Not managing expectations in someone with PPMS

Not managing expectations results in angry patients. How not to get it right? 

Please note that the details of this case has been fictionalised, but illustrate a real-life scenario.

Yesterday one of my new patients with primary progressive MS came back for a follow-up visit after undergoing investigations to assess whether, or not, he was eligible for our compassionate use programme of off-label cladribine. He had been specifically referred to me by his consultant neurologist for cladribine therapy. He had rapidly progressive MS and gone from diagnosis to EDSS 6.5 (bilateral support) in approximately 8 years, with an 18-month history of a prodrome, i.e. he had noticed mild foot drop on exercise and this had been dismissed by his GP as a possible trapped nerve. Please note that 18 months from symptom onset to diagnosis of PPMS is actually quite quick. 

MS had already taken its toll, he was single having split-up with his long-term partner and had already had to give up work because of MS. He had sexual dysfunction, bladder and bowel symptoms, fatigue and spasticity. The spasticity was causing nighttime leg jerks, or spasms, that were waking him up in the early hours of the morning. As a result, he had interrupted sleep and never woke feeling refreshed. He managed his own activities of daily living but was very slow at doing manual tasks. He was unable to do domestic chores but was still able to drive. He was using a light-weight electric scooter for outdoor mobility. The scooter had been purchased for him by his family. As a result of leg weakness and a dropped foot on the right, he had had several falls. He had previously had physiotherapy for his walking difficulties and had been prescribed a foot-up device, which he was not using, and a lightweight walker. Other issues were social isolation, he rarely got out to meet family and friends, he had a poor diet, a current smoking history of 15-20 roll-up cigarettes per day and he did no exercise. He was also depressed and very anxious about the future.

After assessing him I ordered an MRI of his brain and spinal cord with gadolinium enhancement as well as a lumbar puncture to measure his spinal fluid neurofilament light chain (NFL) levels. His MRI showed a moderate brain lesion load, several spinal cord lesions with cord atrophy. None of the lesions enhanced after the administration of contrast or gadolinium. His spinal fluid showed locally synthesised oligoclonal IgG bands, compatible with his diagnosis of PPMS, and the NFL levels were well within the normal range for his age.

In summary, we have a middle-aged man with rapidly worsening PPMS with no signs of active focal inflammation on MRI or on spinal fluid analysis (NFL levels), i.e. his PPMS was inactive. I told him that based on our current treatment guidelines he would not be eligible for treatment with off-label cladribine. He was furious and wanted to know why. I tried to explain to him that we have no hard evidence at present on whether or not cladribine is effective in people with inactive PPMS. I said to him that his worsening disability may be due to damage from the past and/or early ageing in neuronal pathways in the spinal cord with no reserve capacity. He didn’t buy this explanation and wanted cladribine regardless of the potential consequences to his health. I was not prepared to give in and tried to give him hope. He may become eligible for ocrelizumab if NICE gives it a green light for use on the NHS in PPMS. However, the NICE single technology appraisal of ocrelizumab for the treatment of PPMS is unlikely to happen for many months, possibly years. He isn’t prepared to wait. Another option I offered him was the possibility of volunteering for an upcoming treatment trial. I explained that both alemtuzumab (EDSS <=6.5) and ocrelizumab (EDSS <=8.0) PPMS trials will be recruiting patients later on this year. He asked if they were placebo-controlled and I said yes. He was adamant that he is not prepared to go into a placebo-controlled trial. The consultation ended with him telling me that he will have to make plans to travel abroad for HSCT. I explained to him why I thought the latter was not a good idea, but he was not in the right frame of mind to accept any further advice from me. In short, I had let him down.

On leaving my consulting room he accused me of not caring and that I should have given him treatment despite having no evidence. Therein lies the rub; people with PPMS are so desperate to try anything to halt, or slow down, their worsening disability that they are prepared to take risks without necessarily the evidence of any potential benefit. We the healthcare professionals are trying our best to practice evidence-based medicine and where we don’t have evidence to at least apply some basic scientific principles. In an ideal world, I would be treating this patient with ocrelizumab and in a less than ideal world with off-label rituximab. Unfortunately, the NHS does not cover the costs of rituximab for PPMS. Cladribine may become an option in the future when we have data that could support some efficacy in worsening, but inactive, PPMS. This is why it is so important that DrK’s proposed Chariot-MS study is funded. As for HSCT, I am not aware of any evidence to support its use in worsening, inactive, PPMS. In fact with an EDSS of 6.5, I suspect the myeloablative chemotherapy, which is potentially neurotoxic, may actually make things worse. This why our London HSCT treatment criteria exclude patients who have more advanced MS. 

