Relapsing and Progressive Multiple Sclerosis: Understanding the Differences

Accurate diagnosis is important in order to adjust treatment according to MS type as wells as individual response.

By Flavia Nelson, MD

Multiple sclerosis (MS) is a complex disease. Symptoms can be subtle, especially early in the disease, and they may vary significantly among patients. This complicates the process of making an accurate diagnosis. Disease course can also differ in every patient, and determining type is especially difficult when slow progression from disease onset is the only presenting symptom. Nevertheless, it is important to adjust treatment according to MS type as wells as individual response.

Although patients with MS are often knowledgeable about symptoms and available treatments, I frequently come across many who are not clear on their disease type, stage, or what defines an exacerbation. Most importantly, they are unclear about when or why they should report it to their treating physician.

In order to help physicians not very familiar with MS to be better able to guide patients in understanding disease types or whether they may have progressive MS, it is necessary to first review some basic information.

Disease Types

There are three major types of MS: Relapsing-Remitting (RR), Primary Progressive (PP), and Progressing Relapsing (PR). It is worth noting that what is referred to as Secondary Progressive (SP) MS is not a type but more the late phase of relapsing-remitting disease. The typical progression of symptoms seen in SPMS makes it appear similar to PPMS. In cases when an event clearly consistent with an exacerbation is present many years prior to the onset of progression and followed with a prolonged period with what appears to be lack of disease activity, SPMS is often the most likely diagnosis.

Relapsing-remitting is the most common type of MS, affecting approximately 85 percent of patients. It is characterized by relapses (also called ‘exacerbations’ or ‘attacks’) during which patients experience acute neurological dysfunction either with new symptoms or old symptoms becoming more severe. Relapses are followed by remissions, which are periods without obvious disease activity. A relapse is defined as new or recurrent neurological symptoms present constantly for 24 to 48 hours without improvement. Relapses usually last days to weeks before reaching a plateau and complete or incomplete recovery may occur. Duration and recovery depend on the severity of the attack, how soon it is treated, and the stage of the disease. Recovery is typically most rapid and most complete early in the disease.1 I always instruct patients that relapses should be reported to the treating physician as soon as identified, as prompt medical treatment of relapses (IV or oral steroids) may reduce irreversible damage and accumulation of neurological disability. Of note, incomplete recovery from an exacerbation has to be differentiated from true progression.

Exacerbations should not be confused with Uhthoff’s phenomenon, also called “pseudo exacerbations,” which can be described as recurrence of previously experienced neurological symptoms after a temporary increase in body temperature from either an outside source (weather) or inside source (exercise, fever). An increase in body temperature decreases nerve conduction velocity in the brain and spinal cord, making old symptoms re-appear. In general the symptoms of a pseudo-attack resolve within hours after cooling down and resting. A good example is a patient who likes to work in the garden on sunny days: after a period as short as 30 minutes she/he may begin to experience tingling sensations in the hands and feet (which were present during a previous exacerbation), but these gradually resolve after going inside and drinking ice water. It is also important to remember that neurological symptoms may also worsen due to extreme fatigue (travel), a high stress level (weddings, moving), physical activity (restarting an exercise program too hard too fast), and with presence of infections.

Although not always easy, it is also important for patients to learn to differentiate a relapse from normal fluctuations of the disease. This helps the physician not only make the correct diagnosis and sometimes clarify disease type but most importantly evaluate disease activity and treatment response. Magnetic resonance imaging (MRI) of the brain serves as an important additional tool to be used in conjunction with disease behavior for diagnostic as well management purposes. In two recent papers by Sormani, et al. enhancing lesions on MRI were found to correlate with exacerbations and disability in some of the largest meta-analysis done on the subject to date.2,3

Progressive relapsing is the least common disease type, affecting only about five percent of patients. It is characterized by an initial course that simulates primary progressive disease, but with one or more superimposed attacks that appear after the progressive disease is well established.1

Primary progressive disease affects about 10 percent of patients with MS. This type is characterized by slow accumulation of neurological disability without acute attacks of neurological dysfunction. The most common symptoms are leg weakness, leg stiffness and difficulty walking, slowly worsening over one to two years. These are often accompanied by urinary symptoms such as frequency and urgency and are often caused by involvement of the spinal cord. A search for other similar conditions should be performed by the physician. An example would be a 55-yearold male, who over the last 18 months has noticed worsening difficulty lifting his left leg while playing golf. He also notices loss of flexibility of both legs and clumsiness of his hands; his feet feel numb to touch. Patients may also experience typical MS symptoms like fatigue, memory problems, visual abnormalities, and depression, among others. It is important to remember that sometimes when a careful history is taken, a patient with progressive symptoms may recall an isolated episode of acute neurological symptoms, such as vision loss in one eye, that may have preceded the development of progressive neurological disability by one or two decades. Often, these patients have not sought medical attention for the original symptoms or a definite diagnosis was never reached. This scenario is more consistent with secondary progressive MS and is seen in up to 60 percent of patients who were originally diagnosed with RRM.1

