Is it not time to extend the diagnosis of MS into the asymptomatic phase?

At a continuing medical education (CME) meeting I co-chaired in Vienna, a concept emerged that is silently gnawing away at my consciousness and has changed my thinking.

The concept concerns how we deal with the problem of the radiologically isolated syndrome (RIS) or asymptomatic MS.

I have openly criticised the New McDonald criteria for not allowing us to make a diagnosis of asymptomatic MS. Why? Because if we buy into the concept of time is brain and our treatment aim is to maximise lifelong brain health then we really need to be able to treat RIS. Why? People diagnosed with RIS, currently a pre-disease state, already have evidence of end-organ damage. People with RIS have smaller brains than age- and sex-matched healthy controls. When you interrogate RISers, about 25% of them already have significant cognitive impairment in at least two domains. In other words, the biological processes that drive MS (‘The Shredder’) are present in the asymptomatic stage. What we then have to rely on is that one of their next lesions occurs in an eloquent pathway to cause an attack so that MS can be diagnosed and only then treated, or not. I say possibly because in many countries early MS, or clinically isolated syndromes (CIS), can’t be treated and the person has to wait to have a second attack. Possibly, a more worrying statistic is that about 10% of people with RIS, who are diagnosed with MS, go onto present with primary progressive MS. This proportion is similar to the proportion of PPMSers in the wider MS population. As you know PPMS is more advanced and less modifiable than MS in the early or so-called relapsing phase (RRMS). I hypothesise that if we treated RIS we may be able to prevent, or at least delay, a proportion of them presenting later with PPMS.

The debate we had at the weekend meeting is that if you have someone with RIS and you offer them a formal neuropsychological assessment and they come back with cognitive deficits can you count this as a sentinel event, or an attack, and diagnose them as having MS? We all agreed that we would still need to show dissemination in time and space, which could now be done using MRI and/or CSF analysis (presence of locally synthesised oligoclonal IgG bands).

I will now argue for using cognition as one of the neurological domains for defining MS. Some of my colleagues disagreed with me, but a lot nodded their heads in agreement. We need consensus on this. Clearly, the implications of #ThinkingCognition are enormous and it will allow one to make a diagnosis of MS in a proportion of patients in the so-called prodromal or asymptomatic phase of MS. The implications of this proposal are to change our diagnostic criteria for MS.

As we start to have this debate in MS our colleagues in Alzheimer’s and Parkinson’s disease have stolen a march on us. They have been disappointed time and again with failed DMT trials. By the time you are diagnosed with Alzheimer’s disease or Parkinson’s disease, it is too late to modify the disease; i.e. you have lost too much brain. Therefore there is a strong move to try and diagnose people with AD and PD before they present clinically. The principle is now so entrenched in the neurodegenerative disease space that most AD trials currently recruiting are recruiting high-risk cohorts with early pathological biomarkers of disease (amyloid-beta imaging and/or positive ApoE4 carrier status).

Up until now, we in the field of MS have been so far ahead of our colleagues working in AD and PD in terms of disease-modification. They have learnt from us that early is better. I am therefore surprised that we are letting them steal our thunder. I am aware that some of you would argue that as MS is not such a disabling disease we can afford to wait. Tell that to the 50% of unemployed MSers with an EDSS of 3.0 or less and also tell that to the 10% of RISers who present with PPMS a few years down the line.

We as a community need to take the ‘Time Matters MS’ mantra seriously and walk the talk. I, therefore, propose that we include cognitive impairment as part of our assessment of someone with RIS and if we find cognitive impairment we use that as evidence of an attack (cognitive relapse) and if they then fulfil McDonald criteria for dissemination in time and space, and other conditions are excluded, they have MS.

If you don’t agree with me let’s start a debate.

Please have your say and complete this short survey.

Thompson et al. Diagnosis of multiple sclerosis: 2017 revisions of the McDonald criteria. Lancet Neurol. 2018 Feb;17(2):162-173.

The 2010 McDonald criteria for the diagnosis of multiple sclerosis are widely used in research and clinical practice. Scientific advances in the past 7 years suggest that they might no longer provide the most up-to-date guidance for clinicians and researchers. The International Panel on Diagnosis of Multiple Sclerosis reviewed the 2010 McDonald criteria and recommended revisions. The 2017 McDonald criteria continue to apply primarily to patients experiencing a typical clinically isolated syndrome, define what is needed to fulfil dissemination in time and space of lesions in the CNS, and stress the need for no better explanation for the presentation. The following changes were made: in patients with a typical clinically isolated syndrome and clinical or MRI demonstration of dissemination in space, the presence of CSF-specific oligoclonal bands allows a diagnosis of multiple sclerosis; symptomatic lesions can be used to demonstrate dissemination in space or time in patients with supratentorial, infratentorial, or spinal cord syndrome; and cortical lesions can be used to demonstrate dissemination in space. Research to further refine the criteria should focus on optic nerve involvement, validation in diverse populations, and incorporation of advanced imaging, neurophysiological, and body fluid markers.

