study supports two studies conducted in the UK45,46 in which practising neurologists were surveyed, and the results also indicate that misinterpretation and misapplication of current MS diagnostic criteria is a contemporary problem.
Towards improved diagnosis
A specific and sensitive biomarker that distinguishes MS from other diseases would help to prevent misdiagnosis. Numerous cerebrospinal fluid and serum biomarkers of MS have been investigated47,48,49,50, but a test with high specificity and sensitivity remains elusive. Many candidate biomarkers have only been investigated in cross-sectional studies in patients with confirmed diagnoses, rather than in prospective studies of patients undergoing evaluation for suspected MS. Furthermore, attempts to replicate results from promising biomarker studies, such as the recent interest in the potassium channel Kir4.1, have not been successful51,52,53. New candidate biomarkers, such as C-peptide binding to erythrocytes54, might have better specificity for MS, but require further validation and replication. The emerging understanding of the varied underlying genetics of MS55,56 associated with a variety of immunological processes might explain why identification of a single body fluid biomarker for MS has been challenging. For these reasons, emerging diagnostic methods that focus on non-coding RNA57,58,59,60 could ultimately be more successful.
Some evidence suggests that novel imaging techniques have greater specificity for a diagnosis of MS than do current MRI approaches. The relationship between MS lesions and veins has been recognized for over 50 years as a result of autopsy studies61, and in preliminary studies, fluid-attenuated inversion recovery (FLAIR) MRI has revealed this relationship in vivo, demonstrating that the presence of the so-called central vein sign has promising specificity for MS62. Similarly, although cortical lesions are a long-recognized aspect of MS pathology, the sensitivity of conventional MRI for the visualization of such lesions continues to present methodological challenges63. Nevertheless, detection of cortical lesions by a variety of methods might differentiate MS from its common mimics64,65, and the incorporation of cortical lesions into MS diagnostic criteria could improve specificity66. Volumetric imaging might also aid diagnosis of MS: thalamic atrophy in particular has been identified early in the disease course of MS67,68,69, and several studies have suggested that MRI assessment of thalamic volume differentiates MS from other disorders that can mimic MS70,71,72. As is the case for candidate fluid biomarkers of MS, thresholds for diagnostic accuracy of these imaging markers have not been validated or replicated in larger cohorts, and further studies in prospective cohorts undergoing evaluation for MS are needed to determine the potential of these MRI methods to improve MS diagnosis. Ultimately, an approach to diagnosis that combines several clinically applicable laboratory and imaging methods might have greater sensitivity and specificity for MS than any candidate method alone. This multimodal methodology has shown promise in other neurological diseases73.
Until a highly accurate approach for the diagnosis of MS has been developed sufficiently for clinical use in the wide spectrum of patients who are evaluated for suspected MS, practical clinical interventions might help to prevent misdiagnosis. Such interventions should include education for physicians in the appropriate use of current MS diagnostic criteria45,46.
The problem of delayed diagnosis
The contemporary data concerning MS misdiagnosis suggest that careful deliberation and monitoring is prudent when considering a new diagnosis of MS, but delays in the diagnosis and treatment of patients who do have MS remain a considerable and well-documented problem with important consequences13,74,75,76,77,78,79. MS is an inflammatory and neurodegenerative disease, and inflammation, which manifests as relapses and acute gadolinium-enhancing MRI lesions, occurs more frequently in younger patients80,81,82. Early inflammatory activity might have a profound impact on the risk of developing early and late disability, and might be a risk factor for early transition into the progressive phase of the illness83,84.
Since 1993, over a dozen DMTs that alter the natural history of MS have been approved for use in the USA and around the world; these therapies reduce inflammatory activity and the associated disability that is seen early in the course of MS85. Subgroup analyses of many pivotal trials of DMTs strongly suggest that the greatest benefit of these therapies is observed in younger patients with the highest risk of ongoing inflammatory disease activity86,87,88,89,90,91,92,93.
Studies have also suggested long-term benefits of treatment that is started early in the course of MS94. For example, a 2012 follow-up study of an early pivotal trial of IFNβ1b revealed that patients who were treated with this DMT were significantly more likely to be alive after a median of 21 years than were patients who were treated initially with placebo and received the DMT later95. Furthermore, numerous studies demonstrate that DMTs prevent future disability in patients with CIS14, suggesting that treatment should be considered even in patients who have not yet met the diagnostic criteria for MS but who present with syndromes that are typical of demyelination and are, consequently, at high risk of developing MS. In one of these trials, participants with CIS who received a placebo for up to 2 years rather than treatment with IFNβ1b had poorer clinical outcomes, even at 11 years after the start of the study96. Accordingly, the first clinical trial to evaluate the benefit of DMT in patients with presumed presymptomatic MS (that is, RIS) is ongoing97.
