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Types of Multiple Sclerosis
Multiple sclerosis (MS) is a chronic, progressive disease that leads to increasing disability in most individuals. Descriptions of the disease have always included two types of clinical processes, an acute process involving relapses and a chronically persistent progressive process, for which the underlying pathogenic mechanisms of onset are unknown.

The vast majority of individuals present with the acute relapsing-remitting form of the disease, and the treatments that are currently available to treat MS are most effective for these individuals. For the majority of those patients who eventually transition to secondary-progressive MS (SPMS) and for those whose disease course is progressive from onset, primary-progressive MS (PPMS), treatment options at this time primarily involve symptomatic management and rehabilitation to mitigate the impact of the disease progression.

In spite of the apparent differences in clinical manifestation between the disease courses, the consensus has been that these differences are more quantitative than qualitative and that the relapsing and progressive courses of MS fall along a disease spectrum, with genetic and environmental factors contributing to the variations. While continuing to examine the apparent similarities and differences between the MS disease courses, the international MS community has come together to expedite the development of effective disease-modifying and symptom management therapies for progressive forms of MS.

The International Progressive MS Collaborative has identified the following five research priorities: experimental models for progressive MS; identification and validation of treatment targets and repurposing opportunities; proof-of-concept clinical trial strategies; clinical outcome measures; and symptom management and rehabilitation strategies.
The Four Main Types of MS
In 1996, the International Advisory Committee on Clinical Trials of MS originally identified four disease courses MS. The original four disease courses (types) of MS in 1996 were:
Relapsing-Remitting MS
Primary-Progressive MS
Secondary-Progressive MS
Progressive-Relapsing MS

These four provided purely clinical types based on data and consensus at that time, but time has shown that imaging and biological correlates were lacking. Increased understanding of MS and its pathology, coupled with general concern that the original descriptors may not adequately reflect more recently identified clinical aspects of the disease, prompted a re-examination of MS disease types.

The changes that were adopted in 2013 by the committee: they retained three of the disease course descriptions first developed in 1996, they included the addition of clinically isolated syndrome (CIS), and they eliminated progressive-relapsing MS (PRMS). In addition, modifiers have been added to promote more effective conversations about disease activity and progression and shared decision-making about treatment options. The modifiers, such as "active" and "not active," incorporate information from MRIs, relapses and degree of disability.

Accordingly, the new classifications also provides guidelines for how often MRIs should be used to assess someone's MS. Under the old criteria, doctors waited until someone had another event with more clinical findings and more disability. The newer criteria include utilizing MRI with gadolinium (a contrast agent) to help make a diagnosis sooner and to recognize changes in established MS so that treatment changes can be considered.

You may see differences in the way the MS disease courses (also called "types" or "phenotypes") are defined here on our website and in our other resources including print publications. This discrepancy is due to others not knowing about, not yet updating, or not wanting to adapt to the new standard. The revised courses, as discussed above, were updated from the descriptions first published in 1996 and developed by the International Advisory Committee on Clinical Trials of MS in 2013 , based on advances in the understanding of the disease process in MS and in MRI technology.

The current four disease courses (types) of MS (New as of 2013):

Clinically Isolated Syndrome (CIS)

Relapsing-Remitting Multiple Sclerosis (RRMS)

Secondary-Progressive Multiple Sclerosis (SPMS)

Primary-Progressive Multiple Sclerosis (PPMS)

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The 1996 vs 2013 MS Phenotype Descriptions for Relapsing Disease

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Relapsing Disease Images Above: *Activity determined by clinical relapses and/or MRI activity (contrast-enhancing lesions; new or unequivocally enlarging T2 lesions assessed at least annually); if assessments are not available, activity is "indeterminate." **CIS, if subsequently clinically active and fulfilling current MS diagnostic criteria, becomes relapsing-remitting MS (RRMS).

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The 1996 vs 2013 MS Phenotype Descriptions for Progressive Disease

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Progressive Disease Images Above: *Activity determined by clinical relapses assessed at least annually and/or MRI activity (contrast-enhancing lesions; new and unequivocally enlarging T2 lesions). **Progression measured by clinical evaluation, assessed at least annually. If assessments are not available, activity and progression are "indeterminate." MS = multiple sclerosis; PP = primary-progressive; PR = progressive-relapsing; SP = secondary-progressive.



Clinically Isolated Syndrome (CIS)

Clinically isolated syndrome (CIS) was not included in the initial MS clinical descriptors. CIS is now recognized as the first clinical presentation of a disease that shows characteristics of inflammatory demyelination that could be MS, but has yet to fulfill criteria of dissemination in time. Natural history studies and clinical trials of MS disease-modifying therapies (DMTs) have shown that CIS coupled with brain MRI lesions carries a high risk for meeting diagnostic criteria for MS. Clinical trials of MS DMTs show fewer treated individuals with CIS who develop a second exacerbation (the defining event for "clinically definite MS") and reduced MRI activity.

With neurologic symptoms caused by inflammation and demyelination in the central nervous system (CNS), this first episode — which must last at least 24 hours, according to definition — is typical of MS but does not yet meet the criteria for a diagnosis of the disease. Sometimes, people who have a CIS will not go on to develop MS. An MRI will better determine the likelihood that someone who has a CIS will develop MS. If lesions on a brain MRI are seen with a CIS, there is a higher chance the patient will develop MS.

This will provide a more detailed sub-class will give two types of CIS:
CIS Not Active
CIS Active

The new classification provides a way, using these newer diagnostic criteria, to diagnose and treat a person as having MS with the first clinical event, if they have certain findings on their MRI. Correspondingly, individuals who have experienced CIS and who are considered at high risk of developing full-blown MS (that is, their CIS is accompanied by MS-like lesions seen on MRI) may now be treated with a DMT.

For More Detail:

Clinically isolated syndrome (CIS) is one of the MS disease courses. CIS refers to a first episode of neurologic symptoms that lasts at least 24 hours and is caused by inflammation or demyelination (loss of the myelin that covers the nerve cells) in the central nervous system (CNS). CIS can be either monofocal or multifocal.

With CIS, an MRI may demonstrate damage only in the area responsible for the current symptoms; with MS, there may be multiple lesions on MRI in different areas of the brain. A person with CIS, by definition, is experiencing the first episode of symptoms caused by inflammation and demyelination in the CNS; a person with MS has experienced more than one episode.

Monofocal episode - The person experiences a single neurologic sign or symptom. For example, an attack of optic neuritis — that’s caused by a single lesion.

Multifocal episode - The person experiences more than one sign or symptom. For example, an attack of optic neuritis accompanied by weakness on one side — caused by lesions in more than one place.

The episode usually has no associated fever or infection and is followed by a complete or partial recovery.

CIS Progression To MS

Individuals who experience CIS may or may not go on to develop MS. In diagnosing CIS, the healthcare provider faces two challenges: first, to determine whether the person is experiencing a neurologic episode caused by damage in the CNS; and second, to determine the likelihood that a person experiencing this type of demyelinating event is going to go on to develop MS.

High risk of developing MS: - When CIS is accompanied by MRI-detected brain lesions that are similar to those seen in MS, the person has a 60 to 80% chance of a second neurologic event and diagnosis of MS within several years.

Low risk of developing MS: - When CIS is not accompanied by MRI-detected brain lesions, the person has about a 20% chance of developing MS over the same period of time.

According to the 2010 revisions to the diagnostic criteria for MS, the diagnosis of MS can be made when CIS is accompanied by MRI findings (old lesions or scars) that confirm that an earlier episode of damage occurred in a different location in the CNS. As MRI technology becomes more advanced, it's likely that the diagnosis of MS will be made more quickly and there will be fewer people diagnosed with CIS.

An accurate diagnosis at this time is important because people with a high risk of developing MS are encouraged to begin treatment with a disease-modifying therapy in order to delay or prevent a second neurologic episode and, therefore, the onset of MS. In addition, early treatment may minimize future disability caused by further inflammation and damage to nerve cells, which are sometimes silent (occurring without any noticeable symptoms). Several medications are now approved by the U.S. Food and Drug Administration (FDA) for CIS: Avonex®, Betaseron®, Copaxone®, Extavia®, Glatopa™.

