The contemporary spectrum of multiple sclerosis misdiagnosis
A multicenter study
Abstract
Objective:
To characterize patients misdiagnosed with multiple sclerosis (MS).
Methods:
Neurologists at 4 academic MS centers submitted data on patients determined to have been misdiagnosed with MS.
Results:
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.
Conclusions:
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.
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© 2016 American Academy of Neurology.
Publication History
Received: January 28, 2016
Accepted: June 9, 2016
Published online: August 31, 2016
Published in print: September 27, 2016
Disclosure
A. Solomon reports no disclosures relevant to the manuscript. D. Bourdette reports section editor Current Neurology and Neuroscience. A. Cross reports consulting for AbbVie, Biogen EMD Serono, Novartis, Mallinckrodt, Teva, Roche/Genentech, Genzyme/Sanofi; Scientific Advisory Board: Roche, Associate editor for Annals of Clinical and Translational Neurology; Research support: Biogen and Teva. A. Applebee, P. Skidd, and D. Howard report no disclosures relevant to the manuscript. R. Spain reports funding from the Conrad Hilton Foundation. M. Cameron reports consulting for Acorda therapeutics, MD consult, and ReWalk. E. Kim reports serving on advisory boards of Teva and Genzyme. M. Mass reports no disclosures relevant to the manuscript. V. Yadav reports consult for Biogen Idec and serving on an advisory board for Genentech. R. Whitham reports serving on a data safety monitoring board for a clinical trial sponsored by Chugai Pharmaceutical. E. Longbrake reports speaking and consulting for Genzyme. R. Naismith reports speaking for Acorda, Biogen, and Genzyme and consulting for Acorda, Alkermes, Biogen, EMD Serono, Genentech, Genzyme, Novartis, Pfizer, Questcor. G. Wu reports serving on an advisory board for Biogen Idec and speaking for Pfizer. B. Parks reports consulting for Biogen Idec and Novartis, serving on an advisory board, and holding stock or stock options greater than 5% of the company or greater than $10,000 in value (Regeneron). D. Wingerchuk reports serving on a clinical trial adjudication panel for MedImmune, research support from Alexion and TerumoBCT, and compensation for serving as editor in chief of The Neurologist. B. Rabin, M. Toledano, W. Oliver Tobin, and O. Kantarci report no disclosures relevant to the manuscript. J. Carter reports serving on the data safety and monitoring committee for Alder Pharmaceuticals, compensation for developing a drug treatment monograph for Omnicare/USciences, and research support from Roche, Sanofi, and Genzyme. B. Mark Keegan reports consulting for Novartis, Bionest, and Bristol-Myers Squibb and receives research support from Caridian BCT. B. Weinshenker reports data safety monitoring board membership for Novartis and Mitsubishi and MedImmune for adjudication committee membership. He reports for travel to attend an EMA conference supported by Alexion and royalties from RSR Ltd. and from Oxford University for patent for neuromyelitis optica IgG for diagnosis of neuromyelitis optica. Go to Neurology.org for full disclosures.
Study Funding
National Multiple Sclerosis Society PP2074. Anne H. Cross was supported in part by the Manny and Rosalyn Rosenthal–Dr. John L. Trotter MS Center Chair from the Barnes-Jewish Hospital Foundation.
