An ethical quandary

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The two case studies below are creating an ethical quandary in my MS practice. Can you help me please?

Case 1

The first is the 40-year old woman with MS who is NEDA-2 (no evident disease activity) on DMF (Tecfidera) with no documented relapses in the last 4 years and a series of annual MRI scans with no new or enlarging T2 MS lesions. However, there has been a worsening of her disability; increasing bladder problems and a progressive spastic paraparesis (weak legs). Her EDSS has moved from 4.0 to 5.5 in the last three years. She has self-diagnosed herself as having secondary progressive MS and wants to switch to siponimod. Unfortunately, according to the current NICE approval and NHSE guidelines, this patient is ineligible for siponimod because she has inactive MS (NEDA-2). 

Do I recommend she stops her DMF so that her MS can reactivate, which will then make her eligible for siponimod? Most MSologists would say yes, mainly because the development of SPMS is one of NHS England’s stopping criteria. The problem I have is we, the patient and I,  have no idea how active her MS will become if and when her MS reactivates. For example, she could have a catastrophic spinal relapse that leaves her doubly incontinent and quadriplegic or it may be on the other side of the spectrum, i.e. one or two new asymptomatic MRI lesions on her annual MRI follow-up. If you were in her position would you stop your treatment to develop active MS? 

Case 2

The second is the 40-year old woman who started natalizumab as a first-line therapy 11 years ago after presenting with two disabling relapses in a four-month period. She has done exceptionally well on natalizumab, i.e. she is NEDA-3 (no relapses, no MRI activity and no change in her EDSS). In fact, her original disabilities from the two relapses recovered. At present she is fully functional, working full-time and very active physically. For example, she plays competitive tennis in her local sports club and ran the London marathon 2 years ago. Her current EDSS is 1.0.

The problem is that her serial annual MRI studies demonstrate that she has progressive macroscopic (visible by the naked eye) brain volume loss. Being an intelligent woman and a self-taught MS expert she knows this is a poor prognostic sign and she wants to stop natalizumab and have HSCT or alemtuzumab. She is aware from reading The MS-Blog (formerly the Barts-MS blog) that alemtuzumab and HSCT have a greater impact than natalizumab on end-organ damage or brain volume loss. After HSCT and alemtuzumab treatment brain volume loss is on average in the normal range (please see BEYOND NEDA).

Would you allow this patient to switch treatments? Under the current London MS HSCT guidelines she would not be eligible for HSCT as she has not failed natalizumab; please note, progressive brain volume loss is not considered a treatment failure. What about alemtuzumab? Applying the strict NHSE guidelines she would not be eligible for alemtuzumab as her MS is inactive at present. However,  one could argue that we need to go back to 2010 when she started natalizumab and ask ourselves now would she have been eligible back then if alemtuzumab had been available? The answer is yes as she had what we call rapidly evolving severe MS; in 2021 someone with rapidly evolving severe MS could be treated with alemtuzumab first-line.  Should we apply treatment criteria retrospectively? 

This patient is JCV negative. If, however, she seroconverted to being JCV positive it would be easier to justify to NHS England for the switch to alemtuzumab, i.e. NHSE guidelines support the principle of derisking PML. The one thing I can’t tell this patient is whether or not alemtuzumab or HSCT will have an impact on her brain volume loss as we simply don’t have the data from a cohort of patients making the switch from natalizumab to alemtuzumab 10+ years into their disease. In other words will the smouldering or real MS that causes the accelerated brain volume loss respond to a potent IRT treatment strategy 11 years after diagnosis? This patient understands there is no data on natalizumab-switchers to support her request, but she is willing to take the risk of either alemtuzumab or HSCT. What do I advise her?

HELP! It is not easy being an MSologist. Please note these two scenarios are based on real patients of mine and are not hypothetical and represent the MS world I live and practice in. 

Conflicts of Interest

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General Disclaimer: Please note that the opinions expressed here are those of Professor Giovannoni and do not necessarily reflect the positions of the Barts and The London School of Medicine and Dentistry nor Barts Health NHS Trust.

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.

40 comments

  • You cant be treated with alemtuzumab first line in 2021 ….. even if you have rapidly evolving or so i was told ….