We seem to be caught between a rock and a hard place. We are trying to give PPMSers hope, but are we selling them false hope? In future, I am going to spell out more clearly how we define active PPMS so that when patients come for follow-up assessments they are forewarned and prepared for a possible decision of no treatment. Would you agree?

MSers also need to be made aware of therapeutic lag and reserve capacity. What does this mean for this patient? Even if we could initiate ocrelizumab next week we may not be able to prevent further deterioration in his lower limb function, i.e. progression today is driven by inflammatory damage in the past and by switching off inflammation now this may not be noticeable to him. In other words, progressive MSers may not be able to notice a slowing down in worsening of their progression. To expect flat-lining and improvement in functioning we probably need add-on neuroprotective and remyelination therapies and possibly even neurorestorative therapies. Please note add-on therapies targeting recovery of function will only work long-term if they are given on top of anti-inflammatory DMTs. What is the point of repairing and protecting the damaged nervous system to leave MS untreated? 

Do you agree all MSers with advanced MS and worsening disability should be informed of this information?

Another component that needs to be tackled is this man’s lifestyle. He is smoking that is almost certainly making him progress faster. In addition, there is a lot of symptomatic therapies that could be tried to help him. He needs an anti-spastic agent and possible treatments for his bladder, bowel and sexual function. He may also be eligible for a trial of fampridine. A graded exercise programme may help with his mood and improve his long-term outcome. It is important to remember that treating MS, in particular, advanced MS, is a partnership between the patient and the team of HCPs looking after them. This patient was expecting a quick and easy pharmacological solution to his advanced MS and was not addressing lifestyle issues that are just as important as any DMT. 

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48 thoughts on “Not managing expectations in someone with PPMS”

  1. A very difficult situation, but you can at least understand why people with PPMS are so desperate to be treated. Anything is better than simply watching yourself deteriorate week after week. This poor man seems to have an awful quality of life.

  2. Very informative article prof. Gavin. However, taking a MRI that is not enhancing doesn't prove anything. You might of missed the window in the year when it was active. Or active MRI stays active for a length of time? Also Barts are pushing for treating of all ppms patients. Could you not turned a blind eye? And given this patient caldribine? Given it's safest high efficacy dmt?

    1. Please also let me add, I understand your hands are tied and treating patients with unlicensed drug means your opening yourself to a lawsuit if that treatment fails or being struck off. But if all the Neuros got together and said enough is enough. Surely the system has to change?

    2. Anyone seen some Flying pigs….the Association of British Neurology meeting was this week apparently wonder it they agreed on anything:-(

    3. Primum non nocere is a Latin phrase commonly used in medicine; it means "first, to do no harm". Cladribine is an irreversible drug and as an immunosuppressant is associated with significant risk. There have been deaths associated with the use of cladribine for MS. How can we prescribe the drug without knowing if it will have benefits? I did offer this patient a repeat MRI in 12 months time to see if he has any new lesions that would make his disease 'active'.

    4. Thanks MD and Prof G. But still sad when your falling off a cliff and you grab for a rope but none is there.

    5. Deaths from cladribine? Is this from lymphopenia? Can't that be derisked by dose adjustment? What about the risk of your life being further upended?

    6. This is the first I've heard about people with MS dying after using Cladribine. Out of all the current highly effective DMTs, I got the impression – from reading this blog – that Cladribine was the safest of the bunch. I'm about to take my second dose so obviously can't change my mind now. Feeling somewhat apprehensive…yet hopeful. Cladribine seemed to me to be far less scary, in terms of side effects, compared with Alemtuzumab or Natalizumab.

