Primum non-nocere is a Latin phrase that means “first, do no harm”.
On the tube this morning I recognised one of our medical students reading Henry Marsh’ book “Do no harm”. He is a semi-retired neurosurgeon, turned author, who uses his past patients to discuss ethical dilemmas and to criticise the NHS. His book does showcase the life of a surgeon, warts and all. It is clear that to be a good neurosurgeon you have to be a team player. In surgery, it is critical to get the clinical decision-making correct, i.e. when and when not to operate. Surgery is also a technical speciality above all else; from the age of about 55 a surgeon’s skills deteriorate so it is best to be operated on by someone who is in their prime. In short, if you make the wrong clinical decision and you get things wrong technically then you will get a suboptimal outcome; i.e. you will do harm.
I remember from very early on in my medical school career being told to do no harm. It is important to understand that this phrase dates back from a bygone era; an era when we hardly had any treatments that worked.
Wikipedia: It is often said that the exact phrase “First do no harm” is a part of the original Hippocratic oath. Although the phrase does not appear in the AD 245 version of the oath, similar intentions are vowed by, “I will abstain from all intentional wrong-doing and harm”. The phrase “primum non nocere” is believed to date from the 17th century. Another equivalent phrase is found in Epidemics, Book I, of the Hippocratic school: “Practice two things in your dealings with disease: either help or do not harm the patient”. The exact phrase is believed to have originated with the 19th-century English surgeon Thomas Inman.
In the modern era, we have to walk a tightrope of treating people to prevent future harm from a specific disease, knowing well that a small number of patients will be harmed from the side effects of the treatment. In other words, modern medicine has become a balancing act between the outcome of a population of patients at the expense of a small number of patients with adverse events.
In the MS space, natalizumab epitomises this dilemma. Natalizumab is one of our most effective DMTs; it is very effective, easy to use and has few adverse events, which are uncommon. Unfortunately, however, in JC virus-positive individuals it may result in PML a life-threatening infection of the brain. A lot has been done to derisk this complication, but unfortunately, there are still pwMS developing PML as a complication of natalizumab.
One industry analyst said to me that he had no idea why natalizumab was still on the market. He felt it should have been withdrawn after the PML crisis emerged. I said to this individual that he clearly hasn’t seen the impact that natalizumab has on people with MS’ lives. Natalizumab is a truly a transformative drug, which is why I refer to the treatment of MS as being represented by two eras; pre- and post-natalizumab.
It is clear that pwMS understand that to maximise outcomes for pwMS some individuals have to pay the price of suffering adverse events. This is why it is not surprising that pwMS are prepared to take greater risks than their risk-averse neurologists (see below). I recall working with a rheumatologist who made the point that if he didn’t have a few of his patients dying each year from the complications of his treatment decisions then he was not treating his patients actively enough. The corollary is that a rheumatologist without a body count is being too conservative.
Could the same analogy be levelled at neurologists? I think yes. I am still seeing far too many pwMS for second or third opinions who are very disabled from watchful waiting, slow escalation or sideways switching when they should have been treated with high efficacy treatments years ago. We really need to change the behaviour of MSologists from being risk-averse to becoming risk-takers. This also means pulling no punches and telling pwMS how bad MS really is and that to maximise your outcome you need to treat the disease effectively early on.
At Barts-MS we are taking this principle to the extreme with our #AttackMS trial. As always the ideas underpinning this trial are already being adopted by our team so that by the time we get the trial funded and up and running we may not be able to do the study because we would have lost equipoise.
Wikipedia: Clinical equipoise, also known as the principle of equipoise, provides an ethical basis for medical research that involves assigning patients to different treatment arms of a clinical trial. In short, clinical equipoise means that there is genuine uncertainty in the expert medical community over whether a treatment will be beneficial.
I would be interested to know the MS Community’s opinions on the #AttackMS trial.
Heesen et al. Risk perception in natalizumab-treated multiple sclerosis patients and their neurologists. Mult Scler. 2010 Dec;16(12):1507-12.
BACKGROUND: Natalizumab is associated with the potentially life-threatening side-effect progressive multifocal leukoencephalopathy (PML). Little is known about patients’ and physicians’ risk estimates and attitudes towards natalizumab treatment.
METHODS: Consecutive natalizumab-treated patients (n = 69) and neurologists (n = 66) in two centres and cooperating private practices received an evidence-based three-page information leaflet about natalizumab-associated PML and an evaluation sheet.
RESULTS: After reading the information, patients were significantly more likely than physicians to intend continuation of natalizumab treatment and willing to accept higher risks of PML: 49% of physicians would stop treatment at a PML risk of 2:10,000 or lower, while only 17% of patients would do so (p < 0.001). This difference could not be explained by risk calculation abilities or lack of understanding. Both groups overestimated natalizumab treatment effects.