  • re the 1st case
    How can weak legs and worsening bladder problems be classed as No EVIDENCE disease activity? Because it didn’t show up on an MRI?

    If MRIs weren’t around, would doctors withold treatment when they could see the patient is getting worse?

    Isn’t it true that 4/5 or 80% progress in MS? So why in god’s name is there all this faff on with “criteria” for drugs to try and help with it?
    All boils down to cost I presume?

    • I’ve been wondering if the doctor could just declare this worsening to be a relapse and fulfill the criteria that way.

  • Hi Prof G
    Your second case describes my situation almost exactly (including the tennis!). However, my brain volume has never been monitored. How do I find out if it is shrinking?
    Thank you for continuing to ask all the right questions!

    • It is perhaps safe to consider that it is shrinking unfortunately, in the absence of reliable measurements. Radiologists can discuss volumetric annual changes, etc…but it is well documented that Tysabri does not stop the accelerated dementia side of things.

  • Why isn’t there a RRMS arm in the octopus trial if clear underlying progression in MS is continuing regardless of current DMTs.

  • Two difficult cases….in case 1’s shoes i would be tempted to stay put. Coming off treatment to purposefully reactivate MS is the equivalent of walking of taking off your body armour and hoping to take one in the leg rather than one in the head. Case 2 goes back to yesterday’s discussion on patient choice. If you can find a way to deliver her request then you will be doing more for her than most nuerologists would be prepared. A question….HSCT is not available to either patient but if they had the means, they could pursue this treatment option abroad. It may be the best option for both parties. This topic is never discussed on the blog but it must crop up in your consultations from time to time. Is there a reason it is such a taboo subject? it would not surprise me if the majority of readers have not considered it at some point

  • The whole SPMS thing is a complete nonsense …how can increasing disability be classified as NDA when it is patently actively getting worse,….needs a total rethink ..

  • Absolutely the same here. Wanted to get on the HSCT route but got refused as not enough activity (why can’t we freeze MS as early as possible and have the best possible outcome rather than being forced to wait for the patient to decline?! It’s nonsensical to me – pwMS don’t get better, the best possible outcome is to hit pause – so surely we should hit pause as early as possible) yet I can’t tolerate any DMTs so having to use fasting as only treatment.

    Concerned about smouldering MS and reducing brain volume but without any means of tracking it. Why is cognition not a measure (it’s the main area I see degradation) instead of only physical infirmity being the NICE measure of progression.

  • Professor G,
    I have close to 50 MS patients who have cognitive (presumed superficial and deep GM, cerebellar, etc. PIRA ( smoldering ) and LE and neurogenic bladder spinal cord PIRA ( smoldering ), despite being on many of the stronger, or weaker, MS DMT’s, who finished their 1st or 2nd round of oral Mavenclad here in the USA under my care. All 50, even within months after round 1, and especially months after round 2, have stabilized. About 10 of the 50 slightly improved, despite longstanding MS ( patient reported for cognition–not SDMT or Neurotrax, which I did not do, or have available ), and ( patient reported, and motor examination confirmed, for somewhat improved asymmetrical LE strength). Do you have generic injectable Cladribine at your disposal for these 2 patients? As you well know, better than anyone, Cladribine can find autoreactive B>T cells where they hide and penetrates all 3 compartments of the CNS. (Rejdak, with the elimination of the Oligoclonal bands, which I think is vital data for hemispheric cognition and cord motor/ bladder stabilization). Then you could follow later, if needed, with immunologically safe, broad antiviral, including Covid 19, CNS penetrant, with excellent brain atrophy reduction data ( end organ ), Teriflunomide. These are my ” 2 cents ” for what it is worth, since you asked.

    Clifford Reed MD–West Reading, Pennsylvania

    • Very interesting observations. This is why we are doing the CHARIOT-MS trial; we think the intrathecal (within the meninges or CNS) effects of cladribine on the CNS resident B & T cells are important drivers of smouldering MS. Thanks for sharing your data and experience. I am not sure teriflunomide penetrates the CNS to any significant degree, whereas cladribine does.

    • Hello from Harrisburg, PA. I am so glad there is at least one U.S. neurologist reading this blog, and I hope there are many more.

