How will we know if we have cured MS?
The current thinking is that MS is an autoimmune disease of the central nervous system that is driven by focal inflammatory lesions. We think the MS lesion, or focal inflammation, is responsible for both acute (now) and delayed (in the future) neuronal loss. Permanent loss of neurological function (impairment or disability) is due to neuronal loss, which can be measured clinically (neurological and neuropsychological examinations), electrically (evoked potentials), on MRI (brain atrophy or loss of brain volume) and/or biochemically (spinal fluid neurofilament levels).
Acute Neuronal Loss (the Shredder or Scissors): Inflammation transects neuronal processes, or axons, acutely that results in loss of function. If the lesion is an eloquent site it causes a relapse. Loss of function is then restored by the surviving axons taking over the function of the lost axons, or other areas of the brain taking on new functions, we call this axonal and cortical plasticity, respectively. Recovery can only occur if there is sufficient reserve capacity. The accumulation of damage and ageing reduces reserve capacity, which explains why recovery from relapses tends to fail with more advanced disease and with age. This is why it is important to treat MS early so as to protect reserve capacity.
Delayed Neuronal Loss (Slow Burn): Neuronal processes (axons) that survive being transected are compromised and never recover fully. They may remain demyelinated, or if they are remyelinated the myelin sheath never gets back to what it was in health. In addition, the so called microenvironment within the chronic MS lesion is stressful to the axon. All this programmes the previously damaged axons to die off over time. This is why anti-inflammatory therapies that switch off the development of new focal inflammatory lesions may not prevent the delayed neuronal loss that characterises progressive MS. Even if we were able to cure MS as an autoimmune disease we may not be able to stop, or prevent, progressive disease from occurring in the future as it may already be programmed to occur from previous damage that has accumulated in the past. In other words progressive MS is like a ticking ‘time bomb’.
Premature ageing: We seem to forget that as we get older we lose brain this is what we call age-related cognitive, or neuronal, decline. From the age of 35 our brains start to shrink and our neuronal systems start to fail. The manifestations of this are not that subtle; how often do you battle to find the right word, or remember an important fact, only to find that your memory has failed you. Similarly, your balance is just not as good as it once was; you realise that you can’t put on your trousers standing-up unsupported and you have to resort to sitting down, or holding onto to a piece of furniture, for balance. If we all lived long enough we would all dement from natural ageing. Evolution never designed our brains to live as long as we are living today. What protects us from the ageing process is brain reserve; the more brain reserve we have the later we will present with our dementia. As MS reduces brain reserve we hypothesise that people with MS (pwMS) will notice age-related cognitive decline earlier than the general population. So even if we cure you of your MS you may still get a drop off in neuronal function earlier than expected that is simply due to ageing. However, this drop-off in neuronal function will interpreted as MS-, and not age-, related decline.
The insights above highlight some of the reasons why we started the ‘Brain Health: Time is Brain’ campaign and why it is going to be so hard to prove that we have cured MS. However, if we don’t define what a cure looks like we won’t find it. I am very aware that a lot of people in the field disagree with me on this.
Defining a cure in MS: Based on what I have said above you may be cured of our MS, but still have progressive disease. The difference between progressive disease that is due to previous damage and that which is due to premature ageing is that the former should burn-out, i.e. after a period of time your worsening disability should stop. In comparison, premature ageing is unlikely to stop. In comparison defining a cure in people who are young, with reserve capacity, who have been treated earlier would be easier. Importantly, a cure can only really occur in relation to induction treatments, i.e. treatments given as short courses that address the underlying ‘cause’ of MS. Maintenance treatments that need to be given continuously can’t cure MS, because when you stop the treatment MS disease activity returns.
Let’s say we have treated a group of pwMS early in the course of their disease with an induction therapy and they have gone into long-term remission with no evident disease activity (NEDA). How long should we wait before declaring a victory over their MS; 15, 20 or 25 years? In the past I have proposed defining a cure as NEDA at 15 years post treatment as a starting point. Why 15 years? This is the most commonly accepted time-point used for defining benign MS and therefore it is a standard end-point that should be accepted by the wider community; this may be wishful thinking many in the field are saying that we can’t cure MS therefore we should not be having this discussion. In addition, the average time to the onset of secondary progressive MS is ~14-15 years, so one would expect to see a significant proportion of people manifesting with SPMS in this timeframe if we had got the autoimmune hypothesis wrong; I estimate at least a third should have SPMS if our hypothesis is wrong. The problem with 15 years is that it is too long to wait; some pwMS want to know ‘now’ if induction therapies offer a cure, therefore we need data to convince the naysayers and laggards to support the ‘cure hypothesis’. Hopefully convincing data will change their minds and get them to at least offer induction therapies to their patients.
