The term “clinically isolated syndrome” (CIS) has been used to describe a first neurologic episode that lasts at least 24 hours, and is caused by inflammation/demyelination in one or more sites in the central nervous system (CNS). The episode can be monofocal or multifocal:
- 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.
While this term is still in use, it is currently under review by MS experts to determine if another term that is more specific to a demyelinating disease process should take its place.
What is the Risk for a Person with a CIS of Developing MS?
Individuals who experience a CIS may or may not go on to develop multiple sclerosis. The challenge for the physician is to determine the likelihood that a person experiencing this type of demyelinating event is going to experience a second demyelinating event in the future, thereby meeting the criteria for a definite diagnosis of MS. Read more about the criteria for diagnosing MS.
- High Risk: When the CIS is accompanied by MRI-detected brain lesions that are similar to those seen in MS, the person has a high risk of a second neurologic event, and therefore a diagnosis of clinically definite MS, within several years.
- Lower Risk: When the CIS is not accompanied by MRI-detected lesions, the person has a lower risk of developing MS over the same time period.
Four 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 clinically definite MS:
- The CHAMPS (Controlled High-Risk Subjects Avonex® MS Prevention Study) study was designed to determine 1) if using interferon beta-1a (Avonex) early in demyelinating disease could delay the second episode of demyelination (which would signal clinically definite MS) and 2) if treatment would have an impact on MRI-detected brain lesions. The subjects in the study had each experienced a single, isolated neurological event suggesting demyelination and had multiple, clinically “silent” (without symptoms) MRI lesions, making them at high risk for a second neurological event and therefore a diagnosis of clinically definite MS.
The results indicated that interferon beta-1a significantly delayed the onset of clinically definite MS, as indicated by a delay in a second clinical attack. In addition, MRI findings showed that the patients receiving interferon beta-1a had a significantly smaller increase in the volume of brain lesions, as well as fewer new lesions.
Based on the results of this study, the Food and Drug Administration (FDA) extended the labeling of Avonex) to include individuals who experience their first clinical episode and have MRI-detected brain lesions consistent with multiple sclerosis.
- The ETOMS (Early Treatment of MS) study was designed to determine whether very low dose interferon beta-1a (Rebif®) would delay the onset of clinically definite MS in people who had experienced one clinical event and had multiple MRI-detected lesions consistent with MS.
Results indicated that fewer people on interferon beta-1a (Rebif) developed clinically definite MS (34%) than in the placebo group (45%) during the study time. In addition, the number of new lesions and the increase in the total accumulation of areas of myelin damage were significantly lower in the treatment group. The dose of Rebif used in the study was 1/6 of that generally used in the United States to treat relapsing-remitting MS.
To date, the FDA has not reviewed the data from this study.
- The BENEFIT (Betaseron® in Newly Emerging MS For Initial Treatment) study was designed to determine whether interferon beta-1b can delay the onset of clinically definite MS in people with CIS who are at high risk for developing MS.
Results indicated that treatment may significantly delay the development of clinically definite MS: At day 255 of the study, one-quarter of patients in the placebo group had developed CDMS while it took 618 days for a comparable number of patients in the treatment group to develop CDMS. At the end of the two-year study, 28 percent of patients in the treatment group had developed CDMS compared to 45 percent of the placebo group.
Based on the results of the BENEFIT trial, the FDA has expanded the indication of Betaseron® (interferon beta-1b) to include individuals who have experienced a first clinical episode and have MRI features consistent with MS.
- The PreCISe study was designed to determine how long it would take individuals with CIS who were taking glatiramer acetate (Copaxone®) to experience a second attack that would confirm the diagnosis of definite MS.
Results indicated that compared to the group taking a placebo, the risk of developing clinically definite MS in the group taking glatiramer acetate was significantly reduced.
Based on the results of the PreCISe trial, the FDA expanded the indication of Copaxone® (glatiramer acetate) to include individuals who have experienced a first clinical episode and have MRI features consistent with MS.
The results of these trials, and the FDA’s approval of expanded labeling for Avonex, Betaseron, and Copaxone support the earliest possible treatment for MS, which many believe may delay the development of permanent clinical disabilities.