Like MS, CIS is two to three times more common in women than men. 70% of people diagnosed with CIS are between the ages of 20 and 40 years (average 30 years) but people can develop CIS at older or younger ages. Based upon clinical symptoms alone, CIS and MS may appear the same. In both, damage to the myelin sheath (demyelination) interferes with the way nerve impulses are carried from the brain, resulting in neurologic symptoms.

According to the 2010 revisions to the diagnostic criteria for MS, when CIS is accompanied by specific findings on MRI that demonstrate that another episode has occurred in the past, the diagnosis of MS can be made.

Many episodes of CIS are mild and resolve without treatment. In other cases, treatment with high dose oral or intravenous methylprednisolone (a steroid) is typically recommended. An MS disease-modifying therapy is often recommended for people diagnosed with a CIS that is considered more likely to progress to clinically definite MS (CDMS), with the goal of delaying a second attack.

Several large-scale clinical trials have been conducted to determine whether early treatment following a CIS can delay the second clinical event, and therefore the diagnosis of CDMS. Based on the results of these studies, the U.S. Food & Drug Administration (FDA) has expanded the indication of several medications used to treat MS to include individuals who have experienced a first clinical episode and have MRI findings consistent with MS. The results of these trials, and the FDA's approval of expanded labeling for certain medications used to treat MS, support the earliest possible treatment for MS, which many believe may delay the development of permanent clinical disabilities.

At this time, it is difficult to predict the future course a person who is diagnosed with a CIS will experience.



Relapsing-Remitting Multiple Sclerosis (RRMS)

This is the most common form of MS with clear defined phases of relapse (repeat attacks or exacerbations), with progressive worsening of nerve functions with each attack, followed by phases of relief (or remission) where normal conditions are restored partially or completely. During remission, all symptoms may disappear, or some symptoms may continue and become permanent. However, there is no apparent progression of the disease during the periods of remission.

A more detailed sub-class will give four types of RRMS: Active Not Worsening, Active Worsening, Not Active Not Worsening, and Not Active Worsening. At different points in time, RRMS can be further characterized as either active (with relapses and/or evidence of new MRI activity) or not active, as well as worsening (a confirmed increase in disability over a specified period of time following a relapse) or not worsening.

Previously, those diagnosed with PPMS were not considered eligible for treatment with a disease-modifying therapy (DMT). However, under the new descriptions, people with active PPMS (those who have new inflammation or a new relapse) may talk with their doctors about possible treatment with a DMT.

This will provide a more detailed sub-class will give four types of RRMS:
RRMS Active Worsening
RRMS Active Not Worsening
RRMS Not Active Worsening
RRMS Not Active Not Worsening

Approximately 85% of people with MS are initially diagnosed with RRMS.

For More Detail:

Relapsing-remitting is the most common disease course of MS, characterized by clearly defined attacks of new or increasing neurologic symptoms. These attacks, also called relapses or exacerbations, are followed by periods of partial or complete recovery (remissions). During remissions, all symptoms may disappear, or some symptoms may continue and become permanent. However, there is no apparent progression of the disease during the periods of remission.

At different points in time, RRMS can be further characterized as either active (with relapses and/or evidence of new MRI activity) or not active, as well as worsening (a confirmed increase in disability over a specified period of time following a relapse) or not worsening. An increase in disability is confirmed when the person exhibits the same level of disability at the next scheduled neurological evaluation, typically 6 to 12 months later.

Following a relapse, the new symptoms may disappear without causing any increase in level of disability, or the new symptoms may only partially disappear, resulting in an increase in disability. New lesions on MRI, as shown by the arrows, often occur as part of a relapse. However, new MRI lesions indicating MS activity may also occur without symptoms of which the person is aware.

RRMS is defined by inflammatory attacks on myelin (the layers of insulating membranes surrounding nerve fibers in the CNS), as well as the nerve fibers themselves. During these inflammatory attacks, activated immune cells cause small, localized areas of damage which produce the symptoms of MS. Because the location of the damage is so variable, no two people have exactly the same symptoms.

Why are modifiers used to characterize RRMS?