  • For case 1, can it be a matter of looking harder? Ie using high power imaging systems? Analysis biolocal markers?. .. Anything that might lead more conclusive evidence of progression?

    • Case 1 is progressing. Do you mean new T2 lesions?

      In the past, I have argued that case 2 is also progressing. However, the consensus in the wider MS community is that progressive BVL loss not linked to anything clinical can’t be used to label someone as having SPMS. This is why I am on a mission to change the nomenclature of MS to capture the real MS or smouldering MS.

  • I was previously treated with Tysabri, but continued to relapse & MRI showed similar changes to this lady, as such I chose Alemtuzumab.

    In Aug I will come to end of 5 year post treatment monitoring period & I have had no relapses since, nor any changes in MRI results at all. I feel stronger, walking has improved & haven’t felt this ‘well’ since before diagnosis.

    Therefore, I would highly recommend Alemtuzumab!

  • it is perhaps easier to approach those cases with a 4×4 matrix. Current risk/benefit and future risk/(perceived benefit). Many doctors worry only about the first ratio. I can relate to the situation of that second patient:

    1A) Approach 1: Do nothing, first ratio.
    Benefits: no relapses, no increase in EDSS
    Risks: short term secondary malignancy and opportunistic infections

    1B) Approach 1: Do nothing, second ratio.
    Benefits: none as will probably be shifted to Siponimod
    Risks: SPMS, secondary malignancy, etc…

    2A) Approach 2: Drop Tysabri in favour of an IRT, first ratio.
    Benefits: no noticeable benefits compared to approach 1
    Risks: Side effects (thyroid, etc), minimal immune recovery risk, unquantifiable risk of not responding to the second treatment as well as Tysabri and losing the real benefit of Tysabri.

    2B) Approach 2: Drop Tysabri in favour of an IRT, second ratio.
    Benefits: the optionality of a cure vs the quasi-certainty of SPMS conversion when staying on Tysabri
    Risks: the absence of reliable comparative figures on how well late-starters such as Patient 2 do after 5-10-15 ys on an IRT compared to early-starters (within 2 ys of diagnosis)

  • Perhaps the most important point from the two cases above is the conclusion that MS is a progressive disease from the outset and even with effective (and expensive) treatments such as DMF and Tysabri, disability and end organ damage will continue to accrue (perhaps at a slower rate). I’m guessing your fellow MSologists will also have noticed similar outcomes with their own patients.

    Getting patients on to Alemtuzumab or HSCT may help to slow down the accumulation of disability and end organ damage. Isn’t it time for MSologists / MS researchers to move away from the focus (of the last 40 years) on relapses and focal inflammation to address the real driver of MS? The Chariot and Octopus studies are a start – but neither have started and results will be years away. Getting relapsing patients on such trials should be a priority (given that neuro- degeneration starts early).

    In the meantime (I’m not a doctor), surely there’s a case for suggesting both patients follow the Brain Health Matters approach, use Alpha Lipoic Acid as a supplement (same dose as the current trial) and take simvastatin each day (same dose as the current Simvastatin trial). Perhaps adding Metformin? I’m not sure if doctors can make such suggestions / prescribe medication in this way, but patient 1 is heading down hill rapidly and, if I was her doctor, I’d be doing everything possible to limit further deterioration.

    • very true. But if thinking in a risk/benefit framework, the added risk of a phases 1 and 2 of an add-on neuroprotective therapy does not make sense for a NEDA-3 patient. Perhaps Phase 3/3B with reservations.
      As you know there isn’t anything close to Phase 3 in clinical trial, so nothing expected within 5-10ys. By then, Patient 2 would have (most likely than not) converted to SPMS.
      From memory, that NIH study says that 54 was the age after which DMF and Tysabri do not work.

      It is perhaps now the time to add to the well established “treat early treat effectively” mantra a “treat with the best bed mid cycle before its too late”. Time (in “time is brain”) is a a continuum after all.

  • Case 2: Has BV loss been compared for Alem. and Nat. over an extended number of years in like for like trials? A lot of the comparisons of Alem and Nat don’t seem to be very ‘equal’ in that those on Alem are often much recently diagnosed.

