Help! How do I manage progressive brain atrophy in a patient who is NEDA-3?
End-organ damage is a catch-all phrase for the degeneration of the brain; it occurs as part of the ageing process that some consider pathological and others as a normal fact of life. I have hinted that I consider it both because end-organ damage is potentially modifiable via lifestyle modifications and pharmacological interventions. If it was a normal process it should not be modifiable. How can you be more normal than normal? Making ageing a disease also has political ramifications, for example, it will almost certainly incentivise Pharma to develop treatments for ageing.
In MS end-organ damage is massively accelerated by the MS disease process itself, i.e. inflammation and demyelination, and from delayed downstream processes triggered by inflammation, for example, energy failure, microglial activation, ongoing inflammation driven by antibodies, possible slow viral infection and its consequences and comorbidities. It is clear that all people with MS will have end-organ damage, but what can we do about it? To be honest, apart from early treatment to prevent damage, we haven’t got an evidence base about how to manage this problem in MS.
As an example, I saw a patient earlier this week. He has relapsing-remitting MS diagnosed in the mid-2000s and started on interferon-beta (Avonex). He also has type 1 diabetes which he developed when he was 14 years of age, 8 years before he was diagnosed with MS. His diabetes was poorly controlled initially but is now well controlled on an insulin pump. He has renal (proteinuria), eye (retinopathy) and hypertension as complications of his diabetes. His hypertension is controlled on medication. He has been relapse-free and his MRI has not shown any obvious new lesions over the last 6 years; i.e. he is NEDA-3. He does not smoke, but he drinks between 3 and 4 units of alcohol per day. He was referred to me because he is sick and tired of injecting himself with interferon and he has heard of a new drug called ocrelizumab. He wants to be switched to it because is more efficacious and only give every 6 months. His treating neurologist said no, hence his referral to me for a second opinion.
When I went through his history it is clear he has had no relapses in the last 6 years and is fully functional and working full-time. I reviewed his MRIs and I agree he has no new lesions over the last 6 years, but he has developed quite profound and progressive brain atrophy over this timeframe; he is definitely not NEDA-4. What do I do?
Do I switch him from interferon-beta to ocrelizumab? Or do I leave him on Avonex, which is doing its job and rendering him NEDA-3?
If I do switch him to ocrelizumab, will it normalise his brain volume loss? Will he become NEDA-4?
What is causing his brain volume loss? MS, hypertension, diabetes, alcohol or something else?
Do I tell him about his gross brain atrophy, which he is blissfully unaware of?
Do I offer him a formal cognitive assessment to see if he has cognitive impairments? If he has a cognitive assessment and they come back abnormal, which they are likely to, how do I tell him? Will knowing he cognitively impaired affect his management?
Do I offer him a lumbar puncture to measure his spinal fluid neurofilament levels?
Do I recommend any add-on off-label treatments that may help?
Or do I just take the easy option and send him back to his neurologist with a recommendation to leave things as is?
Can I suggest we debate these issues over the next few days and I can then potentially do a live webinar on the issue of end-organ damage and how to handle the problem of progressive brain volume loss on DMTs when you are NEDA-3.
Y E S P L E A S E. It is time to address this conundrum head on!
Here is a first shot to get the ball rolling:
Question In the absence of clear clinical data, what is the cost/benefit of speculation* for a NEDA3 MSer?
*Speculation defined as decision making in the absence of certainty.
Framework:
Accute BVL confirmed on MRI and CSF NFL
Constraints:
1) Patient is on already on a high efficacy drug today, no optionality for escalation but can move laterally (let’s assume a generic case of a JCV-, no family planning, etc… where all high efficacy drugs are on par in terms of risk)
2) Patient is a speculator in the sense that patient is fully aware that brain is time and that the cost of no action outweighs the benefits of waiting for clinical trial.
3) The question should be addressed at the patient level than population level.
4) Money, health system, insurance, bioethics committees etc… would allow for any treatment option, add-on or else
5) In our out of a clinical trial
6) Decision (action or inaction) to be taken in 2019
Multiple typos – take 2:
Question:
In the absence of clear clinical data, what is the cost/benefit of speculation* for a NEDA3 MSer?
*Speculation defined as decision making in the absence of certainty.
Framework:
Accute BVL confirmed on MRI and CSF NFL
Constraints:
1) Patient is on a high efficacy drug already , no optionality for escalation but can move laterally (let’s assume a case of a JCV-, no family planning, etc… where all high efficacy drugs are on par in terms of risk)
2) Patient is a speculator in the sense that patient is fully aware that brain is time and that the cost of no action outweighs the benefits of waiting for clinical trials to conclude.
3) The question should be addressed at the patient level rather than population level.
4) Health system, insurance, bioethic committees etc… would allow for any treatment option, add-on or else. Money and mobility are not an issue otherwise.
5) In or out of a clinical trial.
6) Decision (action or inaction) to be taken in 2019
“It is clear that all people with MS will have end-organ damage, but what can we do about it? To be honest, apart from early treatment to prevent damage, we haven’t got an evidence base about how to manage this problem in MS.”
We need some hard truths here – neurology / MSology are still in the dark ages. My dad’s friend died from MND and the neurologist (apart from getting the diagnosis right) was next to useless. The disease ran its course.
The MSologists know they are pretty rubbish at understanding the shredder and more importantly how to stop it. I’ve lost track of all the effort which has gone into giving a title to the disease e.g. now one disease not four, Progressive is now Advanced. Then there’s the continuing debates – T v B cells, inflammation v degeneration, NEDA 1,,2,3…
A huge amount of measuring damage or rather, identifying ways of measuring damage, has taken place without any progress being able to do something about it. What is the point in telling someone they are loosing brain tissue and in the next breath telling them there’s nothing that can be done?
Rather than focusing on terminology and measurement techniques, focus on why the brain is atrophying and how this can be stopped. The treatment pyramid flatters to deceive as only one of the four areas is available to patients – anti-inflammatories. What has happened to all the work on neuroprotectants and remyelination? In 2019 we are not in a good position with regard to stopping brain atrophy in MSers. What happened to Promise 2010?
I would suggest that the researchers / MSologists spend the next five years understanding neurodegeneration and how to stop / slow it. No more international conferences – stay in the lab. Given the time and investment to date, the experts still can’t answer the most basic questions about this disease. If MS research was a business and I was the new CEO I’d sweep away the top dogs and introduce some new blood and fresh ideas. Anyone in the MS field who has been there for 25-30 years should hang their heads in shame. A person newly diagnosed with PPMS is no better off than they would have been in 1989 (no treatment options, whatever this blog says). One has to ask why?
Re: “I’d sweep away the top dogs and introduce some new blood and fresh ideas.”
Are you saying I am too old to stay in the game and that I should retire?
Another 5 years.
I’d like you to crack the ebv link before you head off into the sunset.
You need to call it a day before you become a member of the dinosaur brigade. You mustn’t join the ageing neuros who turn up at actrims, ectrims, lactrims, pactrims and give the same presentation they’ve given since 1993 wearing the suit they bought in 1978. You’re better than that!
The EBV vaccine experiment will take 5 years to set-up and 20 years to report out! I will be 80+ when we get a result 😉
Seriously? My family contributed to your crowdfunding appeal a while back for analysing data on virus shedding, after that emotive video with people imagining not having MS any more etc. – I had hopes!
The second stage of the saliva study is happening; i.e. we have the grant to test whether or not we can stop EBV shedding with an oral anti-EBV drug. This study is about to start. This study, however, is in pwMS and is not the prevention study I am referring to which involves an EBV vaccine study at a population level (normal people at a young age).
Thank you for supporting our study; we used the data to do the power calculations for the oral antiviral study. It is much appreciated.
Holden DW, Gold J, Hawkes CH, Giovannoni G, Saxton JM, Carter A, Sharrack B. Epstein Barr virus shedding in multiple sclerosis: Similar frequencies of EBV in saliva across separate patient cohorts. Mult Scler Relat Disord. 2018 Oct;25:197-199.
“This study is about to start.”
That’s fantastic news!! This is the one thing that gives me hope of a true, tolerable treatment for MS.
Thank you all. 😊
Nucleoside analogs can be started now as add on therapy with patients paired by dmt treatment. One ocrevus patient + combivir, one – combivir. One tsyabri +, one -. You should have some indications on the bvl of the patients over two years time with enough enrolled to make a conclusion whether that class of antivirals works.
How about the ibudilast as an add on too?
There really are options for add on therapies on top of existing dmts that it is really frustrating to see how vested everyone is in finding a single treatment to work, rather than accepting that individual treatments may attack specific aspects of the disease but not be good at others.
You have to generate an evidence-base and get therapies licensed. If not who is going to pay for these treatments? Unlicensed and off-label treatments come with risks and in this situation very little evidence that they have any clinical benefit.
🙂
@Christopher Lazarski
“One ocrevus patient + combivir, one – combivir. ”
Unfortunately the antiretroviral trial that ProfG was a part of, was poorly designed and was a failure. I don’t see anyone setting a new antiretroviral trial seeing this poor (and quite misleading) result, unless more positive patient data accumulate. Also combivir or any other antiretroviral combination would be a sufficient treatment and not an add on. It would be an excellent trial for progressive MS to slow brain atrophy, but…
On the positive side, the HERV theory is seing progress with the trial of temelimab (by GeNeuro), a monoclonal antibody that targets an HERV-W protein.
Again you will have cheap generic drugs with no trial behind them that can be as efficient as a very expensive new monoclonal antibody. Well…
Why misleading?
“Why misleading?”
Misleading towards the efficacy of antiretroviral treatment in MS in general.
But who said they were effective? Please don’t get ahead of yourself we need to get the evidence.
“But who said they were effective?”
Let’s see how the GeNeuro trial goes (it has first positive results).
In the meantime the role of retroviruses is being furtherly investigated as well as the use of antiretrovirals that seem to control them
https://www.nature.com/articles/s41586-018-0784-9
Kevin, have you read some of our earlier posts on beyond NEDA that addresses the issue of add-on combination therapy trials? For example, ‘BEYOND THE B-CELL’?
Let me first say I appreciate this website but 100% agree with your post Kevin. I understand the complete and utter frustration with the state of MS research in progressive MS. It is no coincidence as to why progressive patients are searching for their own answers and treatments based on anecdotal studies and early inconclusive trials as current MS treatments have miserably failed them.
I would ask Dr. G for meaningful advice in a CURRENT patient (ie. today, not in 20-30 years from now after trials get from bench to the pharmacist) on how to treat a non Gd+ progressive MS patient.
According to Dr. G stats over 1 million of 2.5 million MS patients are wheelchair users and likely thousands more are converting from RRMS to SPMS. What can be done right now for these patients?
There are no approved remyelination, neurodegeneration or neurorestoration products, despite researchers knowing these have been needed for the last few decades. The study of the treatment pyramid is more like Mt. Everest and we are stuck at the bottom using minimally effective immunosuppressant treatments which, at best, will delay a patient’s progression slightly but to the same devastating endpoint.
Where is the urgency for treatment of progressive MS?
Is HSCT the best bet?
Dr. Richard Burt, lead investigator of HALT MS HSCT trial, states HSCT is not the answer in progressive MS. I believe he indicated it is only for people with MS highly aggressive RRMS non responsive to current DMDs, which accounts for < 15% of MS population:
(https://www.medscape.com/viewarticle/907779#vp_2)
Yet, somehow the agenda for neuroinflammatory DMDs is still being pushed for progressive MS, even though the most potent DMD (cyclophosphamide) does not work or may work to slightly slow progression for a period of time but to the same miserable endpoint of disease.
How is the brain atrophy measured? Is it just MRI or is his cognitively impairment obvious in the consultation? If it were me, I’d appreciate being told a) that it’s a significant loss, above what should be happening at his age b) that it’s not clear whether it’s ‘just’ the MS that’s causing it or whether lifestyle factors are part of the equation c) find out how he feels about modifying that which is changeable i.e. the alcohol d) discuss any ‘cons’ about changing drug. I can empathise with his fed-upness re: injecting himself. It IS a burden. It was only when I was switched to fingolimod that I appreciated how big that burden had been! If he were started on the new drug and it didn’t suit, presumably he could revert to Avonex? Finally, the psychological factor: a treatment change could be a big motivator for him to live as well as he can in the best frame of mind. More extensive and more frequent monitoring could equal more attention paid to him could equal a new lease of life. Just my thoughts.
This patients atrophy was obvious and assessed with the naked eye. A good example of what it looks like can be seen in a previous post on this blog on ‘HOW BAD IS YOUR END-ORGAN DAMAGE?‘.
As someone who is in the dark with regards to what is/isn’t happening in my brain I would welcome all the tests you mention and would want to know and understand the results. As far as I am concerned knowing the truth would be a positive, even if treatments are not going to help I would like to be informed of my condition.
If we started doing routine brain volume measurements we would find this scenario being very common and it could, therefore, trigger lots of tests without a treatment option. NEDA-4 may be the MS equivalent of Pandora’s box. What we need is clinical trials and lots of them. What we are talking about here is progressive MS.
Neurological conditions seem notoriously difficult to crack.
I am I think with Kevin on this one .
Despite all the headline news I presume research has been done across the uk into how many people still progress to SPMS with DMTs ?
In my opinion if that has not significantly changed then there is a major problem .
We have posted on this already. New data shows that high efficacy DMTs are reducing the number of patients being diagnosed with SPMS. The question is this just a delay or is it actual prevention. The data on progressive brain volume loss suggests it is a delay, with the possible exception of some patients treated with NIRTs (non-selective immune reconstitution therapies), i.e. HSCT or alemtuzumab.
“with the possible exception of some patients treated with NIRTs (non-selective immune reconstitution therapies), i.e. HSCT or alemtuzumab.”
Question 2:
Who are the exception? What traits do they have in common? what do we know so far (even if not much at all)?
Tony
We don’t know. Clearly, the intensity of T-cell depletion may be important because myeloablative HSCT is superior to non-myeloablative HSCT that looks better than Alemtuzumab. We found out this week from Lawrence Young, an EBV expert, that EBV also infects T-cells so this may be another important reservoir to eliminate if our treatments are working as anti-EBV drugs.
I’m eager to hear your argument for *not* offering him Ocrevus, or something stronger. That seems like a no brainer (unfortunate pun).
Is it ever ethical to withhold information from adult patients? Keeping us blissfully unaware seems to go back to the days of not telling patients when they’ve got terminal cancer.
Under NHSE guidelines you can only really escalate if you have evidence of lack of efficacy. You can switch sideways for intolerance, but then this person would have to be treated with alemtuzumab, rather than ocrelizumab under NHSE guidelines. Unless alemtuzumab was contra-indicated.
“you can only really escalate if you have evidence of lack of efficacy.”
Gross BVL is lack of efficiency in by book…
I did mention to him that he had some shrinkage of the brain; what I am not sure about is whether or not is due to MS or the other comorbidities. I need to work that one out and see if there is some reversible factor I can target.
I remember learning years ago that it takes around 7 compliments to off-set the psychological impact of one criticism.
For me somehow the same logic applies i.e. Make him aware of his BVL. Put this in the wider context: that this applies to every PwMS. Explain the limitations of DMTs in respect to BVL. But, most importantly, offer him something – that if he cuts down the alcohol, exercises and eats well etc he may slow down BVL moving forward.
This guy has already psychologically abandoned and rejected Avonex and even if your decision has to be sending him back leaving things as they are, offering him something that incentivises, will negate his feeling totally bereft, even victimised.
Or even better: Offer him real hope with HSCT
This patient will not be eligible for HSCT under our current guidelines. You have to be failing at least one high-efficacy DMT.
But HSCT is neurotoxic, is it not, and could make him worse? It’s primarily suitable for those with active, inflammatory disease?
Yes, I did mention to him that he had some shrinkage of the brain and that this could be due to MS and/or diabetes and/or hypertension and/or alcohol. The question is which one. I avoided saying gross brain atrophy because alcohol-related brain atrophy is partially reversible. I am not sure how much he really drinks.
“I am not sure how much he really drinks.”
If he said himself that he drinks 3-4 units per day, the real amount is almost certainly higher. We (patients) usually minimize these figures to a doctor. It’s in human nature.
I would say, treat this person more effectively w/ ocrelizumab, rituximab or cladribine as a DMT, generic cladribine if cost is a problem.
Beyond that, I would try plausible but unproven approaches such as statins, high-dose biotin, antivirals.
More speculatively, metformin seems to help with aging. Does anything downregulate the inflammatory activity of glial cells? What about psychedelic drugs being recently shown to promote neural plasticity? (https://www.cell.com/cell-reports/fulltext/S2211-1247(18)30755-1). Lots of unknowns here.
Would / should it require clinical experience before trying some of this stuff on such advanced MS patients heading straight towards serious disability? If you were this patient knowing what you know, what would you choose as a DMT and what would you take beyond it?
Question 3: please addreas all the points raise by TOM.
I am not in a position to offer unlicensed treatments. What we need is a continuously recruiting, adaptive, trial platform that everyone with possible progressive or worsening MS is recruited onto and followed using standardised protocol.
RE: “Would / should it require clinical experience before trying some of this stuff on such advanced MS patients heading straight towards serious disability? ”
Yes and No. We sometimes treat people with off-label treatments because we have our backs against a wall, but in these circumstances, we have to define a treatment target that is measurable, for example, a raised CSF neurofilament level. We can’t use brain volume as it is unreliable at an individual patient level, i.e. it is all over the place, and is affected by comorbidities and other drugs.
Re: “If you were this patient knowing what you know, what would you choose as a DMT and what would you take beyond it?”