CONCLUSION: Patients had a significantly worse perception of multiple sclerosis as a malignant disease. We conclude that patients were willing to accept a higher risk of PML than neurologists. Coherent with their perception of risks and benefits, patients were also more willing to continue treatment. Open information about treatment-related risks is appreciated and might support shared decision making.
CoI: multiple
A fantastic analogy, to the point, and no holding back. This I feel is the only way forward in the journey of all involved to help patients with M.S brutal honesty is a far better call than years of false hope.
When I learned that the largest group, from across different countries, to seek end of life at places such as Dignitas are those with neurological conditions it endorsed my existing view that it is as horrendous to die in a piecemeal fashion via loss of self as it is via those things that can take you out quickly.
This isn’t a view I shared out of sensitivity to the feelings of others until some who’d lost family to cancer, including a friend who sister died in her early 40s, responded to my explaining escalation versus induction exactly as you’ve described ProfG concerning neurologists being conservative – ‘Why would they let you get worse?’ / ‘They’d never do that with cancer !’ The friend I’ve referenced said ‘that’s perverse, why wouldn’t they wanna take the guarantee of positives over possible risks?’ Her sister had surgery on her brain that had a high chance of killing her. She was already terminal, but was offered it to give her more time with her two young children.
You haven’t mentioned the change regarding Alem. I perceive this as a retrograde step, that endorses and entrenches the escalation model. I was diagnosed four years ago and learned of your rationale for hitting early and hard. At that time I was hopeful of seeing a rapid sift away from the escalation model, but now I can’t help but feel saddened that my reaction to your post is if this is ever gonna happen it’s gonna be a long way off into the future.
Oh! and any neuro surprised at the results of the above study should, I suggest, do a basic psychology course😏
FI agree with your cancer analogy 100% I use it all the time. It IS perverse. I even have a good friend with cancer and she agrees with me!
Re: “You haven’t mentioned the change regarding Alem. ”
I think everyone who reads this blog knows my position on alemtuzumab and HSCT for that matter. We should be able to use both these options early on. Who is taking the risk; the regulator, the neurologist or the patient?
Sorry, I only meant that you hadn’t referenced it in this post.
Your position is very clear for anyone who reads this site and wish all neuros were of the same view.
As a patient totally agree with this. I’m upset I don’t have the option of HSCT in the US I would take it.
Agree neurologists need to be more up front with patients about how malignant this disease is. Often you just hear”it’s not the bad disease it used to be we can treat it” then patients get lulled into escalation therapy or watchful waiting and one the damage is done it cannot be undone.
More hard hitting treatment choices earlier please and let patients decide risk tolerance. Not treating hard enough early on leads to progression and a life not worth living which I will argue is the biggest risk of all.
Therefore “watchful waiting” has the worst possible side effect one could imagine.
These results don’t surprise me at all and I hope the neurology community will finally take to heart tour recommendations prof g. Sweeping change to the current approach is needed with greater urgency. These are people at the prime of their lives and under treatment does not only harm them it deprives our global community of their potential.
Is there not another aspect to this to some degree in that it seems that many are on heavyweight therapies which – whatever the side effects – are not stopping progression?
That may not be true if taken early enough.
Exactly.
Great read.
Re: “stopping progression?”
Stopping progression should be reframed as preventing progression; treat early and effectively.
How early is necessary is what I ask myself.
So we don’t need to read your other posts about how people on DMTs are getting worse, progressing? There is no need for funding from the UK MS Society to research how to stop progression, the real disease? Everything should be about giving the current DMTs as early as possible, and hoping that’s early enough? Except if you have early onset, slow PPMS as I do, with little evidence of “relapse activity”, this boat sailed many years ago.
No comments on the #AttackMS trial? If someone from Biogen is reading this post can you please nudge your decision-makers about doing it ASAP? Thanks.
Bumped into this
Impact of informative censoring on the treatment effect estimate of disability worsening in multiple sclerosis clinical trials
https://www.msard-journal.com/article/S2211-0348(19)30937-X/fulltext?fbclid=IwAR2OLo9-B26jgn_eUMOgiqOkrvLCI0fSIrfixS3jyK1aXL_CDQ22hRAK8Wg
I think the trial is a good idea as it may stop neurologists from diagnosing and then handing patients a bunch of brochures and telling them decide months later on treatment. Perhaps this will get neuros to view even “mild” ms like the malignancy it really is and great with more urgency. I do worry that only 3 doses before unblinding will not be enough to show statistically significant results unless you follow people for at least 2-3 years and show longer term outcomes. If results are not good on this it could backfire in a big way. I agree it’s critical to undo the escalation or watchful waiting mindsets. As a patient I will live the rest of my life wishing doctors had treated me more aggressively in the few months post diagnosis. Yes I wasn’t asking for it but I didn’t know enough then and certainly hadn’t found this blog.
sorry, but I couldn’t find the Q&A post for December and I have a question re cladribine
I believe its currently given as 2 short doses 1 year apart and then nothing.
are there figures for those needing further treatment after the second course?
Ask Barts December is now live!