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.

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.

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 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:

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.

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:

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.

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:

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.

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:

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: