“I received an email query from a young woman who has had a clinically-isolated syndrome (CIS) and had difficulty getting onto an injectable 1st-line therapy because of confusion around the guidance from NHS England regarding eligibility for treatment. The guidance simply states that ‘Patients are eligible for treatment within 12 months of a clinically significant clinically isolated syndrome when MRI evidence predicts a high likelihood of recurrent episodes’. The question proposed is what is a high likelihood of recurrent episodes? This guidance refers back to the Association of British Neurology (ABN) 2009 guidelines and is deliberately loosely-defined to leave it up to the neurologist to make a judgement call. In the past we had to make sure all patients with CIS fulfilled MacDonald criteria for having multiple sclerosis, i.e. dissemination in time and space, and had a high lesion load (>9 T2 lesions) and/or an active lesion(s) (Gd-enhancing lesion) on their baseline scan. This guidance is based on the Queen Square and other data sets demonstrating that baseline lesion load, and baseline activity (Gd-enhancement), predicts a poorer prognosis and more rapid conversion time to clinically definite MS or the next clinical attack.”
“I personally think the prescribing guidance, based on baseline lesion load and/or presence of Gd-enhancing lesions, is outdated and is not in keeping with our current understanding of multiple sclerosis. It is clear that MS has a relatively long asymptomatic period and what determines when you present with your first clinical attack is whether, or not, a new lesion happens to occur in a clinically eloquent site. Therefore baseline MRI is an indicator of how long you have had the disease; the higher the lesion load the longer you have had the disease the and the more likely you have underlying end-organ damage. If our aim is to prevent damage with DMTs the lower you lesion load the earlier you are in the course of the disease the more there is to protect. According this logic you are lucky if you present with a low lesion load as you are earlier on in the course of the disease and hence more likely to benefit from DMTs. Please remember that the aim of DMTs is to prevent damage not repair damage; to maximise this prevention strategy you have to start treatment early.”
“Please remember that what we see on MRI in terms of lesions is only the tip of the MS iceberg; the majority of disease is not visible on MRI. All the CIS trials included patients with abnormal MRI scans and they have all shown that patients started early do better. So why wait? When you interrogate CISers at baseline you find a significant proportion (30-50%) have cognitive impairment, fatigue and depression. These hidden symptoms are probably due to gray matter involvement that is not visible on routine diagnostic MRI scans. If you apply specialised data analysis tools to the MRI scans in CISers you find a large proportion of them have baseline gray matter atrophy indicating that their disease has been active (shredding the cortex) prior to their CIS presentation.”
“What is not frequently communicated to patients is that those CISers who access injectable therapies early, compared to those who have to wait until their second attack or were only started treatment as part of the open-label extension studies (typically 18-24 months later), do better. This has been elegantly shown with regard to cognitive outcomes in the BENEFIT study. The EDSS data is relatively weak in relation to disability, but that is not unexpected as the EDSS a very poor outcome measure for tracking disability early in the course of MS; in statistical jargon the EDSS has a floor effect and this was seen in the BENEFIT study.”
“What I can say is that in general UK neurologists are the outliers when it comes to prescribing DMTs for CISers. In almost every country in the world CISers with an abnormal scan will be offered the option of going onto a treatment. Most UK neurologists would rather wait for the second attack, during which time irreversible damage could potentially accumulate. What you have to remember is that when you present with CIS some CISers are not ready for DMTs. They go often in denial and are not interested in knowing about the link between CIS and MS, and their future prognosis. It is not wise to push the issue with these patients, but to support them and be there if and when they are ready to make a decision. Poor adherence to DMTs are a problem and if you are not ready for treatment you are unlikely to adhere to your treatment. Therefore we really need to adapt and personalise decision making; doing things relatively slowly may result in the best long-term outcomes.”
“What I haven’t discussed in this post in detail are the other prognostic factors that we tend to take into account when profiling CISers at baseline; these include whether or not there are lesions at the back of the brain in the so called posterior fossa, is there obvious baseline brain atrophy, which is a very poor prognostic sign, the type of clinical attack (motor/cerebellar vs. sensory), was the first attack mono or polysymptomatic (polysymptomatic attacks have been linked to worse outcomes in some studies), the degree of recovery from the attack (poor recovery poor prognosis), sex (males do worse), ethnicity (Asians and Africans do worse) and whether or not the spinal fluid analysis was abnormal (CISers with CSF OCBs do worse). In addition, to the disease profile personal factors come into the decision including psychological state, level of background knowledge and if you are a female whether or not you are planning to have children. Outside the UK and other countries with socialist healthcare systems, medical insurance coverage and being able to afford DMTs, are sadly a crucial factor deciding access to DMTs.”
“What do you do if your neurologist refuses to offer you DMTs for CIS? I suggest you have a frank discussion about why and ask him/her to justify their reasons. If the latter are unacceptable to you, you can always ask for a second independent opinion; the NHS Charter allows this. A reasonable compromise is to ask for a monitoring follow-up scan at say 3, 6 or 12 months on the condition that if your disease has been active (increased lesion load or active lesions) you can be started on treatment. This would indicate you have developed definite MS.”
Wont you have to at least wait for symptoms to subside before starting DMT?To confirm it isnt PPMS
Re: "Wont you have to at least wait for symptoms to subside before starting DMT?To confirm it isnt PPMS."Most patients presenting with CIS have symptoms and signs that come on over days and have a clear attack. Unlike PPMS when the symptoms appear gradually over months to years. In addition, by the time the diagnostic work is complete for CIS the symptoms and signs may be remitting. It is also not uncommon to treat the CIS attack with steroids. Therefore it is very unusual to get the diagnosis of CIS and PPMS confused.
Thanks for this post Prof G. It was I who asked the question. The situation around DMDs for CIS would appear as clear as mud. I imagine just a handful of CIS patients are receiving treatment as neurologists are so unclear how to interoperate the policy. The baseline lesion load you refer to has been banded about with me when defining high risk cases. I know the definition of high risk in the SPC of Rebif is being used as a yard stick and effectively this excludes all CIS cases as it actually refers to CDMS. This is despite Rebif being licensed for a single demyelinating event. Surely using this outdated definition can no longer be justified given it seems to refer to the 2005 diagnostic criteria and not the 2010? The main point of using DMDs at the CIS stage is to delay conversation to CDMS so using the SPC of Rebif definition makes no sense at all as by that point the patient already has it. The 2010 criteria allows the diagnosis of MS on much less lesion load. Furthermore it is my experience not all neurologists are aware of the CIS prescription guidelines full stop and still think you are only eligible after two relapses. I certainly spent several months quoting the commissioning paper to no avail. I agree with you patients should ask to be referred elsewhere but the problem is you are against the clock. You have 12 months from the date of the CIS and the reality is wrestling with the NHS system is painstakingly slow. Being referred to someone else takes time and the waiting lists can be long. Finding a proactive neurologist is like finding a needle in a haystack and by then time may have ran out. Of course some CIS patients will have already had another relapse at that point so I guess that’s one way to solve the problem. I genuinely think this issue needs looking at a patients are being failed. On another matter is it standard practice for Trusts to use the same diagnostic code for both CIS and MS when collecting and maintaining data? Does this practice not make it difficult to identify CIS outcomes in relation to DMD’s by not defining the differences between them?
Re: "I genuinely think this issue needs looking at a patients are being failed."I agree and is part of the reason why we run this blog. You may find my previous post on the diffusion of innovations of interest. http://multiple-sclerosis-research.blogspot.co.uk/2014/04/clinic-speak-diffusion-of-innovations.htmlMay be we should start a lobby with the MS Society, MS Trust and other stakeholders to change things? If you feel so strongly about this you should do something about it. At the end of the day it is local, regional, national and international MS Champions that change the world for the better.
Prof G, are all patients told they have CIS now? Is it law now that you must tell a patient? If not, how do Neurologists decide whether to tell or not? I come from an age of being told not to tell other patients in the ward what illness I had.
Re: "Prof G, are all patients told they have CIS now? Is it law now that you must tell a patient? If not, how do Neurologists decide whether to tell or not?"In my practice all patients are told about the link between CIS and MS. There is no law stating that you have to tell patients they have CIS and are at risk of developing MS. There are still many, typically old-school, neurologists who think it is best for patients no to know this. For example, I saw a patient earlier this year who had had a spinal cord lesion 4 years ago and represented with another attack. The last attack has left her troublesome bladder problems, reduced walking ability and poor balance. Maybe if she was told that she had CIS and was offered DMTs 4-years ago she may not have had this attack and would not be disabled.I recall a case I saw 20 years ago that was not told about the link between CIS and MS and when she had a critical illness-life insurance application turned down on the high likelihood she would develop MS she was livid. As a result of this she couldn't get a mortgage. Since then we have had the democratisation of knowledge via the internet and web; anyone who has CIS knows about the MS link between CIS and MS as soon as they type it into a search engine. So in the internet-era most neurologists tell their patients up front.
After CIS you should get an induction therapy.Regular injections for perhaps the rest of your life and it may not even be MS – doesn't sound good at all.
What is induction therapy?With odds of developing MS at 80% I think I'll risk taking dmds. Doing nothing is a bigger risk as far as I'm concerned. If I had no lesions I would be content to see how things go but I do and my CIS floored me in no time at all. Its hard to be in denial when you have experienced something so severe.
Induction therapy is one-time hard hitting treatment that potentially knocks the disease out.Alemtuzumab does that in early RRMS but it can have severe side-effects and it isn't approved for CIS.
There are many mimics of MS on MRI and clinically. MS being the most common for the MS type lesion pattern.So it is important a correct diagnosis of CIS (caused by MS) is made, lumbar puncture could help in the diagnosis and a second follow up MRI. Otherwise a DMT for MS may not help if the patient has one of these mimics. It could make symptoms worse. MS mimics include sarcoid, lyme and sjogen. I remember reading a study and 10% of the MSers were found to have sarcoid.
Situation: MRI shows many small lesions. Mild symptoms that would usually not be investigated have been present for a few weeks
Would there be a reasonable 'guess' as to the percentage of people with CIS who are offered DMDs as an option to slow/halt damage and progression? Or is this recommentation much too young to have had a significant impact on treatment plans?
I'm trying to find this out as I imagine the figure is extremely low. I know I'm the only one in my trust on a DMD. If CIS and MS are coded together though I don't know how this figure can be established.
Two Trusts near me have no CIS patients receiving DMT's. I suspect this is a common theme across England.
With reference to Prof G's comment above about lobbying, I definitely think the time has come/is well past time for MSers to be a lot more vociferous/militant/call it what you will about all sorts of aspects of their lives in relation to the state and what it provides, or not, as the case may be. As well as the example above about trust record keeping/statistics etc, there all sorts of other things for example the lack of NICE approval for Sativex and Fampyra, the difficulty in getting some benefits to which people are entitled and have in most cases contributed to the tax system which supports them. Also, the difficulty some people experience with getting a Blue Badge. I would be pleased to join with others to help form such a group – although the various MS charities campaign and lobby etc I think there is merit in MSers taking direct action, as well, maybe as a totally separate organisation. Thoughts, anyone?
I think the difficulty is MSers fall into two main groups, those that are not too affected (yet) and therefore getting on with their lives and those that are affected and therefore concentrating on just surviving. MS is also (luckily) not infectious so does not carry the same fear factor and public interest in comparison to the AIDS movement.
It's not that simple there are loads of people with active MS that are trying to get on with their lives. Reading the posts on this website, there are different symptoms, different opinions and different NHS carte. If we were all the same, there would have been a cure by now.
"A reasonable compromise is to ask for a monitoring follow-up scan at say 3, 6 or 12 months on the condition that if your disease has been active (increased lesion load or active lesions) you can be started on treatment. This would indicate you have developed definite MS.”If I was in the position of being CIS again and wanted to be on a DMT I would be pushing for a follow up MRI at 6 months, requesting full blood tests for lyme, HIV, vit D, etc and possibly lumbar pucture. I was surprised not to have full blood tests done when I had my first relapse. It does not seem to be standard practice and it would of put my mind at rest. I do think MRI and full blood tests should be done during the first relapse. I had to request my blood tests then the neurologist was very good and I had them done after that appointment.
I remember finding out about a patient with CIS and she was turned down for DMT. So she wrote to her MP and that got her on to a DMT.
Team G,The UCL/Barts MS Research Day 2014 video uploaded a few days ago. Did I hear correctly on Dr Millers speach on DMT's for RRMS that Alemtuzumab can be recommended for 'active RRMS' and he says this may mean after '1 relapse or activity on an MRI scan'. So this means after CIS?? He says this at 19.34 mins in http://www.youtube.com/watch?v=cOO7blVRsgo. Please could you clarify thanks.
NICE state "active MS" this could be read as active on an MRI scan.As to CIS…it would need to be MacDonald MS i suspect
The problem with the queen square data is that a <1.5 T MRI was used, so we cannot interpret the data for modern patients. Also, counting lesions is irrelavent unless the lesions are actually typical multiple sclerosis lesions and not "UBO"s, microvascular disease, or old periventricular leukomalacia. My experience is that nearly 100% of patients with CIS and >10 classic multiple sclerosis lesions on initial MRI develop CDMS eventually. I guarantee you than many of the 20% in the queen square data did not truly have initial scans suggestive of MS. I get radiology reads like "consistent with demyelinating disease" all the time in a patient with migraine with visual aura and nonspecific tingling who actually just has UBOs.I definitely agree with Dr. G's essential point that CIS with typical MS lesions on MRI is just MS despite not meeting the diagnostic criteria. Whether or not the lesions correspond to attacks is largely random, and injury to the brain can add up over time and can be irreversible.
To the lady who asked the original question, the MS Trust have offered to forward to you an email from me about being in the same situation. It was them that told me about this blog. On Friday I was diagnosed as having had a CIS 5-6 weeks ago with an 80% chance of developing MS in the future. I'm not content to just sit here and wait for that to happen so I'd be ever so grateful if you could let me know more about your experience and how you found your proactive neurologist. I'd be ever so grateful.
I have no problem with that. You are welcome to email me.
Not sure if this post will still be monitored.Whatsbis thebbetter indicator of likely progression from CIS to MS, MRI or Oligoclonal band presence in CSF only ? I had a single area of inflammation within the cord identified on a lumbar MRI but 3 weeks later a full MRI showed this inflammation had resolved and there were no signs of inflammation or lesions elsewhere in spine or brain. A LP provided a positive result for Oligoclonal bands kn the csf only. Loss of sensation in the left foot and to a lesser extent the left leg was the only symptom which partially resolved. Does the lack of brain lesions or presence of Oligoclonal bands serve as the better indicator or risk of CIS to MS ? Thanks
I would also be interested to hear opinion on this question
I would also be interested to hear reply to above question. I am diagnosed cis with over 20 brain lesions and 1 spinal lesion. Have positive lumbur puncture but no new lesions since baseline although spinal was only done recently so have no baseline to compare spinal mri with.