Deep phenotyping: We are therefore proposing to do a deep phenotyping project to look at pwMS who are NEDA-2 post-induction therapy to see if we can find any evidence of ongoing inflammatory, or neurodegenerative, MS disease activity. We propose interrogating them in detail and comparing them to a similar cohort of pwMS who are being treated with maintenance DMTs. Deep phenotyping is simply a term to interrogate brain and spinal cord integrity in a lot of anatomical and functional detail to see if induction therapy has stopped ongoing damage and protected reserve function. At the same time we look for evidence of ongoing inflammation in the periphery and spinal fluid.
One of the problems I am finding with pwMS who have had an induction therapy and are now in long-term remission is that they forget that they have MS and get on with their lives. They disengage from the MS community; they stop reading MS blogs and stop coming to MS research meetings. In short these people act as if their MS has gone away; they act differently and start to believe they have been cured of MS. Therefore, I see the biggest problem of doing this study will be difficult recruiting subjects; who will want to take a day off work and come into a research unit to be interrogated in detail? Deep phenotyping will include quantitative neurological examinations, multiple questionnaires (PROMS), multidimensional MRI scans, a full set of sensory evoked potentials and central motor conduction times, detailed neuropsychological testing, a large number of blood tests and a lumbar puncture. The latter is to make sure spinal neurofilament levels are normal and to see if the oligoclonal bands (antibodies) have disappeared. I am hoping they will have disappeared. If we can show that the majority of the subjects in induction therapy cohort has stabilised with no evidence of progressive disease compared to the maintenance DMT group we may convince the field of the value of induction therapy. What do you think? Will you be convinced?
17 thoughts on “ResearchSpeak & BrainHealth: deep phenotyping & curing MS”
Prof G I assume you have time on your hands sitting in a hotel room in New York, jet-lagged with nothing to do. An Englishman in New York? Thanks for the post. I am convinced by your arguments, why aren't other neurologists? Is it because they are scared of using induction agents? Is the risk of these agents too high?
Money incentives? I'm only ten week post first Alemtuzumab round but as a poor I'd be v. willing to help for a cash incentive. Do you not do this in the UK?
Financial incentive for a study such as this is a slippery slope. Financial incentive is given for Phase I drug safety syudies in normal volounteers but that's it.
Whelp, time is brain but for most healthy people, time is money. I get it, am willing to help without it, but if most people in the study are still working thanks to treatment…There's so much damn money floating out there for MS in these dinners and drug reps. Why does none of it ever come to us?
Don't forget PPMS.You have not cured MS until you have a cure for PPMS as well. That is, a cure for people for whom "the horse has bolted" long before they present with clinically evident symptoms, i.e. long before they could ever have any inkling of having MS.
We will never forget PPMS.
I believe you. I'm off to listen to Bob Marley's "Everything's gonna be alright".
Give this one a go too.https://www.youtube.com/watch?v=t-l91O9VxN0
Splendid stuff. I'm really mellow now. :o)
The questions you are asking are important to Ms researchers, perhaps MS neurologists, and future MS patients. However, it's unclear what benefits are there for the study participants. Can you rethink the study from the standpoint of the "cured" patients? Will the results inform their individual prognosis and/or care? For example, some minor abnormalities may suggest retreatment. Alternatively, normal finding may provide the peace of mind – if they are predictable of no relapses or progression within the next x years (in the ideal world, x should be large). Another group which may be willing to participate would have close relatives with MS who might directly benefit from the induction therapy, and who would like to know how effective it is in real life.
I am completely convinced, just need to find a neurologist in Brazil also agrees with this idea …
It is not only pwMS on induction therapy that have got on with their lives. There are people that have had the disease for much longer than 15 years that have not been involved in the MS community, they don't even have a neurologist. Their disease at onset could have been highly active. This is another problem with the study, it's missing a chunk of people.
What you need to do is make it easier for people to register for these trials/ I'd happily dedicate time to being part of this study and I am between alemtuzumab courses currently, like the Rituximab study posted yesterday and the Alemtuzumab vs HSCT trail mentioned months ago and others, we see one or two posts and then never hear anything about them again. Before you mention fund raising I know this is difficult but I think recruiting cohorts will be easier if the process is made easier.
Excellent post – we should send you to NY more often. I may volunteer for your project – 8 years NEDA following Alemtuzumab.
Brilliant post; one of your best. You are like a fine wine maturing with age and getting more eloquent. The issues you cover in this post really get to the heart of the problem that is MS. I sincerely hope the wider MS community reads this post and the messages on board. Keep up the good work.
Very insighful and clear post thank you. Your work is utterley life changing for MS patients. Please may I clarify when referring to induction treatment are you talking about the injectables or monoclonal antibodies as potential options to reduce disability.
Sign me up Prof G!!!