RIS: To treat or not to treat, that is the question
Treatment Considerations in
the Radiologically Isolated Syndrome.
Curr Treat Options Neurol. 2020;22:3.
Radiologically isolated syndrome (RIS) is an inaptly named condition in which changes of central nervous system inflammation suggestive of MS are incidentally found on brain and spinal cord MRIs in persons with no neurologic symptoms or signs. Much has been written about RIS in terms of the risks of developing clinical MS and of the need to start treatment to prevent or delay development of MS. This paper reviews the risks of converting from RIS to clinical MS using data from central nervous system MRIs, and blood and spinal fluid findings. It also discusses the pros and cons of starting a disease-modifying therapy in persons with RIS. Most interestingly, data are also reviewed indicating that persons with RIS may not be entirely without neurologic changes since testing for cognitive functioning revealed lower than expected results. Two randomized, placebo controlled clinical trials with oral disease-modifying therapies are also reviewed. Results from these trials, will, hopefully, reduce the uncertainty as to whether preemptive treatment of RIS with a disease-modifying therapy is of benefit.
1. Central nervous system inflammation and demyelination identical to that seen in MS can occur without clinical symptoms or signs. Autopsy studies as well as analyses of large series of central nervous system MRIs document the presence of “asymptomatic” MS.
2. Such findings are uncommon in the general population, occurring in 0.2% of autopsies and 0.06% of routine MRIs. However, the frequency of MRI changes suggestive of MS is as high as 10% in first-degree relatives of persons with MS, confirming a genetic predisposition for this illness.
3. Upon finding changes of RIS in an individual at least two key questions need to be addressed. How many of individuals with “asymptomatic” MS will become symptomatic, and will early treatment of “silent” MS be of benefit?
4. Three studies addressed the issue of conversion from clinically “silent” to symptomatic disease. The researchers found a conversion rate from RIS to clinical MS of 34% after five years of follow-up and 53% after ten years of follow-up.
5. Several characteristics have been identified that increase the risk of conversion from RIS to clinical MS. These are younger age (<37 years, extending even into childhood), male sex, and lesions on MRIs in posterior fossa (the back of the brain) and spinal cord.
6. Additional risk factors for conversion are the presence of oligoclonal bands of antibodies (OCBs) in spinal fluid and elevated levels of neurofilament light chains (NfL) in blood. Changes in the eye (retina), when present, also increase the risk of conversion from RIS to clinical MS.
7. By definition a person with radiologically isolated syndrome never had neurologic symptoms and has a normal neurologic exam. However, recent studies showed subtle changes in thinking or cognition in such individuals. RIS individuals had lower than expected abilities, in some instances similar to persons with clinical MS. Though the risk for conversion from RIS to clinical MS was not increased in such individuals, it does indicate that persons with RIS may have functional difficulties related to their brain lesions.
8. Central nervous system MRIs in persons with RIS show mild loss of tissue (atrophy), indicating that the lesions on MRIs are affecting tissue health.
9. At what point should one treat persons with RIS with disease-modifying therapies? This remains very controversial. Most neurologist would initially withhold treatment, since, as noted above, persons can have years of central nervous system inflammatory disease and remain asymptomatic. Indeed, as noted above, with a 10-year follow-up of persons with RIS, almost half remained symptom free.
10. While surveys of neurologic health care providers indicated that a majority would not initially consider treatment of persons with RIS, if in follow-up there were new MRI lesions, especially of the spinal cord, and if there were active inflammation, as manifested by the lesions showing contrast enhancement, most neurologic health care providers would begin therapy.
11. Additional factors that could influence starting treatment would be rising levels of NfL (explained in more detail in a previous blog on this website) and/or increased worsening of cognitive functions (assuming there are no other diseases present that could contribute to this).
12. Low levels of vitamin D are associated with an increased risk of MS. Treatment with vitamin D supplements to maintain high normal levels of this vitamin have been advocated as a therapy for RIS.
