CIS - THE CLINICALLY ISOLATED SYNDROME

[Quixotic1]

CIS - the Clinically Isolated Syndrome

WHAT IS IT AND WHAT DOES IT MEAN?

With the growing evidence that the Disease Modifying Drugs are most useful in treating MS when they are used early in the course of the disease, there has been a flurry of research into what indications there might be to determine who is most at risk to develop Multiple Sclerosis.  Ideally we would like to be able to identify who really is at risk for MS when a patient shows up with suggestive symptoms.  The best way would be to have a blood test, that only MS patients had, but no one else had.  This would be called a "biomarker".  Unfortunately, despite intensive research, no suitable biomarker has yet been indentified.  We are left with trying to predict which patients who have early signs "suggestive of MS" will convert into "definite MS".  

Since RRMS (by far the most common kind) is characterized by symptoms and problems that occur in repeated attacks (Dissemination in Time) and by symptoms and problems that occur in different parts of the Central Nervous System, CNS (Dissemination in Space), our best bet is to look at those people who have only had their first attack.  This is a situation called a "Clinically Isolated Syndrome".  Waiting for a second attack may take many months or even many years.  We know from studies over the last 15 years that early treatment can help delay someone from having that second attack and getting those additional symptoms and problems that would make up the picture of full-blown MS?  How do we know which people with a CIS are most likely to "convert" from suspected MS to Definite MS?  Where can we look to make the best judgment so we can start treatment to prevent or substantially delay this conversion.

The diagnosis of MS requires that we find evidence that the disease has "acted up" on more than one occasion, more than 4 weeks apart.  This is called "Dissemination in Time".   This is what is missing in the person with CIS.  They have only had one attack.  This means that without further information we cannot make a diagnosis of MS.  The McDonald Criteria allows us to look at the MRI and, over time, find evidence that there is another attack on the central nervous system.  But, we want to predict as early as possible so we can treat and the MRI often does not yield enough information.   This is where the study data on CIS plays a role in predicting who will convert to MS.

Over the recent years, doctors and patients have used the term CIS to mean a variety of things - so much so that it has become a confusing term.  I found an comprehensive article published in the journal, Multiple Sclerosis, in 2008. (Mulitple Sclerosis 2008; 14: 1157-1174)  The method to explore this topic was to bring together 18 experts in the MS field from all over the world into a task force.  They met and worked on this in 2007.   They worked together to formulate some recommendations for the analysis and work up of a patient with CIS.  This group included some of the most well-known names in the field.  This was needed because the McDonlad Criteria - has not been the thorough diagnostic aid that some had hoped.  In fact, the Criteria have been most useful in "predicting" which patients who did not fulfill all the clinical requirements - of spread of the disease in time and space - were most likely to develop MS rather than being useful in "diagnosing people with MS."  In fact, many neurologists have misinterpreted the McDonald Criteria and misused it, as we have discussed so many times in the forum.


THE DEFINITION OF CIS

The task force felt that there were actually several "subtypes" or classes of CIS that had confused practitioners and that might have caused too much variability when they were lumped together in studies.  So, they proposed the following groups so that neurologists would have a clearer approach to diagnosis.

First they decided that the term CIS should ONLY  refer to the patient that had one, single attack of symptoms and signs that suggested an underlying inflammatory, demyelinating disease.  In general, this referred to the appearance of one or more symptoms which appeared fairly suddenly - over hours or days to maybe a week.  They defined the classes of CIS based on whether this first attack involved only one symptom, called "monofocal", such as an attack of optic neuritis without any other symptoms, whether there were two or more symptoms, called multifocal, like facial numbness and weakness of a limb, and whether there was associated MRI features consistent with demyelination.  They included one scenario, though, that had previously been ignored.  This was the patient who had no symptoms, or just very non-specific symptoms (like dizziness or headache), but somehow had MRI lesions found that suggested evidence of multifocal disease of a demyelinating type.  This means those people who have MRIs done for some other reason than looking for MS, like as a work up for headaches or after a head injury.

The Classes of CIS

First some definitions:

Mono = one

Focal = spot, place (monofocal - just one spot)

Multi = more than one (multifocal - more than one spot)

I     CIS - clinically monofocal, at least one asymptomatic MRI lesion.  This person has had one attack and has only one symptom suggestive of a demyelinating lesion in the CNS (for example hypereactive reflexes in one limb).  However, they also have at least one lesion on the MRI for which there is no correlating symptom.  That MRI lesion should be consistent with MS.