Authors
Author Contributions
Andrew J. Solomon, MD: conceptualization and study design, analysis and interpretation of the data, and drafting of the manuscript for intellectual content. Dennis N. Bourdette, MD: conceptualization and study design, analysis and interpretation of the data, and drafting of the manuscript for intellectual content. Anne H. Cross, MD: conceptualization and study design, analysis and interpretation of the data, and drafting of the manuscript for intellectual content. Angela Applebee, MD: analysis and interpretation of the data, and drafting of the manuscript for intellectual content. Philip M. Skidd, MD: analysis and interpretation of the data, and drafting of the manuscript for intellectual content. Diantha B. Howard, MA: conceptualization and study design, analysis and interpretation of the data. Rebecca I. Spain, MD: analysis and interpretation of the data, and drafting of the manuscript for intellectual content. Michelle H. Cameron, MD: analysis and interpretation of the data, and drafting of the manuscript for intellectual content. Edward Kim, MD: analysis and interpretation of the data, and drafting of the manuscript for intellectual content. Michele K. Mass, MD: analysis and interpretation of the data, and drafting of the manuscript for intellectual content. Vijayshree Yadav, MD: analysis and interpretation of the data, and drafting of the manuscript for intellectual content. Ruth H. Whitham, MD: analysis and interpretation of the data, and drafting of the manuscript for intellectual content. Erin E. Longbrake, MD, PhD: analysis and interpretation of the data, and drafting of the manuscript for intellectual content. Robert T. Naismith, MD: analysis and interpretation of the data, and drafting of the manuscript for intellectual content. Gregory F. Wu, MD, PhD: analysis and interpretation of the data, and drafting of the manuscript for intellectual content. Becky J. Parks, MD: analysis and interpretation of the data, and drafting of the manuscript for intellectual content. Dean M. Wingerchuk, MD: analysis and interpretation of the data, and drafting of the manuscript for intellectual content. Brian L. Rabin, MD: analysis and interpretation of the data, and drafting of the manuscript for intellectual content. Michel Toledano, MD: analysis and interpretation of the data, and drafting of the manuscript for intellectual content. W. Oliver Tobin, MBBCh, PhD: analysis and interpretation of the data, and drafting of the manuscript for intellectual content. Orhun H. Kantarci, MD: analysis and interpretation of the data, and drafting of the manuscript for intellectual content. Jonathan L. Carter, MD: analysis and interpretation of the data, and drafting of the manuscript for intellectual content. B. Mark Keegan, MD: analysis and interpretation of the data, and drafting of the manuscript for intellectual content. Brian G. Weinshenker, MD: conceptualization and study design, analysis and interpretation of the data, and drafting of the manuscript for intellectual content.
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We appreciate the comments of Dalla Costa et al. on our Contemproary 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 two errors fuel 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.
1. Solomon AJ, Bourdette DN, Cross AH, et al. The contemporary spectrum of multiple sclerosis misdiagnosis: A multicenter study. Neurology 2016;87:1393-1399.
For disclosures, please contact the editorial office at [email protected].
We read with interest the multicenter observational study by Solomon et al. which assessed the prevalence and possible causes of multiple sclerosis (MS) misdiagnosis. [1] We are concerned about the interpretation of the results and the assertion of the conclusion that misinterpretation and misapplication of MS criteria are significant contemporary contributors to misdiagnosis.
In the study, patients previously informed of a MS diagnosis were included, [1] but the number of patients screened, the baseline clinical and paraclinical characteristics of the misdiagnosed patients, and the fulfilled MS criteria through which the diagnosis was made were not specified. Therefore, the frequency of MS misdiagnosis is not clear, including whether clinical practice misdiagnosis is mainly caused by misapplication of criteria due to lack of a comprehensive work-up excluding different diagnoses, or to poor performance of the MS criteria in atypical forms of MS. [2] In any case, Solomon et al. must be acknowledged for great efforts in recruiting a large population of misdiagnosed patients, highlighting the importance of a comprehensive clinical and paraclinical assessment for risk stratification of the patient, and a more accurate and personalized risk management of MS.
1. Solomon AJ, Bourdette DN, Cross AH, et al. The contemporary spectrum of multiple sclerosis misdiagnosis: A multicenter study. Neurology 2016;87:1393-1399.
2. Kim SS, Richman DP, Johnson WO, Hald JK, Agius MA. Limited utility of current MRI criteria for distinguishing multiple sclerosis from common mimickers: primary and secondary CNS vasculitis, lupus and Sjogren's syndrome. Mult Scler 2014;20:57-63.
For disclosures, please contact the editorial office at [email protected].