    • No none I am aware of. But outside of brain volume changes alemtuzumab does things to MTR, a marker of tissue integrity/myelination, in NAWM (normal-appearing white matter) that doesn’t occur to the same extent as natalizumab. So I think an alemtuzumab-treated MS brain is a healthier brain than a natalizumab sealed-off brain. But I may just be biased.

      • Thank you for your reply.
        ” … outside of brain volume changes alemtuzumab does things to MTR, a marker of tissue integrity/myelination …”
        That might alter my thinking on Case 2.
        In general though, it seems difficult to truly compare high efficacy treatments in an objective way. From a lay person’s pov it seems as if the variables in trials differ – length of time of diagnosis, age of participants and so on. Also the effect of the risk factors on each individual isn’t easy to know in advance of going on a treatment. So, if someone is doing well on something there is a case for sticking with it. But, absolutely, it is an individual’s right to choose (hopefully with best available knowledge of pro’s and cons of the different options).

  • Stopping treatment in number 1 patient is wrong.
    #2 I don’t know what’s best. Certainly needs to reevaluate treatment plan to minimize damage.
    Part of your problem is NHS has too strict criteria that inhibits your choice as a Doctor. In USA, similar limits from HMO, Medicaid, Medicaid, other insurance. That leaves choices that may not be the best plan

  • The ethical quandary to me in these stories is how bad the NHS NICE restrictions are in giving MSers and their consultants options in treatment. Both patients should have access to IRT if they want to take the risk and to give themselves the best chance of an active and healthy future. And in most Western countries they would have that choice. What I would be interested in helping out with is doing advocacy work to change fundamentally how the NHS and NICE guidelines work, as a MS patient and research scientist.

  • ProfG, what would be your approach for case 1 if there were none restrictions from (national) protocols. Would you also recommend Siponimod in this case?

  • 1 – Regarding the concept of therapy failure: It is my understanding that therapy failure is determined by the NICE guidelines. If that is correct then if they are guidelines can you not operate outside them as long as it can be shown that it was an informed and collaborative process with the patient choice driving the outcome?

    I hear the NICE guideline about annual MRI being refuted and disregarded on the basis that ‘they are only guidelines’. Surely that cuts both ways?

    Am I conflating two different things?

    2 – If a new type of therapy failure occurs and the guidelines/rules are yet to catch up with the ever-evolving nature of drugs, discoveries, diagnostics, pandemics etc does this mean that the informed physician and patient can agree on a course of action even if it doesn’t fit with the now out of date guidance/rules?

    E.g.: If the therapy the patient is on – chosen in good faith at the time – means that if they were to continue on this therapy it would have a significant and measurable deleterious effect on their life/lifestyle, then can it legitimately be regarded as failing?

    Albeit by a different measure but a measure that never even existed 12 months ago so couldn’t be accounted for. What is the wriggle room for informed doctor/patient decision making when these new and unforeseen circs arise?

    Thank you.

  • As an American of a somewhat liberal/left bent, I usually urge my countrymen to adopt an NHS type system. But since I have good employer based insurance, I am currently on the DMF but if tomorrow I called my neuro, I could be on siponimod relatively quickly with a reasonable copay.

    In case scenario 1, could you gradually reduce the dosage of DMF, perhaps to 1 pill per day, than 1 pill every other day, than 1 pill every two days until you have some disease activation that you need but hopefully on a low dose of medication that prevents too serious rebounding?

    Case scenario 2 really sucks, because the brain volume loss may not be inflammation but just an accelerated aging process due to prior damage. And if you take her off her current regimen and she suffers a relapse that could just make things even worse.

    I don’t envy you at all.

  • Yes your life is tough… or lives are tough… we are all hostages of guidelines 😉
    Case 1: patient is not tolerating anymore DMF due to side effects like gastric pain leading to poor adherence. Offer cladribine as she does not bear the idea of subcutaneous injections and plans a pregnancy that rules out teriflunomide… after all one can always change his mind about pregnancy later… otherwise switch to ocrevus as it does not have the side effects of first line and rewrites 2 infusions per year and the patient is willing to tolerate them. Both should slow down progression if the hypothesis of smouldering MS is correct and diagnosis of SPMS was not made by anyone: she is still RRMS and not eligible for siponimod. Save time for it to be used later and try to use a therapy to modify the immune system through depletion until there is room to do so.
    Case 2: JCV- is a bad news as it would have simplified the picture a lot. Brain volume loss could be because of absence of inflammation? She could have lost OCB and her brain inflammation could have stopped. We are also in absence of clinical progression. If I think of loss of brain volume I would think cortex being involved and some cognitive decline should be picked in some way. In absence of this I would consider to test for OCB. Maybe she lost the OCB after natalizumab. If so switch to ocrevus and clean the periphery. If positive…….. infect with JCV? 🙁 Or extend dose to 6 then 7 then 8 weeks. One lesion will someday appear with the hope that the damage is minor but if the poppy field hypothesis is true this is not going to be the case.