Disease activity and progression should be evaluated at regular intervals by neurologic examination and MRI. Being able to characterize the course of your disease at different points in time helps you and your MS care provider discuss your treatment options and expected outcomes. For example:

If you have RRMS that is active and worsening, you and your MS care provider will likely want to consider a more aggressive treatment approach than if there were no evidence of activity or worsening. Together, you can weigh the potential risks and benefits of other treatment options.
If your symptoms have not worsened on the treatment you are currently taking, but you have evidence of new disease activity on your MRI, you and your healthcare provider may discuss switching to another treatment with a different mechanism of action in order to control the disease activity more effectively and help prevent worsening.
If your RRMS is stable without evidence of MRI activity or worsening, you and your doctor can feel confident that the current treatment regimen is working effectively.

How does RRMS differ from progressive types of MS?

While RRMS is defined by attacks of inflammation (relapses) in the CNS, progressive forms of MS involve much less of this type of inflammation.

People with RRMS tend to have more brain lesions, also called plaques or scars, on MRI scans, and these lesions contain more inflammatory cells.
People with primary progressive MS (PPMS) tend to have more spinal cord lesions, which contain fewer inflammatory cells.

In RRMS, women are affected two to three times as often as men; in PPMS, the number of women and men are approximately equal.

RRMS is diagnosed earlier than the progressive disease courses:

Most people with RRMS are diagnosed in their 20s and 30s (although it can occur in childhood or later adulthood), while the onset of PPMS tends to be in ones 40s or 50s.
The transition to SPMS generally occurs in people who have been living with RRMS for at least 10 years.

The most common symptoms reported in RRMS include episodic bouts of fatigue, numbness, vision problems, spasticity or stiffness, bowel and bladder problems, and problems with cognition (learning and memory or information processing). People with progressive forms of MS are more likely to experience gradually worsening problems with walking and mobility, along with whatever other symptoms they may have.



Secondary-Progressive Multiple Sclerosis (SPMS)

Secondary-progressive follows an initial relapsing-remitting course, with continued relapses and progressive neurological damage. Most patients will eventually transition to a secondary-progressive course, in which there is a progressive worsening of neurologic function (accumulation of disability) over time, with or without remissions. SPMS can be further characterized at different points in time as either active (with relapses and/or evidence of new MRI activity) or not active, as well as with progression (evidence of disease worsening on an objective measure of change over time, with or without relapses) or without progression. Disability gradually increases over time during this course.

This will provide a more detailed sub-class will give four types of SPMS:
SPMS Active with Progression
SPMS Active without Progression
SPMS Not Active with Progression
SPMS Not Active without Progression

In most clinical contexts, SPMS is diagnosed retrospectively by a history of gradual worsening after an initial relapsing disease course, with or without acute exacerbations during the progressive course. To date, there are no clear clinical, imaging, immunologic, or pathologic criteria to determine the transition point when RRMS converts to SPMS; the transition is usually gradual. This has limited the ability to study the imaging and biomarker characteristics that may distinguish this course.

For More Detail:

SPMS follows an initial relapsing-remitting course. Most people who are diagnosed with RRMS will eventually transition to a secondary-progressive course in which there is a progressive worsening of neurologic function (accumulation of disability) over time. SPMS can be further characterized at different points in time as either active (with relapses and/or evidence of new MRI activity) or not active, as well as with progression (evidence of disease worsening on an objective measure of change over time, with or without relapses) or without progression.

Following a period of relapsing-remitting disease, disability gradually increases over time, with or without evidence of disease activity (relapses or changes on MRI). In SPMS, occasional relapses may occur, as well as periods of stability.

Why are modifiers used to characterize SPMS?

Disease activity and progression should be evaluated at least yearly by neurologic examination and MRI. Being able to characterize the course of your disease at different points in time helps you and your MS care provider discuss your treatment options and expected outcomes. For example:

If you have SPMS that is active, you and your MS care provider will want to talk about treatment with a DMT to reduce the risk of a relapse.
If you have SPMS that is active and progressing in spite of the medication you are taking, the conversation with your MS care provider might be about the potential benefits and risks associated with switching to a more aggressive treatment strategy.
If your SPMS is not active but there is evidence of progression and accumulation of disability, you and your MS care provider will want to focus on rehabilitation strategies to help improve your function and mobility, and promote safety and independence.
If your SPMS is stable without activity or progression, the conversation with your MS care could focus on rehabilitation and other symptom management strategies to help you maintain function.

How does SPMS differ from the other disease courses?