While young women tend to present with the relapsing form of the disease, men and older women are more likely to present with progressive disease from the onset. Patients with progressive disease often have difficulty determining if they are worsening on a day-to-day, week-to-week, or even month-to-month basis. They are usually able to determine worsening in relationship to major milestones such as one year’s holiday to the next. Things that they can no longer accomplish eventually become evident; like walking to the mailbox. Progression is usually slow, but constant. In patients transitioning to SPMS the progression happens between relapses and is unrelated to incomplete recovery from them, eventually the SPMS patient will stop having exacerbations and only progression is seen. It is important to keep in mind that de-conditioning can mimic progression and physical activity should be encouraged at all levels of disability even in wheelchair-bound patients.

The disease course of progressive MS may have intervals in which the patient appears quite stable, experience some improvement for no clear reason, or show a rapid deterioration of function overall. Eventually, in both primary progressive and secondary progressive disease, a consistent pattern is seen with an increase in the level of disability. However, the rapidity with which the disease worsens cannot be clearly established, since it usually varies among patients and data from research studies vary considerably.1


MS is considered a chronic, autoimmune disorder that attacks the brain and spinal cord creating localized areas of inflammation called “plaques.” Acute (also called “active”) plaques are usually new, but old plaques can reactivate. The difference between an acute (new) and a chronic (old) plaque is the degree of inflammation present. This can be detected by MRI using intravenous contrast and is refered to as plaque “enhancement.” Chronic plaques are scars left in the brain or spinal cord tissue after the inflammation in the acute plaque resolves. They do not “enhance” on an MRI. Acute plaques may or may not cause symptoms. When they do, patients will experience an exacerbation, but a lot of them are silent. The degree of irreversible damage a new plaque may cause determines the degree of recovery from the relapse. Almost all new plaques turn into chronic ones (T2 lesions) some with significant gliosis and myielin/axonal loss (corresponding T1 black hole), and they accumulate throughout the duration of the disease. Although the number of plaques does not correlate well with the number of relapses, it does so with accumulation of disability. Acute or active plaques are not as common in primary or secondary progressive disease as in relapsingremitting. 4


For purposes of diagnosis we will concentrate on PPMS, since a clear diagnostic criteria for SPMS has not been established and characteristics were previously explained. The diagnosis of PPMS can be a true challenge; it involves incorporating the history of the patient’s symptoms and the way they evolved over time with the findings on a careful neurological exam. Engaging both the patient and close family members in this process is essential for obtaining the best possible historical information. The diagnosis should also be supported by typical lesions on brain and spinal cord MRI and often requires further testing, such as a spinal tap or visual performance testing. Other conditions that may mimic PPMS also need to be evaluated and only if and when all the pieces of the puzzle create the right picture can a definite diagnosis be made. In 2001, a group of MS experts from around the world defined the newest criteria for an accurate diagnosis of MS. In 2005, they reunited and revised their previous recommendations making improvements especially in the area of PPMS diagnosis. 5 According to the 2005 McDonald criteria PPMS is defined by at least one year of progression of neurological symptoms without acute attacks and at least two of the following:

  • A brain MRI with lesions typical for MS
  • A spinal cord MRI with lesions typical for MS
  • A positive spinal tap

Patients with PPMS tend to have fewer brain lesions (plaques) than with RRMS and also tend to have more lesions in the spinal cord than the brain. They also have fewer “active” plaques, meaning less evidence of inflammation by number of enhancements. Together the differences between RR and PPMS make PP more challenging to diagnose and treat. Fortunately, there are many strategies available to help patients manage their symptoms so they can remain active and Productive.5