    7. An interesting debate. "first to do no harm" …. I think most non-medical people have at least heard of this. But my question would be, if doctors stuck rigidly to this, would any drugs ever be prescribed or even sold over the counter?

  3. "What is the point of repairing and protecting the damaged nervous system to leave MS untreated?"Excuse me, but that makes no sense at all. It depends on the prevailency of the disease processes involved in different stages of an individual's MS – which are generally poorly understood. None of the current DMTs "treat" MS in that they mostly only stick a crude spanner in the works of the disease process by way of knocking out elements of the immune system. Which will work out better/worse for some than others.

    1. Re: "crude spanner" How can we be so sure they tools we use are crude spanners? Ocrelizumab is a very targeted therapy. Similarly, cladribine, is also quite targeted.

    2. "Ocrelizumab is a very targeted therapy."Not all that effective as in the longest 200 week charts the difference between ocrevus and placebo is almost nonexistent..?

    3. With respect, how can you say that Ocrelizumab and the (repurposed cancer drug?) Cladribine are targeted therapies when the T cell/B cell debate still rages, when they are still undoubtedly immune system wrecking balls with potentially severe side effects, and we don't even yet know whether a relatively safe antiviral would help MS? There is still so little knowledge about MS, particularly progressive MS – it is surely entirely inappropriate to talk of "targeted therapies". I personally – I have progressive MS of nigh on 2 decades – find it preposterous, upsetting to think that some neurologists would perhaps see fit to essentially deny me access to a future neuroprotective unless I was eligible to take an immune system sledge hammer drug as well.

  4. If as you say, there are no MS types and it's all one disease, shouldn't he be given a dmt? Because if not, then technically it's not one disease because there are different rules for the different types.

    1. "Economics rather than science determine treatment within the UK"Unless one is a member of the Royal Family.

  5. Hold on a minute, MS is MS remember? Never too early, never too late? The contrast MRI is a moment in time, BBB stays open for 2 or maybe 4 weeks at most? Who's to know, a month later could be a different picture. And what about those holes too tiny to see on MRI? Agree, most of the worsening now is going to continue regardless, but does that mean you say 'not worth the bother'? If ocrelizumab works why on earth shouldn't cladribine? As we know (if we've read the paper) 'cladribine is a chemical anti CD20' And some of it at least gets into the brain. Start it and gather real world evidence, if enough people do the same in a couple of years we'll know if it's effective. Ps great article in MS Trust Open Door magazine this month ProfG #ThinkHand

    1. I did offer this patient a repeat MRI in 12 months time to see if he has any new lesions that would make his disease 'active'. We need some evidence of inflammatory activity to justify giving him a potentially risky off-label DMT.

    2. I'm very pleased to hear it! Let's hope your fictional patient hasn't disappeared to Mexico in a last ditch what have I got to lose HSCT attempt. It happens. That or Switzerland. Puts cladribine risk in perspective.

  6. In 2013, following an unremitting attack of Optic Neuritis at age 54, I was diagnosed with progressive MS, EDSS 3.0 (self assessed). I assumed that it was PPMS as I could not recall ever being RRMS. In 2014, following appendicitis with Peritonitis, I suffered an exacerbation which took me from EDSS 3.5 (self assessed) to EDSS 6.0 (self assessed) in a very short period (less than 3 months). In 2015 I was diagnosed as SPMS. I was formally assessed as EDSS 6.0. In 2016, as part of a research trial, I was assessed as Single Attack (Optic Neuritis) Progressive. I am now EDSS 6.5 (self assessed).So my questions: The lack of clarity over exactly which type of progressive MS that I have is very confusing and makes it difficult to decide on future treatment options and prognosis. * I believe PwPPMS deteriorate in EDSS more quickly than PwSPMS, why is this? * Why do there appear to be separate future DMT paths for PPMS (Ocrelizumab) and SPMS (Siponimod). Surely progressive disease follows exactly the same path for PPMS and SPMS. As time is Brain, why delay in prescribing DMTs or offer/deny different DMTs depending on a diagnosis of PPMS and SPMS post progression?

