International Group Updates Guidelines on Differential Diagnosis of Potential MS

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The International Advisory Committee on Clinical Trials in Multiple Sclerosis updated their guidelines on differential diagnosis of potential MS.

The International Advisory Committee on Clinical Trials in Multiple Sclerosis released an update to their 2008 guidelines1 on diagnosing multiple sclerosis (MS) from potential mimics. The guide, developed by experts in the field of MS and neuroimmunology, provides neurologists with clarity on the diagnostic processes for MS by identifying red flags that could be suggestive of an alternative diagnosis. The group published its updated consensus recommendations for differential diagnosis of potential MS in the journal Lancet Neurology2.

New information on inflammatory neurologic diseases such as neuromyelitis optica spectrum disorder (NMOSD) and myelin oligodendrocyte glycoprotein antibody-associated disease (MOGAD) has emerged in the years since the 2008 recommendations were published. In addition, laboratory and radiologic diagnostics, and clinical testing, have continued to advance. These changes prompted this update to the 2008 consensus paper.

The consortium, led by the Americas Committee for Treatment and Research in Multiple Sclerosis (ACTRIMS), reviewed 476 relevant studies published after 2008 as part of this guideline update.

Screening for Clinical Presentations of MS

The recommendations are organized chiefly by high-level aspects of clinical presentation, ie, optic neuritis, myelitis, cerebellar and supratentorial syndromes, and progressive symptoms beyond 1 year.

[D]ata from large prospective multicentre cohorts of patients undergoing evaluation for suspected multiple sclerosis will be necessary to confirm the promise of putative biomarkers to complement clinical approaches…

This categorization supports the approach of localizing lesions in suspected relapsing-remitting or primary progressive MS. Within those sections, clinical and paraclinical considerations are treated separately.

Signs Typical vs Atypical of MS

Within the guideline, extensive tables list both clinical and paraclinical presenting features, along with the alternative diagnoses that could be considered for each feature. However, the listed features are not numerically scored, as they were in the 2008 recommendations, according to how strongly they suggest diagnoses other than MS. Graphical displays compare signs strongly associated with MS to those atypical of MS; these are subdivided into clinical, laboratory, and radiologic categories.

Blood and Cerebrospinal Fluid Evaluation

The authors recommend in particular that blood testing be focused in accordance with clinical and other paraclinical findings, rather than in overly broad laboratory panels that may accrue false positives or spur unnecessary investigations.

Diagnostic Considerations in Specific Patient Populations

Diagnostic considerations for patients of different ages, from different racial and ethnic groups, and in different geographic regions should be explored. The authors allude here to topics treated in recent research, including

  • ruling out MOGAD and genetic disorders in children;
  • consideration of diagnoses specific to adults older than age 50;
  • the relatively high prevalence of NMOSD in Asian and Black populations, and that of neurosarcoidosis in Black patients;
  • the ethnicity-specific prevalence of cerebrospinal fluid (CSF) oligoclonal bands; and
  • the geographic distribution of some infectious, inflammatory, and nutritional diseases.

The Challenges of Prodromal or Nonspecific Presentations

There are contrasting challenges of prodromal or nonspecific presentations, and suggestive radiographic presentations without clinical features sufficient to support a firm MS diagnosis.

The authors questioned whether such diagnostic conundrums justify more expansive definitions of MS in its clinical and radiologic spectrums. In support of this, the authors note that MS causes central nervous system (CNS) damage well before its signs and symptoms sufficiently clarify the diagnosis; and findings over 10 years in about half of patients with solely radiologic disease ultimately satisfy the full diagnostic criteria.

Similarly, findings associated with progressive solitary sclerosis may be strongly indicative of MS, without fulfilling its current criteria. The neurologist may well consider whether such presentations warrant presumptive impression of MS, yet still must evaluate and exclude diagnostic alternatives with care.

The Search for Novel Diagnostic Tools for MS, Mimics

The search for novel diagnostic tools for MS and its mimics must continue, according to the authors. These will likely include CSF biomarkers and magnetic resonance imaging (MRI) findings, as well as application of artificial intelligence (AI) to imaging studies. However, the fundamental, time-tested approach to differential diagnosis remains the same. The authors wrote, “[D]ata from large prospective multicentre cohorts of patients undergoing evaluation for suspected multiple sclerosis will be necessary to confirm the promise of putative biomarkers to complement clinical approaches to ensure that there is no better explanation other than multiple sclerosis.”

Disclosures: Several study authors have declared affiliations with biotech, pharmaceutical, and/or device companies. Please see the original reference for a full list of the authors’ disclosures.

This article originally appeared on Neurology Advisor


  1. Miller D, Weinshenker B, Filippi M, et al. Differential diagnosis of suspected multiple sclerosis: a consensus approach. Mult Scler J. Published online September 19, 2008. doi:10.1177/1352458508096878
  2. Solomon AJ, Arrambide G, Brownlee WJ, et al. Differential diagnosis of suspected multiple sclerosis: an updated consensus approach. Lancet Neurol. 2023;22(8):750-768. doi:10.1016/S1474-4422(23)00148-5