Kantarci et al. Primary Progressive Multiple Sclerosis Evolving From Radiologically Isolated Syndrome. Ann Neurol. 2016 Feb;79(2):288-94.

OBJECTIVE: The aim of this work was to evaluate the preprogressive phase in subjects with radiologically isolated syndrome (RIS) who evolve to primary progressive multiple sclerosis (PPMS).

METHODS: A multicenter RIS cohort was previously established. Demographic, clinical, and radiological characteristics of subjects with RIS that evolved directly to PPMS were compared to those that developed a relapsing disease course from onset (clinically isolated syndrome[CIS] or relapsing-remitting MS) and were also compared to two other population- and clinic-based PPMS cohorts.

RESULTS: Of the 453 subjects with RIS, 128 evolved to symptomatic MS during the follow-up (113 developed a first acute clinical event consistent with CIS/MS, 15 evolved to PPMS). PPMS prevalence (11.7%) and onset age (mean ± standard deviation; 49.1 ± 12.1) in the RIS group were comparable to other PPMS populations (p > 0.05). Median time to PPMS was 3.5 years (range, 1.6-5.4). RIS evolved to PPMS more commonly in men (p = 0.005) and at an older age (p < 0.001) when compared to CIS/MS, independent of follow-up duration. Subjects who evolved to PPMS had more spinal cord lesions (100%) before symptomatic evolution than those that developed CIS/MS (64%) and those that remained asymptomatic (23%) within the follow-up period (P = 0.005). Other MRI characteristics in the preprogressive phase of PPMS were indistinguishable from CIS/MS.

INTERPRETATION: Subjects with RIS evolve to PPMS at the same frequency as expected from general MS populations in an age-dependent manner. Besides age, unequivocal presence of spinal cord lesions and being male predicted evolution to PPMS. Our findings further suggest that RIS is biologically part of the MS spectrum.


About the author

Prof G

Professor of Neurology, Barts & The London. MS & Preventive Neurology thinker, blogger, runner, vegetable gardener, husband, father, cook and wine & food lover.


  • My biggest concern is whether we can distinguish the so called brain fog from a real cognitive deficit. Brain fog is experienced from all patients who suffer from chronic inflammation (lupus, hashimoto etc) as well as chronic EBV patients (an understudied patient group). There are studies about blood inflammation and brain fog and can be also proved by the response patients have on strong antiiflammatory therapies such as Ocrevus at these symptoms. MS does cause cognitive decline but without the McDonald criteria these symptoms can be attributed to other conditions.

    • We shouldn't assume that the McDonald criteria are fixed and set in stone. We are already on version 4.0. Version 5.0 may include asymptomatic MS.

  • Its a dificult task to be able to predict who is gonna covert or not to Cis and or Clinical Ms

    On the other hand overtreatment in the asymptomatic fase will impact

    those patients that have benign ms

    What is your answer to those patients?

    Suppose also that they have only one or two brain lessions and no Ocbs?


    • Is there such a thing as benign MS? If yes, can you please define it for me? I would argue that someone with RIS who already has cognitive impairment already has non-benign disease.

      I am not sure what point you are trying to make, but it sounds as if you value your cognition less than your physical functioning. What I am trying to do is to get people to #ThinkCognition and take the impact that MS has on cognition seriously.

  • This blog has been active since 2009 and I think that, as someone with 'PPMS, the arena of MS pharmacological advancements has been throughly rubbish.

    The scenario will be just as bad for another decade. Also, for those MSers that believe that they're now 'cured', they most likely are not. Their CNS is also primed for advance MS, only it's been delayed via new DMTs. It may still very likely occur.

    What we need is clearer thinking and more honesty from you, Professor G.

    • Clearer thinking is difficult if you have cognitive impairment. Have you thought about that?

      Having a preventable dementia that is not being treated is something we would like to avoid. Time is brain so the sooner we protect your brain the better.

    • Re: "I think that, as someone with 'PPMS, the arena of MS pharmacological advancements has been thoroughly rubbish."

      Since we have started this blog ocrelizumab has been licensed for PPMS. Is this not something to celebrate?