  • I can’t begin to imagine how difficult it is for neurologists to make clinical decisions in cases like you describe. The only thing that is clear to me from this, is that the guidelines from Nice / EMA / NHSE etc have to be updated immediately. It simply cannot be that in 2021 with all that is known about MS, that a patient has the option of no drug or being put at risk of a massive relapse and ensuing disability by taking them off a different drug because their MRI says that there’s no change and they need to have “active MS”. It beggars belief.

  • 1. She has a very high EDSS. Mazent isn’t even on the table. She needs lemtrada.

    2. Do what is BEST for the patient. Stop following the restrictions. Always put YOURSELF as the patient and what is best for you —> should be what is best for the patient. Put them on free drug if needed.

    • My thoughts exactly Dr Greene.

      Although I know that Prof G always puts himself in his patients position.
      These “guidelines” are such that they offer only obstacles and illogicality, & prevent the Clinician treating their patient in the most efficacious & timely manner.
      Therefore, I personally would disregard them in cases where I could clearly evidence clinical need for the exception.
      In our professional lives, doing the right thing for every individual patient is more important than arbitrary guidelines that will never fit every case

  • Dear Prof G,
    Case 1: Speaking as a pwMS: If stopping treatement and developing active MS (to get siponimod, or any other wanted and needed treatement) means the chances are 50:50 to become doubly incontinent and quadriplegic or to get one or two new asymptomatic MRI lesions – I would definitely say yes if the first scenario is not irreversible and final. Because, what if it can’t be fixed – what if I would be doubly incontinent and quadriplegic and there is no turning back? Tough question. I would take that risk only if I knew there is even a slightest chance and a way to fix the first scenario outcome – then it’s definitely worth the risk.

  • Are the limitations imposed by the NHSE/NICE the real problem?

    Both cases present a similar problem: MS inflammations as seen on MRI and as clinical exacerbations are well controlled by their current DMTs. However, something more is clearly going on, and both patients are progressing despite being seemingly free from inflammation.
    As an engineer, this to me means that there is an important part we are not measuring. So instead of finding suboptimal ways to deal with a flawed and outdated system, is it not time for an update?

  • I don’t practice in NHS, but from my understanding of the science rather than coverage regulations…
    Case 1) would not stop treatment as still at risk for relapses at that age. No real evidence that siponimod helps inactive spms and any benefits
    in active spms are likely by preventing new lesions and relapses so no different than her current med.

    Case 2) would offer a change to S1P, or alemtuzumab based on differences in brain atrophy outcomes with the understanding true comparative data will likely never exist.

    • He was also former senior advisor for President Trump. Relevant because the Trump administration wanted to remove guranteed insurance coverage for preexisting conditions under Afforable Care Act. This meant if you switched jobs with time in between or was unemployed and had MS during the Trump administration, you had to guess whether the law was going to change and leave you without ability to get coverage. It was in

      So anxiety provoking. I wonder if this guy is thankful he can’t be denied health insurance because of his MS? (FYI an MS attack is triaged last in Emergency Room in States. He is fortunate to have only waited 5 hours). Regardless, I wish him a good recovery. And possible broader view of health care.

  • I had a very aggressive MS progession initially, which incapacitated me for a significant amount of time. For that reason, I would never take a risk of going off my DMD in order to establish my MS is active. I would, however, find it acceptable to retrospectively view standards in order to start a different DMD that might benefit me. (I do think MSers should consider taking a video of self during MS attack to show reviewers how bad an attack affects their function and support aggressive DMD use in future. I think active MS changes needs to be observed by decsion makers in order to avoid rigid standards that create moral quandries)

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