What would a good case study of recovery from ME/CFS look like?

[Sasha]

Impressive individual cases of improvement or recovery can often be a starting point for hypothesis-generation and clinical trials in any disease.

In ME/CFS, the rituximab trial arose from observing impressive remissions in two PwME treated with rituximab for their cancer (IIRC). But lots of PwME have remissions following various interventions, but their stories don't lead to trials.

Suppose one of us had tried something out and had had a spectacular improvement. We'd surely want to share it and try to push for it to be researched. Presumably the first step would be to try to get written up as a case study. But what would make for a case study good enough to make it interesting enough to researchers to take it forward? What information would have to be in it for it to be taken seriously? How, in practice, would you have to do to get it into the medical literature?

Discuss!

 

[Jonathan Edwards]

Not a lot really. I published a case report of someone with arthritis getting better after rituximab. I had already decided to use rituximab bu the case was brought to my attention. There were no measurements before treatment - there aren't in this situation.So we just noted that the person felt better. It was published. But it needn't have been. If someone thinks they have seen a recovery following an unexpected treatment they can set up a pilot trial with actimeters or whatever. Nothing needs to be published to get that started.

 

[Trish]

I think ideally I'd want the person trying the treatment to be diagnosed by a reputable doctor, had ME/CFS of sufficient severity and duration to be more than a temporary post viral fatigue, do a 2 day CPET, then track their symptoms and activity using validated technology for at least 6 months while not doing any treatment. Then do the treatment, and continue tracking symptoms, activity and severity level for at least a year after treatment and do another 2 day CPET.
Even then it would only be likely, not proven to be the treament that helped.

 

[Sasha]

Not a lot really. I published a case report of someone with arthritis getting better after rituximab. I had already decided to use rituximab bu the case was brought to my attention. There were no measurements before treatment - there aren't in this situation.So we just noted that the person felt better. It was published. But it needn't have been. If someone thinks they have seen a recovery following an unexpected treatment they can set up a pilot trial with actimeters or whatever. Nothing needs to be published to get that started.

Suppose, though, that you were the patient. You knew you were going to try an intervention and you had high enough hopes that it was going to work that you decided to start measuring some parameters, with a view to being an influential case study if it worked. What would you do? And if it did work, how would you get it published? Or at least get the right kind of information to the right researchers who might be interested in setting up a pilot trial?

 

[Jonathan Edwards]

Then do the treatment

But that's a trial, @Trish. A case report is where you get a result without having set out to do so.
If we are talking of doing a trial you need a lot more than one case.

 

[Jonathan Edwards]

You knew you were going to try an intervention and you had high enough hopes that it was going to work that you decided to start measuring some parameters, with a view to being an influential case study if it worked.

That's a trial again, and it needs controls and enough patients.
For one person to do it would be hopeless. If they got better they would write to a journal but if they didn't they wouldn't - classic publication bias.

 

[Trish]

Interesting that Jonathan Edwards and my answers are so different.

I was answering from the perspective of seeing so many people claiming they have been cured by LP, ear seeds, supplement protocols etc. In order to weed those out we need better ways to verify whether there really is any evidence that sticking bits of gold plated tat on your ears, or standing on a paper circle and saying NO are effective or nonsense.

 

[Trish]

But that's a trial, @Trish. A case report is where you get a result without having set out to do so.
If we are talking of doing a trial you need a lot more than one case.

I agree that if a clincian is setting out to test a treatment, or to show it is effective, that is indeed a trial, and needs more than one patient and controls.

I was thinking from the perspective of a patient who wants to test a treatment on themself, but perhaps it's expensive, or may have side effects, like low dose naltrexone, or abilify.

I think if I wanted to find out for myself if it was really beneficial or I was kidding myself, I might do the sort of procedure I suggested above, with tracking for significant time before and after. Only then would I think it worth sharing with others that the treatment had or had not worked for me, and perhaps if the effect was dramatic, to push for funding for a proper trial.

Similarly if the initiative came from my doctor, and they suggested they might write it up as a case study, I might want to insist it be done as if in a trial rather than haphazardly, and if it failed, they write that up too.

 

[Kitty]

Admittedly I haven't read a lot of case reports, but I get the impression they focus on clinical observations that might be useful or important.

It could be a serendipitous response to treatment, a pattern of symptoms that suggest a familiar condition but turn out to be something else, or a previously unreported genetic finding.

They do all seem to be written by doctors, though that might only be because search engines tend to put the papers with most views at the top of the list.

 

[Sasha]

You knew you were going to try an intervention and you had high enough hopes that it was going to work that you decided to start measuring some parameters, with a view to being an influential case study if it worked.

That's a trial again, and it needs controls and enough patients.

We are oddly at cross-purposes!

This N=1 attempt would be a trial if it had controls and enough patients - but it's not a trial, it's a patient looking ahead before they try something and trying to get the best scientific use out of it.

For one person to do it would be hopeless. If they got better they would write to a journal but if they didn't they wouldn't - classic publication bias.

