A 49-year-old man with a long history of relapsing-remitting multiple sclerosis presents to the clinic for a routine follow-up visit. The patient was initially treated with glatiramer acetate injections and is now being treated with natalizumab.


An annual surveillance magnetic resonance imaging scan of the brain showed 2 new lesions, indicating active disease.


The patient now presents with evidence that the multiple sclerosis is progressing: He often becomes tired when walking, loses balance more frequently, has feelings of confusion, and has general difficulty with visuospatial recall.


Review a wellness plan, schedule follow-up visits for disease monitoring on a regular basis (2 or 3 times per year is optimal), and determine whether switching to a different disease-modifying therapy might be more effective in controlling progressive disease.

Every patient with relapsing–remitting multiple sclerosis (RRMS) is at risk of transitioning to secondary progressive multiple sclerosis (SPMS). Although not inevitable, the possibility of transition can be discussed at the time of initial diagnosis to support therapy, and the transition is something that clinicians should watch for over the course of the disease. In this case study, we review the status of a patient with RRMS for signs of progression to SPMS.

Case Scenario

Richard is a 49-year-old white man who lives with his wife and sons in the Northeast United States. He is a university professor of marine biology whose research often involves full-day or multiday boat trips on a variety of boats.

Fourteen years ago, Richard began to feel unsteady while on the water, which he attributed to lack of exercise. He increased his exercise, with attention to lower-body strength training. This regimen produced mild improvement that allowed him to take 2 lengthy boat trips over the next year.

History and Diagnosis

Richard was given a diagnosis of RRMS after experiencing 2 clinical attacks over the course of a year at 36 years of age. At that time, he noticed problems reading the computer screen at work, maintaining his balance, and general weakness of the lower limbs. The weakness passed after a few days, although he continued to complain of difficulty with eyesight. After a second episode involving dizziness and loss of balance several months later, Richard’s wife insisted he see his physician, who ordered a baseline magnetic resonance imaging (MRI) series. The scans showed multiple lesions in the brain and on the spinal cord.

A diagnosis of RRMS was made.

The transition to SPMS appears age-related, with the highest risk at 45 to 55 years. Patients with RRMS should be monitored especially closely for clinical signs of progressive disease as they approach this age milestone.1,2

Case Discussion

Treatment and Disease Course

Richard had initially been treated with glatiramer acetate (GA) injections. Over the first 2 years after diagnosis, he experienced 4 more relapses that resulted in loss of time at work and limited his research trips by boat. Each episode of relapse was considered severe and resulted in an accumulation of disability by 38 years of age, at which time he was switched to a higher-efficacy agent, natalizumab.

Richard had no relapses over the next several years, although he noted baseline slowness in information-processing speed at work and while teaching, as well as general difficulty with visuospatial recall, both indicative of cognitive deficits.3 He remained essentially stable for 8 years and was able to go on 1-day boating trips, as long as he was strapped to his seat while the boat was moving.

Three years ago, at 46 years of age, Richard noted extreme weakness of his legs and could no longer climb from the boat to the dock without the assistance of 2 or more students. He began to rely heavily on a cane for balance, and he did not have the strength to walk across campus to his classes without stopping to rest. These challenges resulted in a reduction in his teaching schedule. At the same time, his family noticed that he withdrew from family activities, such as attending his son’s high school basketball games, because he was embarrassed at not being able to climb the bleachers.

During the past year, annual surveillance brain MRI showed 2 new lesions.

View Survey

Testing for MS Progression

  • 25-Foot timed walk is an easily performed outpatient test that assesses gait. Five seconds or less is considered normal time to complete the walk; an increase in time of at least 20% over a previous timed walk is considered significant.
  • Symbol digit modalities test is a rapid, easy-to-perform cognitive test that evaluates cognitive processing speed. The test can be conducted annually to monitor cognitive function in individuals with MS.

Current Visit

Richard arrives ambulating with a cane and accompanied by his wife, whom he seems to rely on to show him the way to the interior office. They express concern that his MS is progressing based on their recent observations that he:

  • Often becomes tired when walking;
  • Loses his balance more frequently, such as when he gets out of bed in the morning;
  • Does not feel strong enough to hold the leash to walk their dog;
  • Often feels confused, particularly in tight new spaces; and
  • Has trouble reading traffic signs, which led him to stop driving.

Discussion: It is important for the clinician to recognize that there is an alternating good-day and bad-day element to MS. A patient can develop new weakness or other signs or symptoms but, a few months later, those changes are gone, due to the fluctuating nature of the course of MS. It is important to confirm those kinds of changes with a follow-up visit a few months later. Nevertheless, the appearance of even a single new sign or symptom in middle age should raise suspicion of SPMS.

Poor Prognostic Indicators

Indicators of poor prognosis in RRMS include:

  • Male gender;
  • Age, 45 to 55 years;
  • Duration of disease, more than 10 years;
  • Indicators of a more severe course of disease early on; and
  • Loss of brain reserve with age.

Richard’s MS has likely been progressing for at least 3 years. Perhaps the failure to switch the initial choice of DMT earlier influenced this outcome. There is accumulating evidence of a window of opportunity early in the disease process to optimize therapy and avoid late progression of disability.

Approaches to Managing the Transition

Given signs of progression, the clinician should first look at the patient’s current treatment and re-evaluate its efficacy. As optimal treatments for SPMS are lacking, clinicians should consider therapies that have shown benefit in clinical trials in a primary progressive MS (PPMS) phenotype.