I would seriously have considered HSCT or alemtuzumab when I was diagnosed; treat early and effectively. I would want to maximise my chances of a good longterm outcome. This is not going to happen now.
However, in this patient, it may be too late to derive the benefits of HSCT at this stage of his disease; in fact, HSCT may make things worse. A damaged brain does not handle the neurotoxicity of chemotherapy very well; this is why most centres have stopped treating advanced or progressive patients with HSCT.
What to recommend for this patient will depend on the results of the investigations I have ordered. If only we had some add-on treatment to address all the problems associated with smouldering MS and post-inflammatory neurodegeneration.
Prof G you say “I would seriously have considered HSCT”, but this would be using HSCT first-line. Do are you really proposing using HSCT as a first-line therapy?
This may explain why I (Kevin) am so angry about the inability of MSologists / researchers to understand and treat progression. This was a story recently posted on the MS Trust website. Should this be happening in 2019? I suspect that there are hundreds or thousands of people with MS in the UK living like this. When cases like this exist we shouldn’t be heaping too much praise on MSologists, but rather asking why lives are being destroyed by a disease which has been studied for 150 years.
“I’m Jen, I’m 37, I live in Lancashire and I’ve been a carer to my husband Dave since we met 13 years ago. He was diagnosed with PPMS in November 2004 and had several sessions of Mitoxantrone chemotherapy to try and halt his rapid progression, which thankfully it did for a couple of years. Sadly, his illness progressed again and in 2014, he became almost permanently confined to his bed. I was forced to quit work the following May as Dave needed 24-hour care as he was now unable to feed himself at all.
So, here we are! 2018 and things tick along OK mostly! Dave has bathroom time three times a week where he’s fully showered and I empty his bowels for him manually. His bladder issues are managed with a sheath catheter and bags, and thankfully he can still eat and drink via mouth. “
But what about the people with MS who have been treated and prevented from becoming progressive? There is a glass half full view of the world.
Good point; NeuroDoc Ganapavan and MD posted on the recent MS-Base data showing how high-efficacy therapies are impacting on the rate of SPMS. It is very reassuring and suggests we are preventing pwMS needing sticks, chairs and beds.
A heart-wrenching story and is one of the reasons why I get up each morning to do what I do. The good news is that we now have a licensed treatment for PPMS and hopefully we will have add-on therapies in the near future to slow down worsening progression even more. And who knows that black swan may arrive early to shift the paradigm to treat, and/or cure, MS.
Are you referring to Ocrelizumab? It may be licensed but NICE have refused to pay for it. So there are no interventions for PPMS.
As someone living with SPMS and brain atrophy/cognitive problems, I strongly feel that your patient should be given all the information that you have on his current disease state. Then he can be asked what it is he would like in the way of assessment and treatment, as well as options for support in reducing his level of alcohol intake and how that might help his symptoms and prognosis.
His main care-giver should be present for these discussions.
Even with cognitive problems, given time and help from others in looking at what is available, he will be able to give his informed preference for treatment.
I am quite shocked at your statements which roughly say ‘let’s not tell him and I’ll decide’ and ‘what’s the point in telling him’ – he is a human being and has a right to be given all information relating to his health. THAT is the point!
The scenario is only after the initial consult. Several investigations have been ordered; can you guess which ones? I am a firm believer in getting as much information on the table before making any decisions or firm recommendations. This patient admitted he probably drinks too much, but he finds it an anxiolytic after a hard day at work. His diet is reasonable and dictated by his diabetes. Any other recommendations.
So, lets put MS on side for a sec.
Have you ever seen BVL after heavy drinking?
Yes. Frequently. It is a well documented cause of brain volume loss even in moderate drinkers (21 to 30 units per week). As you can see it is difficult using non specific biomarkers in clinical practice.
I still don’t understand how a doctor has the right to manipulate a patient and hide his condition from him, to supposedly protect him. This kind of manipulation has been happening to me since day one, by several different doctors. I personally find it appalling.
Tell him that he has an alarming atrophy and that you wish you were able to give him ocrelizumab (which could possibly have some positive effect on his diabetes too btw), if these damn escalating guidlines were different. Try to give him any high efficient DMT possible.
This mirrors perfectly the problem MS -and I guess not only- has today. Doctors know, patients hope blindly and guidlines are like Leviathan.
I would suggest that you treat the patient like an adult, take time to explain all the factors. Then discuss with him / her to facilitate them making their own decision. Surely you can not really believe that you have the right to make choices of such magnitude for someone else.
If that were me as the patient I would be furious – my life, my choice.
Yes, that is why I think he came to me to seek a second opinion.