There are currently no medications approved by the US Food and Drug Administration (FDA) for the treatment of PPMS. Because all of the approved disease-modifying therapies work primarily by reducing inflammation in the brain and spinal cord, they do not work well in a type of disease that is not mainly characterized by inflammation. In RRMS trials investigators look at number of new lesions or number of enhancing lesions on MRI, because in this disease type new lesions can often be seen over the course of a year; a difference in lesion number over two to three years is easily identifiable. Number of relapses per year is another way to measure treatment effect when a drug is compared to another drug or to placebo. All currently approved immunomodulators reduce the number of relapses per year as well as the number of new and enhancing lesions on MRI. Another measure used in RRMS trials is accumulation of disability measured by an objective neurological exam, which includes measurements of walking ability. In PPMS there are no relapses, symptoms progress slowly, and the number of lesions on brain and spine MRI can be stable for some time showing no signs of activity like an increase in number or new “enhancing” lesions. Therefore in PPMS trials there is a lack of easily identifiable measures that can be used to define success for the drug being tested, so measuring treatment effect is also a challenge.

Two drugs recently tested have shown to have a small but positive effect on a particular type of patient. The PROMiSe trial recruited close to 1,000 patients with PPMS to test the effectiveness of glatiramer acetate (Copaxone, Teva) against placebo.6 Because of lack of clear differences between the treated and the untreated group, the trial was terminated early (year three). In a post-hoc analysis by gender, a small reduction in accumulation of disability was seen in the treated males but not in females. The investigators concluded that the effect of the drug was easier to measure in males because they tend to have more aggressive disease and progress faster. This is the basis of the drug’s use in patients with PPMS.

Another recent trial tested the drug rituxamab (Rituxan, Genentech/Biogen-Idec) against placebo in a two-year trial. Results showed a reduction in the number of enhancing brain lesions in a small group of treated patients when compared to untreated and a small decrease in accumulation of disability in younger patients (<51 years). No differences were found in patients who did not have active brain lesions or were older than 51 years. Progress has been made with symptom management as well: a new drug Fampridine (Ampyra, Acorda) has shown to improve walking speed (25 percent improvement on timed 25 foot walk in approximately 30 percent of patients) in clinical trials and has been FDA approved since 2010. Currently, an important PPMS research study is ongoing. The drug being tested, FTY-720 (Fingolimod), was FDA-approved for RRMS (Gilenya, Novartis) in 2010. To improve the success of this trial the investigators have carefully designed better measures for treatment effect. INF B1b (Betaseron, Bayer) is approved in Europe for treatment of SPMS.

Along with identifying effective medications to slow disease progression, researchers are looking for ways to repair and protect brain tissue that has already been damaged. The Nervous System Repair and Protection Initiative founded by the National MS Society brought together a team of researchers from US and Europe to study possible mechanisms for restoring brain function. In the meantime, there is a lot that can be done to enhance mobility, safety, independence, and promote wellness to improve overall quality of life.7

Reprinted with permission from Broca’s Area, the publication of the Texas Neurological Association.

Dr. Nelson has no relevant disclosures.

Flavia Nelson, MD is Assistant Professor of Neurology, Associate Director MRI Analysis Center Multiple Sclerosis Research Group at University of Texas Medical School at Houston.

  1. Perkins, G. D., & Wolinsky, J. S. (2006). Fast Facts: Multiple Sclerosis. Health Press (2nd edition).
  2. Sormani MP, Bonzano L, Roccatagliata L et al. Magnetic resonance imaging as a potential surrogate for relapses in multiple sclerosis: A meta-analytic approach. Annals of Neurology. 2009;65: 268-275.
  3. Sormani MP, Bonzano L, Roccatagliata L et al. Surrogate endpoints for EDSS worsening in multiple sclerosis: A metaanalytic approach. Neurology. 2010;75: 302-309.
  4. Kutzelnigg, A., & Lassmann, H. (2005). Cortical lesions and brain atrophy in MS. Journal of the Neurological Sciences, z 3 3 (1-2), 55-59.
  5. Polman, C. H., Reingold, S. C., Edan, G., Filippi, M., Hartung, H.-P., Kappos, L., et al. (2005). Diagnostic criteria for multiple sclerosis: 2005 revisions to the “McDonald Criteria.” Annals of Neurology, 58, 840-846.
  6. Wolinsky, J. S., Narayana, P. A., O’Connor, P., Coyle, P. K., Ford, C., Johnson, K., et al.; PROMiSe Trial Study Group. Glatiramer Acetate in Primary Progressive Multiple Sclerosis: results of a multicenter, multinational double-blind, placebo controlled trial. Ann Neurol 61:14-24, 2007
  7. Goodman, A. D. (2009). Talking About Primary Progressive MS. National Multiple Sclerosis Society. Available at: www.

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