Paper #1 - "Better explanations" in multiple sclerosis diagnostic workup:
A 3-year longitudinal study.
Calabrese M, Gasperini C, Tortorella C, Schiavi G, Frisullo G, Ragonese P, Fantozzi R, Prosperini L, Annovazzi P, Cordioli C, Di Filippo M, Ferraro D, Gajofatto A, Malucchi S, Lo Fermo S, De Luca G, Stromillo ML, Cocco E, Gallo A, Paolicelli D, Lanzillo R, Tomassini V, Pesci I, Rodegher ME, Solaro C, group R.
Neurology. 2019;92:e2527-e37.
Paper #2 - Incidence of multiple sclerosis misdiagnoses in referrals to two academic centers
Marwa Kaisey, MD, Andrew J. Solomon, MD, Michael Luu, MPH, Barbara S. Giesser, MD, Nancy L. Sicotte, MD
Multiple Sclerosis and Related Disorders
May 2019; Volume 30, Pages 51–56
Key Points:
1. Criteria for making a diagnosis of MS have changed greatly in the past several decades.
2. The most recent criteria were published in 2017. They emphasized the need to show disease activity in different parts of the central nervous system occurring over different periods of time periods (so called “dissemination in time and space”). They also emphasized the importance of having “typical” changes on central nervous system MRIs and to have evidence of central nervous system inflammation in the spinal fluid (“oligoclonal bands of antibodies”).
3. None of the symptoms or signs of MS are only found in MS. Thus, it is essential to exclude other diseases that may mimic MS.
4. Two recent articles from MS specialty centers examined the accuracy of an MS diagnosis on patients referred to them for a second opinion. The first study involved patients referred to 22 specialized MS center in Italy. The second study evaluated patients referred to two MS centers in the United States.
5. A total of nine hundred thirty six patients were studied. Using the criteria for diagnosis noted above, both groups reported very similar findings.
6. Alternative, non-MS diagnoses were made in 163 of 667 (24.4%)
patients in the first study and 18% of the 241 new patients in the second study.
7. The most frequent alternative diagnoses in Paper #1 were nonspecific neurologic symptoms in association with atypical brain MRI lesions of suspected vascular origin (40 patients), migraine with atypical lesions (24 patients), and neuromyelitis optica spectrum disorder (14 patients). In Paper #1 MS was diagnosed in 401 (60.1%) patients according to the 2017 diagnostic criteria. However, even with three years of follow-up, no diagnosis could be made in 15% of the referred patients.
8. In Paper #2,the most common alternative diagnoses were migraine (16%), typical MS-like lesions on central nervous system MRIs but without any symptoms and a normal exam, a condition erroneously named “radiologically isolated syndrome” (9%), abnormality of the boney vertebrae affecting the spinal cord (“spondylopathy” - 7%), and changes in the peripheral nerves (“neuropathy” in 7%). Unfortunately, MS was also diagnosed in persons with clinical symptoms and MRI findings atypical for MS.
9. Both papers noted “red flags” that should make one suspect a diagnosis other than MS. These included the absence of oligoclonal antibody bands in the spinal fluid, the presence of MRI lesions atypical for MS, the absence of dissemination of lesions in different regions of the central nervous system (“dissemination in space”), and normal optic nerve tests.
10.Most distressingly, in Paper #2, the misdiagnosed group received approximately 110 patient-years of unnecessary, potentially toxic MS disease-modifying therapies. Unfortunately, no data were presented in Paper #1 on the numbers of persons inappropriately treated with disease-modifying therapies.
11. The bottom line: New diagnostic criteria for MS have allowed larger numbers of persons to be diagnosed with MS earlier in its course. However, lack of understanding, and misinterpretation of findings by healthcare providers still leads to high percentage of persons being misdiagnosed and inappropriately treated. Obtaining a second opinion from an MS specialty center from healthcare providers specializing in MS will reduce the frequency of misdiagnosis.
In the mid-20th century the diagnosis of MS was based almost entirely on clinical grounds. Persons who had multiple episodes of symptoms suggestive of central nervous system dysfunction and who had findings on neurologic exam supporting central nervous system dysfunction, with no other apparent cause present, were diagnosed with MS. In the subsequent 70-odd years showing inflammation in the spinal fluid and demonstrating lesions in the brain and spinal cord with MRIs have greatly increased the accuracy of diagnosing MS. Nevertheless, unlike diseases such as cancer and diabetes, there is no specific test that is unique, or only found in persons with MS. Thus, a diagnosis of MS must be based on, first, excluding “MS look-alikes”, then establishing that symptoms, signs, and laboratory findings are compatible with a progressive central nervous system disease involving multiple areas of the brain and spinal cord that changes over time.
Unfortunately, with the advent of increasingly sensitive tests, lesions are now being seen in the brain and spinal cord resulting from causes other than inflammation. These include changes due due to blood vessels, changes occurring in migraine, and changes that occur just as a result of aging. This has led to the an increasing number of persons to be diagnosed with MS based on symptoms that may occur with the disease, but with either no, or atypical findings on physical exam and no signs of inflammation in their spinal fluids. While persons with eventually proven MS may have normal exams and normal spinal fluids, the two studies noted above indicate that absence of such changes greatly reduces the probabilities of a person having MS. Unfortunately, due to health provider inexperience, at discussed in Paper #2, persons misdiagnosed with MS are often placed on disease-modifying therapies, therapies that are not only expensive, but can result in significant, and even fatal side effects.
Given the complexity of making a diagnosis of MS, I would strongly urge all persons newly diagnosed with MS, or those in whom the diagnosis is “uncertain,” to have an evaluation by a neurologist specializing in the treatment and diagnosis of MS, at an established, approved MS specialty clinic.
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