II     CIS - clinically multifocal, at least one asymptomatic MRI lesion.  This patient had had just one attack, but has indications that there are more than one demyelinating lesion in the CNS.  An example of this might be optic neuritis and L'Hermitte's Sign.  On the MRI there should be at least one lesion that doesn't have a corresponding lesion, ie. at least one asymptomatic MRI lesion.  The MRI lesion(s) should be consistent with MS or demyelination.

III    CIS - clinically monofocal, MRI may appear normal; no asymptomatic MRI lesions  This patient has had just the one appearance of a single symptom, like pain on eye movement with visual disturbance, and their MRI is normal; there is no asymptomatic MRI lesion.  Approximately one third (1/3) of all patients with CIS will have a normal baseline MRI.

IV    CIS - clinically multipfocal, MRI may appear normal; no asymptomatic MRI lesions  This patient has more than one symptom, for example facial numbness and a urinary urgency of a neurolgical type.  The task group deems this a "rare" occurrence, but the article does not elaborate, stating that they believe this is a rare occurence.

V    CIS - no clinical presentation (no attack) to suggest demyelinating disease, but MRI is suggestive.  An MRI done for some other reason happens to show multiple lesions that are suggestive of demyelination.  But the patient has had no symptoms OR they have had very non-specific symptoms like fatigue, headaches or dizziness.

con't below

[goofysmom1]

Thank you for this!  It is great to have it all explained in one place!  This should definitely be a HP!  Since my MS neuro believes that I have CIS at this point, all of this is very important information to think about - and to discuss with my neuro at my next appointment.

Thank you for all you do for us here.

Hugs,
Chrisy

[tarter]

To: Quix

Makes great reading and shall help me understand this complex neurological process.
I cant wait for my next neuro appointment I will be able to educate this man to come out of the box!

The time scale is the most educating pce of info incredible that the Neuro dont ever mention the increase in persentage has the 7/ and 14th/ yr pass, Our chances of going onto develope MS increase significantly.


As usual Quix I am blown away with your knack of discriptive knoledge.

Many thanks tarter

[Quixotic1]

What marks the conversion form CIS to Definite MS?

I left this out.

Two things can tip the scales from CIS to MS.

The first is a second clinical "attack."  Remember that a CIS is a person that has had only one attack.  In people who's CIS was "monofocal" - that is they only showed evidence of damage in one area of the nervous system, the second attack whould be with symptoms or signs that indicate a new area of the cnetral nervous system had been hit.

The second thing is sufficient changes on the MRI.  The McDonald Criteria lists the kind and number of new lesions that can be used to "stand in" for this second attack.

Ideally, a person with a CIS would be on treatment with a DMD and this would take a long time to show up!!

Quix

[ScaredyCat2010]

Though the information you provided is NOT good news for me, I greatly appreciate your efforts to convey this complex topic in layperson's terms. I was recently diagnosed with CIS and the MRI reveals one periventricular lesion. All of my evoked potentials & eye blink test were normal and my neurological examination was mostly unremarkable (my presenting symptom was partial numbness on the left side of my body). However, CSF lab results reveal that, unfortunately, I am positive for oligoclonal bands. My neurologist suggested that since I had chicken pocks at age 25 (I am now 39), oligoclonal bands can present, but he said that only in rare cases would they persist for this many years. So based on the information you provided it looks like I've got almost a 100% chance of developing MS. It is frustrating that my neurologist told me that I had a 30-40% lifetime chance of developing MS. I will definitely discuss this information with him.

Quixotic, I was wondering where you got the graph you posted above? I would like to look at the article at bring a copy to my neurologist. I did look at the article that you posted and if was very informative. Also, could you post which articles you got information from that mention a lower likelihood of developing disability when there is only one or perhaps very few MRI lesions at baseline? Additionally, if you could post a bibliography of any articles you found helpful I would be grateful.

Thanks again,
ScaredyCat2010

[samandsprout]

Such important information!  Truly, thank you for taking the time to compile and share it with us.  It is unbelievably helpful.