13. Are the risks associated with starting treatment with a disease-modifying therapy overshadowed by the benefits of such therapy? The answer at this time is not known. However, there are two double-blind, placebo-controlled trials of radiologically isolated syndrome in progress. Both use an oral disease-modifying therapy. One uses dimethyl fumarate. The other uses teriflunomide. Details of these trials are available. Results from these trials will, hopefully, answer the question whether early treatment of RIS can prevent the development of clinical MS, justifying the risks associated with taking these disease-modifying therapies.
In a previous blog (“Looking backward to capture the future”) I discussed the value of neurofilament light chains (NfL) in assessing both clinical disease activity in MS and detecting the start of MS. By measuring NfL blood levels to detect “silent” or subclinical central nervous system inflammation changes in the levels of tissue injury can be detected. In a slightly different context is the poorly named phenomenon “radiologically isolated syndrome” or RIS. RIS is not really a “syndrome” in the true meaning of the term (“a group of symptoms which consistently occur together, or a condition characterized by a set of associated symptoms.”), since by definition persons with RIS do not have symptoms related to their central nervous system lesions. Nevertheless, the term has been widely used to describe lesions on central nervous system MRIs that are most suggestive of the changes found in clinical MS, but in persons without neurologic symptoms or abnormal findings on exam. The obvious questions upon finding such changes are 1) do these persons go on to develop clinical MS, and 2) should one initiate treatment of such individuals with an MS-related disease-modifying therapy?
Some data are available in regard to the first question. Five-year follow-up of persons with RIS revealed a conversion rate from silent to clinical disease in 34% of individuals. At 10-years of follow-up the conversion rate was 53%. These data stand in contrast to the frequency of clinically silent MS found at autopsy (0.2%), in 0.06% of routinely obtained central nervous system MRIs, and in 10% of MRIs obtained in first degree relatives of persons with MS. All these data indicate that it is biologically possible to have substantive MS-like central nervous system inflammation throughout life and never have clinical symptoms. That said, persons with RIS do have an increased risk of becoming symptomatic.
Certain characteristics of persons with RIS increase their risk of converting to clinical MS. These are younger age (<37 years and even seen in childhood), male gender, and having lesions in the posterior fossa (back of the brain) and/or the spinal cord. Other possible risk factors that have not been definitively established are the presence of oligoclonal bands of antibodies in the spinal fluid and increased levels of neurofilament light changes (NfL) in blood. The latter is particularly concerning since raised levels of NfL are associated with destruction of neurons (nerve cells). While by definition persons with RIS do not have symptoms, recent studies showed mild thinking or cognitive changes in such individuals. In addition, brain volume was decreased in certain areas, indicating a loss of tissue due to the “silent” inflammation. Groups of individuals were studied, so we don’t know on an individual level whether such changes are associated with a greater risk of developing clinical MS.
The second question, one of initiating treatment with a disease-modifying therapy, remains disputed. Most neurologic health care providers in Europe and the United States would not immediately start such treatment. Since low vitamin D levels increase the risk of developing MS, most health care providers would ensure that vitamin D levels were in the high normal range, prescribing supplements if necessary. If, however, new lesions appeared, especially in the spinal cord, and/or if lesions were newly inflamed, as shown by the presence of contrast enhancement, treatment would be considered.
My own approach would be to consider treatment if new lesions appeared in the spinal cord and/or posterior fossa, if blood levels of NfL continued to rise indicating more tissue destruction, if cognitive testing revealed worsening cognitive functioning, and if new lesions appeared that resulted in “black holes” on central nervous system MRIs. Black holes are areas of severe tissue loss, and accumulation of such “holes” indicates a more destructive pattern of brain inflammation. Choosing a treatment will need to be discussed with the person with RIS, in terms of risks, potential benefits, and a review of the uncertainties inherent in arriving at a decision.
The issue of whether treatment is of any benefit in preventing conversion to clinical MS may be resolved with the two double-blind, placebo controlled, randomized clinical trials currently in progress. The trials utilize oral drugs, one dimethyl fumarate, the other teriflunomide. Whether these are the best drugs for this purpose, or whether more potent and potentially more toxic drugs are needed, remains an issue for further research.