Recognizing the Early Signs of Relapsing-Remitting MS Progression

Demyelinated nerve. Coloured transmission electron micrograph (TEM) of a section through an axon (a structure that transmits nerve impulses) that has lost its myelin sheath. The axon (purple center) has only bits of its Schwann cell (pale blue) surrounding it. The Schwann cell would normally produce the myelin sheath (dark blue) as seen in the two smaller axons. A nerve’s myelin sheath helps it conduct electrical impulses and when the myelin sheath is lost, nerve function is impaired. This is seen in nerve disorders such as multiple sclerosis (MS), where patches (lesions) of myelin sheath are destroyed. Magnification: x 3000 when printed at 10 centimetres wide.
A combination of clinical, imaging, and neuropsychological examinations may aid in MS disease progression prognostication.

Due to its heterogeneous presentation, multiple sclerosis (MS) can be challenging to diagnose. Arriving at a correct, timely diagnosis is critical because early treatment with disease-modifying therapy can slow the progression of the condition.1 Even more difficult is determining when patients will experience progression from relapsing-remitting MS (RRMS) to secondary progressive MS (SPMS). The rush to diagnose, however, may result in a misdiagnosis because no definitive diagnostic test or clinical feature exists for MS.2

Arriving at the Correct Diagnosis the First Time

To address the need for improved diagnostic accuracy, in 2017 an international panel of experts sponsored by the US National Multiple Sclerosis Society and the European Committee for Treatment and Research in Multiple Sclerosis revised the 2010 McDonald criteria for diagnosing MS. Previous criteria incorporated patient data from mostly Western countries.2

Highlights of the revised criteria for diagnosing MS include:

  • Specific clinical findings
  • Brain and spinal cord magnetic resonance imaging (MRI)
  • History of attacks
  • Cerebrospinal fluid (CSF) examination

“The McDonald criteria are intended to support early but accurate diagnosis of MS at the beginning of the disease, which usually is 10 to 15 years before people with MS start to evolve from a relapsing-remitting course to a secondary progressive course,” said Jeffrey Cohen, MD, director of the experimental therapeutics program at the Mellen Center for Multiple Sclerosis Treatment and Research at the Cleveland Clinic in Ohio.  “The McDonald criteria are not directly related to determining whether the transition is starting to occur, but they are indirectly relevant in that a correct diagnosis of MS is the first step.”

Why Identifying Early Signs of RRMS Progression Remains Difficult

Approximately 30 years after diagnosis of RRMS, 65% to 90% of patients will transition to SPMS.3 The classic definition of SPMS is deterioration independent of relapses for ≥6 months. As a result, this transition can usher in anxiety and depression, and can negatively affect quality of life.3 To better understand patients’ perspectives during this time, researchers conducted semistructured interviews in 9 patients with MS and 7 MS specialists.3 Both patients and health professionals stated the need for greater education about the transition to SPMS. Patients emphasized that clinicians needed to be sensitive about the reclassification of MS, and they felt that more information on this transition would help clinicians become more empathic.3

Patients stated that education about the possible subtle nature of functional decline, such as noticing tasks they could no longer perform, could inform clinical decisions.3 Only in retrospect did patients acknowledge that had they been instructed as to what signs to notice, they could have alerted their providers of disease progression sooner. Clinicians, too, admitted that they had difficulty reclassifying patients with a diagnosis of SPMS because they disliked delivering negative news.3

Notable Risk Factors for Early RRMS Progression

In addition to monitoring for specific symptoms and relapses, Scalfari and colleagues sought to characterize patients with RRMS who would transition to SPMS.4 In a study of 806 patients with RRMS (76.5% women) and SPMS (64.8% women), the researchers found that risk factors that signaled early transition to SPMS included:

  • Male sex
  • Older age at disease onset
  • High frequency of early relapse

Patients who had more than 3 attacks early in their disease and also had cerebellar and brainstem symptoms were also more likely to progress earlier to SPMS than patients with RRMS without these findings.4 The median time to a diagnosis of SPMS in the study was 15 years.4

Imaging May Detect Deterioration Before Symptoms Appear

Imaging may detect focal white matter brain lesions that some researchers have deemed “silent progression,” referring to the insidious nature of the subtleties of decline in RRMS.5

Recognizing the potential of imaging for discovering subclinical signs of early disease progression, a group of MS specialists revised the imaging guidelines.6 Using specific criteria for MRI of the brain, the consensus concluded that clinicians could detect early signs of MS progression in certain brain regions before patients were aware of increasing disability.6 By conducting imaging studies of the brain every 6 months to 2 years in patients with RRMS, clinicians could alert patients to impending decline.6

Cognitive Impairment Points to MS Disease Progression

Research has suggested that cognitive impairment could help clinicians determine which patients with MS are at risk for early disability.7 In an 8-year longitudinal study of 78 patients (64% women) with RRMS, the presence of cognitive impairment at initial diagnosis was found to be a predictor of disability progression.7

At baseline, patients were evaluated with an MRI and a neuropsychological examination and underwent clinical examination every 6 months. Patients completed a series of cognitive tests — including verbal learning, delayed memory recall, semantic verbal fluency, and visuospatial learning — to measure cognitive impairment. Scoring below the fifth percentile in one of the tests of Brief Repeatable Battery (BRB) was considered a marker of greater decline. Imaging studies measured the extent of cortical thinning, which was also used as a marker of cognitive impairment.7

“MRI remains an impressive tool to monitor the neurodegeneration which, more than the demyelination, drives the evolution toward the progressive phase of the disease,” explained study co-author Massimiliano Calabrese, MD, professor of neurology at the University Hospital of Verona in Italy. “More recently, our research group has pointed out the relationship between the inflammatory profile of cerebrospinal fluid and the risk of evolving into the progressive phase. The analysis of this profile already at the time of diagnosis might shed some light on the future of each patient, at a time when all treatments are most effective.”

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Digital Tool Prompts Patient-Clinician Discussion

One way clinicians are attempting to stay ahead of disease progression is to ask patients about the most subtle of symptoms.8 As such, a team of researchers led by Tjalf Ziemssen, MD, professor of clinical neuroscience and head of the Multiple Sclerosis Center and Neuroimmunological Laboratory at the University Clinic Carl-Gustav Carus in Dresden, Germany, has developed the MSProDiscuss, a digital tool that prompts clinicians to ask patients about their MS symptoms.8

In a multinational study of patients with RRMS (n=89), SPMS (n=62), and those in transition (n=47), the tool demonstrated a sensitivity of 80% and a specificity of 86% in differentiating RRMS from SPMS.8

“Optimizing therapy early is critical for a better long-term outcome in MS, and transition from RRMS to SPMS is a key determinant for long-term disease prognosis,” said Dr Ziemssen. “MSProDiscuss aims to make clinicians more aware of early subtle signs indicative of silent progression, beyond the clinically most obvious impairment of lower limb function.”


1. Katz Sand I, Krieger S, Farrell C, Miller AE. Diagnostic uncertainty during the transition to secondary progressive multiple sclerosis. Mult Scler. 2014;20(12):1654-1657. doi:10.1177/1352458514521517

2. Thompson AJ, Banwell BL, Barkhof F, et al. Diagnosis of multiple sclerosis: 2017 revisions of the McDonald criteria. Lancet Neurol. 2018;17(2):162-173. doi:10.1016/S1474-4422(17)30470-2

3. O’Loughlin E, Hourihan S, Chataway J, Playford ED, Riazi A. The experience of transitioning from relapsing remitting to secondary progressive multiple sclerosis: views of patients and health professionals. Disabil Rehabil. 2017;39(18):1821-1828. doi:10.1080/09638288.2016.1211760

4. Scalfari A, Neuhaus A, Daumer M, Muraro PA, Ebers GC. Onset of secondary progressive phase and long-term evolution of multiple sclerosis. J Neurol Neurosurg Psychiatry. 2014;85(1):67-75. doi:10.1136/jnnp-2012-304333

5. University of California, San Francisco MS-EPIC Team, Cree BAC, Hollenbach JA, et al. Silent progression in disease activity-free relapsing multiple sclerosis. Ann Neurol. 2019;85(5) 653-666. doi:10.1002/ana.25463

6. Traboulsee A, Simon JH, Stone L, et al. Revised recommendations of the Consortium of MS Centers Task Force for a standardized MRI protocol and clinical guidelines for the diagnosis and follow-up of multiple sclerosis. AJNR Am J Neuroradiol. 2016;37(3):394-401. doi:10.3174/ajnr.A4539

7. Pitteri M, Romualdi C, Magliozzi R, Monaco S, Calabrese M. Cognitive impairment predicts disability progression and cortical thinning in MS: an 8-year study. Mult Scler. 2017;23(6):848-854. doi:10.1177/1352458516665496

8. Ziemssen T, Piani-Meier D, Bennett B, et al. A physician-completed digital tool for evaluating disease progression (Multiple Sclerosis Progression Discussion Tool): validation study. J Med Internet Res. 2020;22(2):e16932.