    1. Re: "I believe PwPPMS deteriorate in EDSS more quickly than PwSPMS, why is this?"Yes, over the course of the disease this appears to be the case. But once someone with relapse-onset disease enters the worsening stage (formerly SPMS) they progress at the same rate as PPMSers.

    2. Re; "Why do there appear to be separate future DMT paths for PPMS (Ocrelizumab) and SPMS (Siponimod)."This is based on MS being salami-sliced into three diseases to allow each disease to be classified as an orphan disease. By doing this pharma allowed interferon-beta to get licensed with one pivotal trial. We are now paying the price of this folly. PPMS and SPMS are the same disease and should be treated as such.

  7. This post is a good snapshot of MS today… frustrates the hell out of pwMS, imo.

    1. Re: "This post is a good snapshot of MS today… frustrates the hell out of pwMS, imo."I assume you mean in the UK? If you live in the US, Germany or Australia, for example, this patient would be on ocrelizumab.

  8. What abut pwPPMS who have no/ have not had any lesions on MRI but were given the PPMS diagnosis? I can see this might be tricky for them to get a MS DMT, is that correct or may CSF might be a fair enough indicator of the MS?

    1. Re: "What about pwPPMS who have no/ have not had any lesions on MRI but were given the PPMS diagnosis?"This is very unusual and tend to have lesions in their spinal cord. To make a diagnosis of PPMS you have to show dissemination in time and space and the latter usually requires MRI evidence. If someone has no lesions on MRI I would look for alternative diagnoses.

    2. Thank you, the National MS Society quote the following on their website:"… approximately 5 percent of people with clinically-definite MS do not initially show lesions on MRI at the time of diagnosis. If repeat MRIs continue to show no lesions, the diagnosis of MS should be questioned".

    3. Re: "….approximately 5 percent of people with clinically-definite MS…."This refers to MS and not PPMS and refers to studies done with older generation MRIs. This figure is lower now.

  9. Why are the only treatment options for your patient some irreversible immunosuppressants?In your earlier post, you considered PPMS to be „low level“ RRMS (below the MRI detection level). Then why not start with a simple DMT for your patient. Better than nothing and always a starting point for escalation if necessary. Is this merely a question of NHS cost coverage? If so, Betaferones were approved for treatment of SPMS in other countries many years ago. Why not in the UK?Or do you consider DMT to be fundamentally unsuitable for SPMS/PPMS?

    1. "Or do you consider DMT to be fundamentally unsuitable for SPMS/PPMS?"I would say ineffective. But it it's all you got you try and hope for the best.

    2. Re: "Or do you consider DMT to be fundamentally unsuitable for SPMS/PPMS?"I can only assume you are relatively new to this blog and are not up to speed with our position on this issue. We have evidence from the early 90's that more advanced MS is still modifiable with DMTs, even early generation less effective DMTs. The issue is cost and NHS England guidelines that prevent us from prescribing DMTs to people with so-called 'progressive MS'. In reality is about costs. This is why we explore off-label cheaper options.

    3. Which leads to the other part of my question: "… Betaferones were approved for treatment of SPMS in other countries many years ago. Why not in the UK?"What arguments led NHS to refuse coverage?

    4. Re: "Betaferones were approved for treatment of SPMS.."This refers to relapsing-SPMS and not SPMS in general. This is why several labels refer to relapsing forms of MS. This is another reason why we want to get rid of all these labels and make MS one disease and simply refer to it as active/inactive MS and/or worsening/stable MS.

  10. If you sacrifice your art because of some woman, or some man, or for some color, or for some wealth, you can't be trusted.Miles Davis

    1. Re: "If you sacrifice your art …."I am glad to see you appreciate the practice of neurology as an art and not a science.

  11. This "patient" would probably benefit from attending an MS Centre. I have PPMS and find appointments with my neurologist & MS nurse quite depressing but I gain enormous benefit from attending my weekly exercise class at Chilterns MS Centre. The supportive social environment has a beneficial effect on me and the exercise definitely helps me soldier on. I would find life much more difficult without that regular contact with people who understand how tough it can be.

    1. I agree; the current antiquated Victorian model of healthcare that is provided by the NHS is unsuitable for the long-term care of pwMS. Attending an MS Centre is exactly what this patient needs. Unfortunately, he lives in central London.

