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A New Guide to the Differential Diagnosis of Multiple Sclerosis

Updated consensus approach helps clinicians efficiently improve diagnostic accuracy

photo of doctor performing neurologic exam on a patient

While the differential diagnosis of multiple sclerosis (MS) is extremely broad, not all possibilities need to be considered for every patient who presents with symptoms suspicious of the disease. Instead, clinicians must be vigilant to clinical, laboratory and imaging “red flags” of conditions that mimic MS to guide the investigation.


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So urges the Multiple Sclerosis Differential Diagnosis Consortium, an international group organized by the Americas Committee for Treatment and Research in Multiple Sclerosis (ACTRIMS) in collaboration with the International Advisory Committee on Clinical Trials in Multiple Sclerosis (sponsored by the National Multiple Sclerosis Society and the European Committee for Treatment and Research in Multiple Sclerosis [ECTRIMS]), the Consortium of Multiple Sclerosis Centers, and the Multiple Sclerosis International Federation. Their updated consensus approach to the differential diagnosis of MS was published as a “Personal View” article in Lancet Neurology (2023;22[8]:750-768).

“Key to diagnosing MS is confirming that there is no better explanation for the patient’s presentation,” says consortium co-chair and senior author Jeffrey Cohen, MD, Director of the Experimental Therapeutics Program for Cleveland Clinic’s Mellen Center for Multiple Sclerosis Treatment and Research. “Other relevant conditions must be ruled out in a targeted fashion.”

Dr. Cohen also authored a commentary in the Multiple Sclerosis Journal on the updated consensus approach.

Diagnosing MS: Not always straightforward

The McDonald criteria are still essential for diagnosing MS, but they are most useful in cases with a clinical picture that is highly likely to be MS. With their 2017 revision, the criteria became more sensitive, allowing for earlier diagnosis, but at the expense of reduced specificity, Dr. Cohen explains. He adds that despite recent advances in MS diagnosis, the disease is misdiagnosed up to 40% of the time, even at MS centers.

“The McDonald criteria guide clinicians on making a diagnosis but do not show how to rule out other conditions that mimic MS,” Dr. Cohen says. “The consensus approach addresses that gap.”

The consensus approach update comprehensively covers the differential diagnosis of typical acute presentations of MS ― including optic neuritis, brainstem and cerebellar syndromes, myelitis and supratentorial syndromes ― with detailed tables of features to help make the correct diagnosis. Red flags from imaging and laboratory findings and from clinical signs and symptoms are listed, along with alternate diagnoses suggested by those red flags.

In addition to extensive information on patients who present with a clinically isolated syndrome, the publication includes guidance on the differential diagnosis of progressive neurological syndromes that could be mistaken for primary progressive MS or secondary progressive MS with a previously unrecognized relapsing course.

What’s new in MS diagnosis?

The current consensus approach is an update of a 2008 publication from the International Advisory Committee on Clinical Trials in Multiple Sclerosis led by Miller and colleagues. Since then, the field has expanded substantially, with better information from laboratory, imaging and clinical areas. Updates on the diagnostic approaches and specific red flags indicating potential alternate diagnoses are provided throughout the document.


In recent years, greater knowledge has emerged of central nervous system neuroinflammatory disorders such as myelin oligodendrocyte glycoprotein (MOG) antibody-associated disease (MOGAD) and aquaporin-4 (AQP4) antibody-positive neuromyelitis optica spectrum disorder (NMOSD, or Devic’s disease) and how to differentiate them from MS. The consensus approach recommends testing for AQP4-IgG or MOG-IgG before starting immunomodulatory or immunosuppressive drugs in certain cases. The diagnosis of MOGAD should be especially considered in children younger than 11 years old, and NMOSD in Black patients and those of East Asian ancestry who have a clinical picture consistent with these conditions.

Dr. Cohen notes that the McDonald criteria may be modified in the future to include patients with a so-called radiologically isolated syndrome, i.e., MRI findings characteristic of MS but without clinical features, as well as patients with nonspecific symptoms of MS, which may be a prodromal state. If this occurs, using the consensus approach will be even more important, he says, as the risk of misdiagnosis will likely increase.

Consortium continues to hone diagnostic process

Dr. Cohen also emphasizes that the differential diagnosis of MS varies by demographics, with special considerations for age (particularly pediatric populations and those older than 50); geographic residence, genetic ancestry and travel history; and social determinants of health, such as race and socioeconomic factors. These major areas are being systematically reviewed by subcommittees of the MS Differential Diagnosis Consortium, and reports on these topics are expected to be published over the next year.

Specific diagnostic markers for MS represent an important unmet need and active area of research, according to Dr. Cohen. Promising possibilities for improving MS diagnosis include the presence of free kappa light chains in cerebrospinal fluid, other fluid biomarkers, and the central vein sign and paramagnetic rim lesions on MRI.

“Clinical acumen when assessing a patient with suspected MS is still of utmost importance,” Dr. Cohen concludes. “It sometimes can be a challenging disease to diagnose, even for MS experts.”


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