Consequences of MS misdiagnosis
The growing body of data that support an early treatment window for the prevention of disability in MS13 has the potential to put pressure on physicians to make prompt therapeutic decisions in patients for whom the diagnosis is uncertain. As a result, patients who are misdiagnosed with MS are often unnecessarily exposed to DMTs that are associated with severe and long-term risks, including serious opportunistic infections, the development of other autoimmune conditions, and cancers98,99,100,101,102.
In our 2016 study26, 70% of the patients who had been misdiagnosed with MS had received one or more DMTs, and one-third had received such therapies for 10 years or longer. Of the patients who had received DMT, 24% were exposed to therapy with a known risk of progressive multifocal leukoencephalopathy (PML), an infection that is often fatal. One-third of all the patients who were misdiagnosed had experienced at least one morbidity as a result of their misdiagnosis, and many of these morbidities were related to DMTs for MS. Misdiagnosis was associated with the death of one patient who received inadequate treatment for NMOSD; this death highlights the particular importance of misdiagnosis in patients with NMOSD, as the use of MS DMTs to treat NMOSD is not only inadequate but can also increase the risk of relapses103,104,105,106.
In our study26, four patients (4%) who had been incorrectly diagnosed with MS had participated in a clinical trial of investigational MS therapies. This observation not only raises serious concerns about the exposure of these patients to unnecessary risks, but also raises the possibility that the inclusion of sufficient numbers of misdiagnosed patients in clinical trials could have an impact on the apparent efficacy observed. Similar concern is raised by a report of a post-mortem evaluation of the optic nerve, spine and brain from one of the first patients to die from natalizumab-associated PML, in which extensive examination failed to identify any MS lesions107.
In addition to medical risks, the use of DMTs in misdiagnosed patients is associated with great financial costs. Since 2002, the Wholesale Acquisition Costs (WAC) of new and old DMTs have escalated dramatically108. In 2017, the WAC for nine DMTs is greater than US$80,000 per year, and the WAC of a generic equivalent of glatiramer acetate is $63,193 (Ref. 109). Consequently, if 300,000 people in the USA receive DMTs — a reasonable supposition given that an estimated 400,000 people have MS — at a cost of $85,000 per year, the US market alone would be $25.5 billion per year. Furthermore, DMTs are often taken for decades, as minimal data are available to define a point at which discontinuation might reasonably be considered110. The large cohort of misdiagnosed patients identified in a relatively short period of time in our 2016 study24 suggests that the scope of the problem has substantial consequences for our health-care systems as well as for individual patients.
The tension between efforts to diagnose and treat MS early and the potential for misdiagnosis of MS is a pressing problem in MS care. In the frequent clinical encounters with patients who present with abnormal brain MRI and unexplained neurological symptoms, the perceived urgency to confirm a diagnosis of MS to enable early initiation of treatment can lead physicians to make a presumptive diagnosis of MS, rather than making the more prudent decision to pursue further evaluation or clinical and radiographic monitoring over time. The reluctance to watch and wait, so as to either confirm a diagnosis of MS or identify an alternative diagnosis, might result in misdiagnosis and unnecessary exposure of patients to the risks associated with MS DMTs18,26. Several studies have confirmed that for patients who present without a clinical history or neurological deficit that is characteristic of MS, a subsequent diagnosis of MS is unlikely43,111,112. In many such cases, strict adherence to MS diagnostic criteria and further evaluation — including spinal cord imaging, cerebrospinal fluid evaluation and continued clinical or radiographic monitoring — is likely to clarify the diagnosis, thereby avoiding misdiagnosis and unnecessary, expensive, and potentially harmful treatment. Contemporary studies that use rigorous methodology16 to determine the incidence of MS misdiagnosis are lacking. Such data would improve insight into the scope and impact of the problem, and might suggest approaches that would improve diagnosis of MS while preventing its misdiagnosis.
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A.J.S. acknowledges funding support from the National Multiple Sclerosis Society, the University of Vermont Department of Neurological Sciences, the University of Vermont Department of Radiology, the University of Vermont MRI Center for Biomedical Imaging, and the Intramural Research Program of the National Institute of Neurological Disorders and Stroke for research studies cited in this article. A.J.S. wishes to acknowledge Dr. Daniel S. Reich and the Translational Neuroradiology Section, Division of Neuroimmunology and Neurovirology, National Institute of Neurological Disorders and Stroke for support and collaboration.
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Nature Reviews Neurology (2018)