SPMS occurs in people who initially had a relapsing-remitting disease course. In other words, SPMS occurs as a second phase of the disease for many individuals. Primary-progressive MS (PPMS) is the first — and only — phase of the illness for approximately 15% of people with MS.

In SPMS, people may or may not continue to experience relapses caused by inflammation; the disease gradually changes from the inflammatory process seen in RRMS to a more steadily progressive phase characterized by nerve damage or loss.

The DMTs may be effective for people with SPMS who experience relapses.



Primary-Progressive Multiple Sclerosis (PPMS)

PPMS is characterized by worsening neurologic function (accumulation of disability) from the onset of symptoms, without early relapses or remissions. PPMS can be further characterized at different points in time as either active (with an occasional relapse and/or evidence of new MRI activity) or not active, as well as with progression (evidence of disease worsening on an objective measure of change over time, with or without relapse or new MRI activity) or without progression.

This will provide a more detailed sub-class will give four types of PPMS:
PPMS Active with Progression
PPMS Active without Progression
PPMS Not Active with Progression
PPMS Not Active without Progression

While some evidence suggests that PPMS represents a distinct, noninflammatory or at least less inflammatory pathologic form of MS, abundant clinical, imaging, and genetic data suggest that PPMS is a part of the spectrum of progressive MS phenotypes and that any differences are relative rather than absolute. Analyses of natural history cohorts demonstrate that worsening proceeds at a similar rate in SPMS and PPMS. PPMS remains a separate clinical course because of the absence of exacerbations prior to clinical progression, but it likely doesn't have pathophysiologically distinct features from relapsing forms of MS that have entered a progressive course (SPMS).

Approximately 15% of people with MS are diagnosed with PPMS.

For More Detail:

PPMS is characterized by worsening neurologic function (accumulation of disability) from the onset of symptoms, without early relapses or remissions. PPMS can be further characterized at different points in time as either active (with an occasional relapse and/or evidence of new MRI activity) or not active, as well as with progression (evidence of disease worsening on an objective measure of change over time, with or without relapse or new MRI activity) or without progression.

PPMS can have brief periods when the disease is stable, with or without a relapse or new MRI activity, as well as periods when increasing disability occurs with or without new relapses or lesions on MRI.

Why are modifiers used to characterize PPMS?

Disease activity and progression should be evaluated at least yearly by neurologic examination and MRI. Being able to characterize the course of your disease course at different points in time helps you and your MS care provider have important conversations about your treatment options and prognosis. For example:

If you have PPMS that is active, with new MRI activity or relapses, your conversation with your MS care provider could be about starting treatment with a disease-modifying therapy to reduce the risk of a relapse, as well as rehabilitation to help improve function and mobility.
If you have PPMS that is stable without activity or progression, the conversation with your MS care provider should include the role of rehabilitation to help you maintain function, as well as other symptom management strategies that you may need.
If you have PPMS that is not active (no new MRI activity or relapses) but is progressing with increasing accumulation of disability, the conversation with your MS provider needs to focus on the rehabilitation strategies that can help you maintain function and keep you safe and independently mobile.

How does PPMS differ from the other disease courses?

Although there is a lot of variability among people with PPMS, we know that as a group, they differ in several ways from people with relapsing forms of MS:

Relapsing forms of MS (including relapsing-remitting and secondary progressive in those individuals who continue to experience relapses) are defined by inflammatory attacks on myelin. PPMS involves much less inflammation of the type seen in relapsing MS. As a result, people with PPMS tend to have fewer brain lesions (also called plaques) than people with relapsing MS and the lesions tend to contain fewer inflammatory cells. People with PPMS also tend to have more lesions in the spinal cord than in the brain. Together, these differences make PPMS more difficult to diagnose and treat than relapsing forms of MS.
In the relapsing forms, women are affected two to three times as often as men; in PPMS, the numbers of women and men are approximately equal.
The average age of onset is approximately 10 years later in PPMS than in relapsing MS.
People with PPMS tend to experience more problems with walking and more difficulty remaining in the workforce.
In general, people with PPMS may also require more assistance with their everyday activities.


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New Multiple Sclerosis Types of After to 2013

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Multiple Sclerosis Types of Prior to 2013

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