    • With all due respect in the world, that's bloody just rude Prof G.

      (Frustrated) Person with MS: "I think that, as someone with 'PPMS, the arena of MS pharmacological advancements has been throughly rubbish."

      Gavin Giovannon: "Clearer thinking is difficult if you have cognitive impairment. Have you thought about that?"


      PS. I think the person with PPMS is rightly pointing out that ocrelizumab (like HSCT) is not enough to give people with PPMS a qualify of life they want and deserve and it is not enough to give them certainty about their future abilities.

      If ocrelizumab doesn't do that for people with MS, what on earth (as a doctor) is your point? that the commentor is not thinking clearly or that the commentor is not grateful enough for the, to be frank, ridiculously pitiful results of ocrelizumab in progressive ms.

      Perhaps people will celebrate when you tell them the medical profession can help their disease from wrecking further damage on their most prized asset – the brain that controls EVERYTHING they do.

      Until that time, how on earth can a walking doctor without cognitive impairment tell people suffering from the disease the doctor is treating that they are not grateful enough and should celebrate more cos there is a drug that may slow progression by about 26% in i think 30% or so cases…. (my stats are prolly off, i haven't looked up them recently)

      What a hurtful patronising comment……… Thanks. (a partner of a person with MS)

    • Re: "…slow progression by about 26% in i think 30% or so cases."

      This refers to the lower limbs over a period of 3-4 years. In the upper limb this is close to 50%. Because of the therapeutic lag these figures may be 60%, 70% or even 80% over 5, 7 and 10 year time periods. In addition ocrelizumab can only do what it does; it is an anti inflammatory and reduces further damage. Ocrelizumab does not repair previous damage. However, it is a good platform for adding on additional therapies that could help repair and reverse previous damage.

      The point I want to make is that we have to start somewhere and build on it. Ocrelizumab is the building block. Please think back to interferon-beta and relapsing MS. That was 25 years and look where we are now? The same will happen for PPMS.

  • think a method needs to be found to factor out (control for) the brain mass starting point. Personally, I always had a big head [yet I am not vain ;-)] When I collected my Doctorate at 52 they couldn't find a big enough floppy hat.

    I recognise the trajectories, at "onset", that GG describes and my wife, Ros, would say that there were signs before such as some stumbling.

    In terms of the whole RIS/RRMS/AD/PD debate (and that is not a random throwing together of acronyms) I have always been sceptical. My public comment yesterday spoke of my being puzzled by the twin 1995 diagnoses of MS and AMD. I never clearly identified an RRMS phase in myself yet the prevailing, neurologist based, wisdom was that I was SP rather than PP. Setting aside the possibility that this conclusion was necessary for the Australian Medicare forms, I have always tried to describe myself as "sesqui" progressive (as in "sesqui centenary" -150 years).

    This latest GG post lets me off that hook. I heartily agree with it.

    • Let's cross that bridge if and when we get there. The issue may become a reality of the Aducanumab AD trials are positive. Will the NHS accept pre-symptomatic screening for AD and will they allow treatment before people are diagnosed with AD? These issues are big issues that need public debate.

    • I am not sure neurologists need convincing. What we need is data. There are two DMT RIS studies currently being performed. If either of these are positive we will need to change our diagnostic criteria.

  • It was so hard getting a diagnosis of MS. During diagnosis, my neuro told me that my symptoms could mean any one of 50 different illnesses and he wasn't prepared to call it MS until positive lumbar puncture. I had positive lumbar puncture before anything showed up on MRI. So in my case early MRIs (which were clear) would not have labelled me as RIS.

  • We need certain biomarkers (if OCB-) to call it asymptomatic early MS. Because of the lack of good blood indicators we cannot see easily the trasnformation of the autoimmunity in MS. For example, in SLE, a patient can show positive lupus cells and later those cells can disappear. The same process of establishing the disease may be happening in MS too, but we still dont have the means to monitor it. Many CIS never turn out to have CDMS. And we are not at the point, pharmacologically, to have cheap and safe drugs in order to be on the safe side with someone with possible MS.
    I believe todays neuroscience is not there yet to treat RIS as MS.

  • It took me 12 years and several neurologists to get diagnosed and start meds. Gad dye and cervical spine mri saw a fresh slice in my C 5 space. I almost passed out when they showed me brain lesions, undiagnosed until 3rd exacerbation. Cognitive changes are minimized, scary, easy to hide, and can be devastating in ADL function. Testing can identify areas to work around, reassuring patient it’s not all “in your head” 😎

By Prof G



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