Understanding Misdiagnoses in MS: Copycat Conditions, Testing Barriers, and More

As research in multiple sclerosis (MS) has advanced, one of the pressing challenges facing researchers, clinicians, and patients is the chance of a misdiagnosis. A multitude of factors contribute to this issue including obstacles in testing, copycat conditions, and the downplaying of symptoms. Educating on the risk factors, early signs to look for, potential masquerading diseases, and diagnostic hurdles is an avenue for combating the problems in MS that current research cannot yet address.

The early symptoms of MS can be easily confused for other conditions, downplayed as less serious when they appear mild, and may vary uniquely from patient to patient. The fact that each patient experiences MS in a different way is one of the primary obstacles in efficient diagnoses. These signs range in severity:

Doctor evaluating MRI for MS diagnosis | image credit: shidlovski - stock.adobe.com

• Weakness or fatigue
• Vision issues (double vision, blurriness, and more)
• Tingling or numb sensation
• Bladder issues (frequency, urgency, hesitancy, incontinence)
• Bowel movement issues (fecal incontinence, constipation)
• Muscle spasms
• Balance issues or dizziness
• Cognitive deficiencies (short-term memory issues, attention deficit, and more)
• Neuropathic pain (headache, paresthesia, allodynia, among others)¹

On the surface, some of these symptoms can easily be brushed off or misread as consequences of much milder conditions such as anemia, circulatory lapses, dietary regimens, and even common, treatable sexually transmitted infections. However, over time, these effects can manifest more severely, and individuals can experience MS attacks that involve high-grade fevers, vision loss, intense pain, and sudden loss of limb function or the ability to eat.¹

Identifying risk factors is another prominent challenge in MS. At present, the precise cause of MS and why some individuals are impacted while others are not fully understood. While researchers continually seek to holistically understand MS, current theories lean into the role of genetics, environmental factors, or exposure to certain infections that trigger genes associated with MS. Among these studies, for example, some research has begun suggesting that exposure to Epstein-Barr virus may be linked to later onset of MS.^1,2

Below, Marwa Kaisey, MD, assistant professor of neurology at Cedars-Sinai, and executive committee member of International Women in Multiple Sclerosis, contextualizes the primary barriers to an MS diagnosis including testing limitations, discusses research efforts to mitigate these hurdles, and provides some advice for individuals potentially enduring a misdiagnosis. In her reflections, she also details a prior study that found that around 18% of individuals with an MS diagnosis may not have the disease at all, and that these rates are most linked to atypical imaging or clinical findings.³

Misdiagnoses of MS can occur on both ends of the spectrum: Those with MS could have their condition misinterpreted as another, or those with other conditions could very well be incorrectly diagnosed with MS. The consequences of an MS diagnosis can drastically impact patient experiences and outcomes.

“MS misdiagnosis may increase morbidity as a result of psychological damage, risk associated with DMTs [disease-modifying therapy] and corticosteroids use, inadequate treatment, worsening of underlying disease such as in neuromyelitis optica spectrum disorders..., or delay in treatment of other potentially curable pathologies. Misdiagnosed patients are also sometimes included in clinical trials, which can confuse trial results and expose patients to inappropriate treatment. Other important point to consider is the economic impact of treating misdiagnosed patients, particularly in developing countries,” María Gaitán, MD, and Jorge Correale, MD, wrote in an opinion article published in Frontiers in Neurology in 2019.⁴ In their research on MS misdiagnoses, they found that half of misdiagnosed patients endure that mistake for at least 3 years, and that over two-thirds of these patients are administered DMT for a condition they did not have.⁴

Due to the broad range of symptoms accompanying MS, a plethora of disorders and diseases overlap with MS presentation, and vice versa. As indicated by Kaisey and colleagues writing in Multiple Sclerosis and Related Disorders, migraines are one of the most prevalent explanations in misdiagnoses. Several more serious realities, however, can complicate the diagnostic process. Chronic inflammatory diseases such as vasculitis or lupus have been confused with MS, as well as central nervous system (CNS) infections like syphilis and Lyme disease. Furthermore, with MS-like symptoms clinicians also need to consider the possibility of brain tumors or hereditary disorders. MS can even be misinterpreted as a vitamin B₁₂ deficiency.^1,3

As a result of all these possibilities, a successful MS diagnosis is generally a multifactorial process where multiple other conditions need to be ruled out. The use of MRI has been a useful tool for assessing patients; however, MRI scans can produce ambiguous results. Observed lesions, or white spots, that indicate CNS damage may point to MS, but MS is not the only disease that presents on an MRI in this fashion.¹

The McDonald Criteria, which are an established tool for MS diagnosis with the use of MRI, were updated in 2017 with the hope of reducing the time to diagnosis while also limiting misdiagnosis rates. To differentiate MS from other conditions, these guidelines state the need to look for CNS damage that exhibits dissemination in time and dissemination in space, meaning that the damage occurred in at least 2 different areas of the CNS in events separated by a minimum of 30 days. However, even with set diagnostic criteria, the lack of a definitive test for MS leaves lots of room for improvement in diagnostic procedures.⁵

Kaisey et al mentioned that there has been significant progress in the MS diagnostic realm through the identification of the central vein sign (CVS) profile. The CVS is an established biomarker that was reinforced in a study by Al-Louzi and colleagues published in March 2022. MRI scanning and observation of CVS characteristics in MS lesions led patients to discover that a higher CVS-positive percentage at baseline was linked to the development of new CVS-positive lesions. These findings represent a breakthrough in MS research, suggesting that utilizing CVS in patient MRIs can help distinguish between lesions caused by MS and those stemming from other causes.⁶

Amidst the challenges facing clinicians, researchers, and patients in MS, the recent innovation of the CVS biomarker represents a promising opportunity for scientific efforts to mitigate the impact of misdiagnoses in MS and fine-tune the diagnostic process.

References

1. Bergland C. Why is multiple sclerosis misdiagnosis so common? Verywell Health. September 10, 2023. Accessed December 21, 2023. https://www.verywellhealth.com/ms-misdiagnosis-5235314
2. Mullard A. The quest to prevent MS - and understand other post-viral diseases. Nature. 2022 Mar;603(7903):784-786. doi:10.1038/d41586-022-00808-x
3. Kaisey M, Solomon AJ, Luu M, Giesser BS, Sicotte NL. 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
4. Gaitán MI, Correale J. Multiple sclerosis misdiagnosis: a persistent problem to solve. Front Neurol. 2019;10:466. doi:10.3389/fneur.2019.00466
5. 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
6. Al-Louzi O, Letchuman V, Manukyan S, et al. Central vein sign profile of newly developing lesions in multiple sclerosis: a 3-year longitudinal study. Neurol Neuroimmunol Neuroinflamm. 2022;9(2):e1120. doi:10.1212/NXI.0000000000001120