Health & Wellness

Progressive MS: Your Questions Answered

By Dr. Augusto Miravalle, FAAN


When I was invited to write an article about progressive MS, the first thought that came to mind was: what can I write that will be helpful to our patients and their family members? There is an abundance of literature about progressive MS, presenting eloquent descriptions of the disease process, the complex immunology that is thought to cause this disease, and updates on various therapies available for its treatment. However the more I thought about this topic, the more I realized that this information might still be presented in ways that does not fully answer the most common questions my patients often have about progressive MS. For that reason, I decided to address the most common questions I get asked in clinic, hoping that this could help fill some of those knowledge gaps. Let’s start with a basic one:
What is progressive MS?
The definition of progressive MS has changed during the past 150 years. First described by the French neurologist Jean-Martin Charcot in 1868, the disease was recognized as presenting with an initial course of clinical attacks or relapses. However, a small group of patients experience a progressive accumulation of disability from onset. Progressive forms of MS were initially grouped into the category of “chronic progressive” MS.
In 1996, an international survey of clinicians involved in the care of MS patients proposed a standardized definition for the most common clinical courses of the disease. This resulted in terminology for four subtypes of MS: relapsing remitting, secondary progressive, primary progressive, and progressive-relapsing MS. These definitions were intended to standardize the language used to describe common clinical patterns of the disease. Based on this terminology, PPMS was defined as a progressive disease course from onset, without relapses.
However, these terms led to the assumption that each clinical category represented a different disease process with different response to treatments and prognosis. In order to avoid confusion, these clinical types were updated in 2014. This new terminology focused on two main areas: presence or absence of clinical activity, and presence or absence of progression. With the new designations, all MS types are now classified as either “active” or “inactive”, and “progressive” or “nonprogressive” (based on the prior 12 months). A major point of the new way of classifying the disease is to distinguish worsening because of relapses from worsening because of progressive disease. The term “progression” is now to be used only in context of worsening disability in progressive MS (independent from relapses). 
Is PPMS worse than RRMS? 

While MS is different for every person, there are several factors that may give some insight into how it is likely to progress. These prognostic factors have been examined in several studies, providing two key insights: 
• Your first symptoms may indicate how rapidly your disease progresses. The London Ontario cohort study suggested that patients whose disease manifests with multiple problems simultaneously (such as visual symptoms, balance, weakness, etc.) at the onset might develop a more rapid disease progression. The British Columbia study reported that sensory symptoms alone at onset were associated with a slower time to progression of disability.
• Your age at onset might influence progression as well. Younger age at onset was associated with a slower time to reach disability. Another study has examined prognostic factors over a wider time interval, and found that age at onset was the only factor consistently associated with time to disability progression. However, sex and cerebellar symptoms (balance, coordination) at disease onset were associated with time to selected disability milestones, suggesting that even if age is a key factor, some other factors may exert a variable influence over specific periods of the disease course.
These factors have important implications as they might influence therapeutic strategies. But regardless of the symptoms at onset and age at presentations, it seems that people with PPMS might accumulate disability faster than RRMS. There have only been a small number of studies following patients from diagnosis onward. But the mean times to reach disability milestones have been similar across these studies, and the finding of PPMS patients accumulating disease more rapidly than relapsing onset patients has been universally replicated in all studies.
Is primary progressive MS a different disease than relapsing MS?
This is perhaps the most challenging question to answer. It has been a subject of speculation and debate for many years.
Despite early uncertainty about this topic, recent evidence points towards all forms of MS sharing common disease mechanisms. The various types of MS might simply represent a spectrum of clinical manifestations ranging from relapsing disease with little accumulated disability in the interim, to PPMS where disability accumulates irrespective of relapses, which are relatively unusual. A recent international genome-wide association study found no genetic difference between PPMS and relapsing-onset disease. Pathological studies have also shown no differences between the lesions seen in different clinical subgroups of MS, including PPMS.
However, there have been studies suggesting subtle differences between PPMS and RRMS. PPMS is less frequent than RRMS. Estimates of the frequency of PPMS have varied widely, from 8 percent to 40 percent, with most observers documenting figures of between 10 percent and 20 percent of the total MS population. There also appears to have been a gradual decline in frequency of PPMS since the 1980s. The reasons for this are unclear, but may reflect patterns of earlier referral and diagnosis, and more accurate and earlier classification of disease.
All of these studies suggest that PPMS and RRMS are different clinical manifestations of the same disease, perhaps with associated prognostic features that suggest a more rapid progression in PPMS patients. 
How do we approach the treatment of PPMS?
One of the main issues to understand is that despite the poor prognosis commonly assumed in patients with progressive disease, progression of disability in MS is slow. Large studies suggest that only 6.3 percent of patients had reached disability milestones within two years of disease onset, and 24.9 percent after five years.
More importantly, it has been confirmed in several studies that the earlier PPMS patients start treatment for their disease, the greater the benefits on overall prognosis. The FDA recently approved ocrelizumab, the first disease-modifying therapy for the treatment of PPMS patients. The medication was studied in a large clinical trial and was found to significantly decrease the likelihood of PPMS patients reaching disability milestones. It also demonstrated a significant reduction on worsening MRI outcomes. Previous studies in PPMS patients receiving Rituximab also suggested benefit, particularly in patients younger than 51 years of age, and in those patients who had MRI evidence of active lesions.
In addition to disease modifying therapies, we always pay attention to wellness and overall health. It is well-demonstrated that physical activity, exercise, and cognitive rehabilitation prevents further progression of disability and, in some cases, improves clinical outcomes.
It is always important to have a team of experts to help you develop a personalized treatment approach to your disease. Often patients need to see not only a neurologist, but also a physical therapist, occupational therapist, psychologist, nutritionist, urologist, etc. Every person is different and might have different needs at various stages of the disease. Hence, it is important to regularly see your team and make sure everybody works together to be as proactive as possible to ensure an excellent quality of life.