    2. The Chilterns MS Centre sounds great Sarah, I imagine a lot of us would benefit from a supportive place such as this. It is a shame there are not more of them.

    3. Harrow MS therapy centre, in north west London and MS Action MS therapy centre in Walthamstow, East London. Both probably too far to travel to.

  12. I think "Primum non nocere" should be extended to include "quaedam secundum quid bonum" – or "second, do some good".You have nothing to offer your patient after he had been given the impression that you had – are you surprised he was angry and upset?As for improving his life style – speaking metaphorically here, when life has regressed to a series of boring chores interspersed by biscuits, how would you feel if some medic came along and told you to do without the biscuits – for no reward. You're still going to be as ill as ever, your quality of life won't improve much and the NHS will come along and provide, as usual, the most utilitarian, ugly and uncomfortable "solution" they can possibly get away with (after having paid your taxes like a good citizen for years, you are not worth anything better) – or better still, the cost free option of nothing at all – and make you feel like an inconvenience into the bargain.I, for one, am eating the metaphorical biscuits.

    1. Re: "You have nothing to offer your patient after he had been given the impression that you had …"He was told that he would be eligible for cladribine if he had active MS. The test battery came back as showing he had inactive MS.

  13. I feel for your patient, as I share many of his feelings/frustrations.Whether to treat or not to treat is an almost impossible conundrum, given the unknown benefits and known dangers associated with treating.Even if Ocrevus was available in the UK, its effects of the drug are quite modest (a 20% slowdown in progression is NOT what people with progressive ms are looking for) and the potential side effects may lead to some tragic results down the line. Although dismissed as an outlier, there was a greater than 2% chance of cancer seen in the progressive Ocrevus trials, and the RNA and lupus trials were halted because of patient deaths. I have a gnawing fear that we could very well see a wave of disastrous adverse events 3-5 years out. I've never wished so hard to be wrong. It should be noted that there are neurologists in the US who refused to prescribe the drug because of just these concerns.The upshot of all of this is that the current strategies of MS treatment are ill-suited for the progressive population. Some outside the box solutions need to be explored, and with much haste. Those of us with progressive ms (or, really, with any flavor of the disease) need to rise up and decry the current status quo. Treating but not curing is a wonderful model for creating tremendous revenue for the MS industrial complex, but leaves the MS population to serve as giant pool of guinea pigs in a massive experiment in long-term profound immunosuppression, the likes of which has never been tried before.In short, your patient has every right to be angry, frustrated, and disgusted. In fact, all patients suffering from this disease, along with those who love them and those who treat them should share these emotions. There has got to be a better way…

    1. Sorry for the above typos. "Its effects of the drug" should read "the effects of the drug". And "RNA" should read "RA”.Voice recognition software not 100% accurate, especially when you talk in a New York mumble…

    2. Hello Marc. You have such a wonderful gift for expressing your thoughts and you use your words so eloquently. Have you ever written a book about anything or contributed articles to magazines etc? Thank you for your regular and much valued comments in the BARTS blog.

    3. Thank you for the kind words, flattery will get you everywhere.Aside from my blog, which I've been writing for over nine years, I haven't written anything that's been published in book form. I have had several articles published in MS themed magazines, but these were usually slightly altered versions of blog posts.Truth of the matter is I wish I had not taken for granted my writing skills when I was healthy, and now that I'm sick, being sick takes up so much time and energy that I'm not sure I have the wherewithal to drag a book out of me. Seems that just as youth is wasted on the young, health is wasted on the healthy… At least it was in my case.Thanks again…

  14. ProfG you need solid scientific evidence to back your point and you dont provide any, especially for such a fundamendal issue. And you need to convince your collegues first. I doubt that many are in the same page with you. I think your points have not been either consistent or responsible and you just create frustration to your patients. For you its just an alternative option, for them is a life choice.

    1. Re: "ProfG you need solid scientific evidence to back your point…"I agree that is why we want to do a trial of cladribine in people with more advanced MS. At the moment the only evidence that DMTs make a difference to pwPPMS is for ocrelizumab. At the moment ocrelizumab is not available under the NHS.

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