The current assumption is that all forms of progressive MS are caused by the same neurodegenerative process, although the course of disease varies. The 2 progressive phenotypes (PPMS and SPMS) are believed to have the same response to treatment; therefore, if a treatment works in PPMS, it can be expected to work in SPMS.

Treatments for PPMS

Only ocrelizumab, a humanized anti-CD20 monoclonal antibody, has been approved by the US Food and Drug Administration (FDA) for treatment of both RRMS and PPMS, at a dosage of 600 mg administered intravenously every 6 months. In a 6.5-year, follow-up phase 3 trial (ORATORIO; ClinicalTrials.gov Identifier: NCT01194570), sustained benefit on measures of disease progression was obtained with earlier and continued treatment with ocrelizumab for PPMS.4

Siponimod, a second-generation selective sphingosine 1 phosphate (S1P) receptor modulator, was the first drug assessed for SPMS in a phase 3 trial (EXPAND; ClinicalTrials.gov Identifier: NCT01665144).5 Given orally at 2 mg/d, siponimod has been shown to slow disease progression compared with placebo in a large cohort of patients with SPMS. In 2020, the FDA granted approval to siponimod and ozanimod for the  treatment of activeSPMS as well as RRMS.6,7 This is the same approval that was granted for most of the drug therapies used to treat RRMS.8

Case Update: Treatment Recommendations

  • Review a wellness plan, including healthy diet, adequate sleep, and moderate exercise.
  • Identify and appropriately manage comorbid conditions in MS, which become more common with age.
  • Schedule regular follow-up visits to monitor disease optimally at a frequency of 2 or 3 times per year.
  • Determine if switching to another DMT might improve outcomes in progressive disease.
  • Seek out clinical trials for new targeted therapies for progressive MS for which Richard might be considered.

Currently, outcomes for SPMS are not good. Clinicians do not have the ability to stop worsening of disease in progressive MS, although the tempo of worsening can be improved somewhat for the best possible quality of life. It is important to prepare the patient before progressive features of MS become apparent; having a plan for monitoring clinical signs as a patient approaches high-risk age (45 to 55 years) is key to optimizing health outcomes.

Once the patient has transitioned to progressive MS, that becomes the new phenotype, and the disease will worsen. Research suggests that lifespan might be reduced by approximately 7 years in people with MS compared with the expected lifespan of people without the disease, but this is highly dependent on accumulated disability.9,10 It is important to note that most patients with progressive MS deteriorate slowly.


1. Tutuncu M, Tang J, Zeid NA, et al. Onset of progressive phase is an age-dependent clinical milestone in multiple sclerosis. Mult Scler. 2013;19(2):188-198. doi:10.1177/1352458512451510

2. Sanai SA, Saini V, Benedict RH, et al. Aging and multiple sclerosis. Mult Scler. 2016;22(6):717-725. doi:10.1177/1352458516634871

3. Brochet B, Ruet A. Cognitive impairment in multiple sclerosis with regards to disease duration and clinical phenotypes. Front Neurol. 2019;10:261. doi:10.3389/fneur.2019.00261

4. Wolinsky JS, Arnold DL, Brochet B, et al. Long-term follow-up from the ORATORIO trial of ocrelizumab for primary progressive multiple sclerosis: a post-hoc analysis from the ongoing open-label extension of the randomised, placebo-controlled, phase 3 trial. Lancet Neurol. 2020;19(12):998-1009. doi: 10.1016/S1474-4422(20)30342-2 Correction in: Lancet Neurol. 2021;20(1):e1. doi: 10.1016/S1474-4422(20)30437-3

5. Kappos L, Bar-Or A, Cree BAC, et al; EXPAND Clinical Investigators. Siponimod versus placebo in secondary progressive multiple sclerosis (EXPAND): a double-blind, randomised, phase 3 study. Lancet. 2018;391(10127):1263-1273. doi: 10.1016/S0140-6736(18)30475-6 Correction in: Lancet. 2018;392(10160):2170. doi: 10.1016/S0140-6736(18)32834-4

6. FDA approves new oral drug to treat multiple sclerosis. FDA. https://www.fda.gov/news-events/press-announcements/fda-approves-new-oral-drug-treat-multiple-sclerosis. Published March 26, 2019. Accessed March 18, 2021.

7. Figueiredo M. FDA approves Zeposia (ozanimod), oral therapy for all with relapsing MS. Multiple Sclerosis News Today. https://multiplesclerosisnewstoday.com/news-posts/2020/03/26/fda-approves-zeposia-ozanimod-oral-rrms-active-spms-cis-therapy/. Published May 27, 2020. Accessed March 18, 2021.

8. National Multiple Sclerosis. Disease-modifying therapies for MS. http://www.nationalmssociety.org/NationalMSSociety/media/MSNationalFiles/Brochures/Brochure-The-MS-Disease-Modifying-Medications.pdf. Updated February 2021. Accessed March 18, 2021.‌

9. Lunde HMB, Assmus J, Myhr K-M, Bø L, Grytten N. Survival and cause of death in multiple sclerosis: a 60-year longitudinal population study. J Neurol Neurosurg Psychiatry. 2017;88(8):621-625. doi:10.1136/jnnp-2016-315238

10. Scalfari A, Knappertz V, Cutter G, Goodin DS, Ashton R, Evers GC. Mortality in patients with multiple sclerosis. Neurology. 2013;81:184-192. doi:10.1212/WNL.0b013e31829a3388

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                                                                                                                                       Reviewed March 2021