My question has to do with the definition of a lesion that is "consistent with MS".  I now have a CIS diagnosis with about 10 nonspecific lesions.  Most are "punctate," but I have 2 larger ones.  I think they are in areas that aren't as typical for MS.  So, while MS is in my differential diagnosis, so are some other things like migraines.  In these studies on CIS, what is considered a lesion "consistent with MS"?  Does it have to do with size, location, etc.?  

I am in the process of considering DMDs for CIS and want to have all the information I can.  I don't have a good relapsing-remitting pattern, but rather random, minor symptoms that come and go (for example, a re-occurring tingling patch on the bottom of my foot that sticks around for a couple of days at a time).  I do have a family history of MS.  Oh, and I should add that my MRIs and symptoms are virtually stable for the past 7 years (my second opinion neuro *did* think she saw some change, which is why she pushed me into the CIS category).  So, I guess at least I am not in that 80% of the high risk group who develop MS after 7 years?

So, I am trying to figure out if I *am* in that high-risk category on the chart or not - I have the quantity of lesions, but I am wondering how to tell if they qualify to be counted.  

Thanks!!
Laurel

[Quixotic1]

Shoot!#%#$#%

My JEG file with the image abovew did not include the three references from which this graph was made.  'My bad!

The data for the "Risk to Conversion" and the "Risk to Disability" I got from a lecture by Dr. Timothy Vollner of the Denver MS Center.  It was published online by Peerview Press in a continuing education activity.  Here is the reference for that lecture.  If you want to watch the podcast you need to disable any pop-up blocker.  You can also download the transcript (close the podcast window) into a .pdf file.  the transcript will give you many of the references.

http://www.peerviewpress.com/selecting-immunomodulating-therapy-relapsing-remitting-multiple-sclerosis


There are two slides, #'s 7 and 8 (though I am not sure of this).  the first is the bar graph above.

Here are the references for this slide.  Many slides have their own references.

Tintore M et al.  Neurology. 2006; 67:968-972.

Brex PA et al. N Engl J Med. 2002:346:158-162

Fisniku LK et al. Brain. 2008;138:808-817

The second slide is the one that shows disability status as measured by the EDSS compared to lesions at baseline.  The only reference for this one is

Tintore M et al.  Neurology. 2006; 67:968-972.


In the future I will take care to print the link or the reference cite for what I say.

SCat - Generally (if I remember correctly) a brain infection (like a meningoencepahlitis) would cause just one O-Band.  And these typically do fade with time (a few years).  so, I agree with your neuro that it would be really hard to account for your O-Bands on that basis.  And your episode of partial left-sided numbness is VERY consistent with a demyelinating attack.

Laurel - I have never read an exact definition of what it means to have a lesion which is "consistent" with MS.  However, from my professional work, it would mean a lesion that could be seen in MS.  The question one would ask is, "Would it be reasonably common to see a lesion in this spot in a person with MS?"  Many neuros would say it has to be "classic."  I disagree that the use of the word "consistent with" would have to be so strict in interpretation.

So, lesions in the periventricular region, the subcortical region, the corpus callosum, the cerebellum, the brrainstem and the spine would all be examples of lesions that are consistent with MS - and probably a few others.  But lesions in the meninges, lesions that are clearly infarctions, in the dentate nuclei, if all lesions enhanced simultaneously, infiltrating lesions (without a clear border and extending into the adjacent brain matter) - These would not be consistent with MS.

Then, very punctate (pinpoint) lesions could be considered not as consistent with MS and many docs would require that they be at least 3mm in size.  Remember we are talking about 1 or 2 being enough.  Seven years is a long time.  We can hope that you escaped.  However, MS can be so mild as to only cause minor sensory symptoms, just as you describe with the numb patch.  Since you have had those, I would say you may, indeed, have MS.

We are 7 years in and your course is still very mild.  I have read some sources that say that mildness at 10 to 15 years is "highly indicative" that the course will remain mild.  the problem is that it is not a guarantee.

I have posted studies before that show that 20 years into the illness, 30% of people deemed "benign MS" will require assistance to walk, some number near that will have noticeable cognitive problems and about 12% will have significant cognitive problems.  For this reason, I am deeply adverse to ever calling MS "benign."  (I would have to go back and find those references - which I will, if asked.  Sadly, my organizational skills have gone the way of the dodo bird.))


Quix