How would this be different to Fluge and Mella's publishing their observation of their two ME cancer patients getting spectacularly better on rituximab?

Surely there's a way to do good hypothesis generation from observation of individual cases?

 

[Kitty]

Presumably the first step would be to try to get written up as a case study. But what would make for a case study good enough to make it interesting enough to researchers to take it forward? What information would have to be in it for it to be taken seriously?

It would be hard for an individual patient—there are so many people telling recovery stories that the auto-response is an eye roll. It might be different if several patients experienced a similar response, passed the information on, and others benefitted too. Then it might get published.

Maybe the best case scenario is that the first patient is managed by an interested doctor who thinks the result is plausible enough to put his or her name to it, and has enough credibility to get it published and noticed.

Credibility's probably the biggest hurdle, and some of it is as much about the author and their standing as it is about the contents of the paper.

 

[Jonathan Edwards]

This N=1 attempt would be a trial if it had controls and enough patients - but it's not a trial, it's a patient looking ahead before they try something and trying to get the best scientific use out of it.

I am afraid that is a trial. A trial does not have to have controls or more than 1 case. My initial rituximab trial had no controls and 5 cases. Because I had objective end-points it gave a reliable result. A trial can be done by non-medical people, including patients.

How would this be different to Fluge and Mella's publishing their observation of their two ME cancer patients getting spectacularly better on rituximab?

The problem is if various people try something and only those with success report. For Fluge and Bella nobody was 'trying something'. The observation was purely post-hoc. It is all to do with expectations. Confirmation of expectations is a different situation from noting something unexpected. The need for guarding against subjectivity in trials is a strange and complex thing. You do not need to blind for unexpected or negative results anything like as much. People are not biased to report those.

 

[Creekside]

What information would have to be in it for it to be taken seriously?

I think it would require clinical verification of the ME symptoms before and after the treatment. Of course, we're still waiting for the means to measure ME symptoms reliably.

 

[Jaybee00]

In ME/CFS, the rituximab trial arose from observing impressive remissions in two PwME treated with rituximab for their cancer (IIRC).

No. IIRC they received cyclophosphamide PLUS ritux. Fluge went with trialing ritux before cyclo.

Disabled people going back to work would be good info “to be taken seriously”. See here (trial, not a case study).

https://www.s4me.info/threads/intra...-study-2020-rekeland-mella-fluge-et-al.14925/

 

[poetinsf]

Suppose, though, that you were the patient. You knew you were going to try an intervention and you had high enough hopes that it was going to work that you decided to start measuring some parameters, with a view to being an influential case study if it worked. What would you do? And if it did work, how would you get it published? Or at least get the right kind of information to the right researchers who might be interested in setting up a pilot trial?

With n=1, I'm afraid it is still an anecdote no matter how well you control/document your treatment. One exception could be something you can repeat, like provoking PEM and applying your treatment at the flip of coin. In that case, you could have sufficiently large N with control. (I mind you, this is extremely time consuming. I'm doing this with cumin and I have exactly 2 data points so far!). Even then, all you can say is that the treatment actually worked for you. You don't know if it will work for others till someone else replicates it. If enough people replicate it and can back it up with data, then researchers may take notice.

I think the recovery cases are more likely be noticed by researchers if they are accidental rather than intended. The recovery cases after CCI/IIH surgery, for example. They are still anecdotes, but you have to wonder what's going on there. If the treatment was intended for the recovery, it's more likely to suffer from illusion and bias since the subject and observer are one and the same, and therefore more likely to be dismissed.

 

[Jonathan Edwards]

Suppose, though, that you were the patient. You knew you were going to try an intervention and you had high enough hopes that it was going to work that you decided to start measuring some parameters, with a view to being an influential case study if it worked. What would you do? And if it did work, how would you get it published? Or at least get the right kind of information to the right researchers who might be interested in setting up a pilot trial?

@Sasha,
Do you have an example of the sort of thing you are thinking of?
There is a sort of Catch22 in the way you have described this. If there is an 'intervention' that yo have 'high hopes' of then presumably someone has either proposed this intervention as a therapy or someone has a theory that suggests its use. The person is likely to be a medic or scientist? In which case they should be doing a trial anyway. They are 'the right researchers' - already there.

If one patient tries something like this and then reports back - to anyone else - then sensible listeners will say 'well I have heard the odd story about people getting completely better after goodness knows what so maybe I won't get too excited'. They will assume that only the few that get better will report something - as for the Lightning Process.

What seems much more relevant is reporting the existence of an intervention option that gives rise to high hopes for some theoretical reason to the science community - which is us here - for debate. If anything actually sounded worthwhile to researchers then we could almost certainly get the message through to people who might try it.

The trouble with trying it as a one off is that we simply do not have objective markers that would provide additional evidence of any weight. If you were able to say 'I got much better and look, my BRIM receptor levels rapidly normalised from 76.3 to 12.2 over the period of treatment' then researchers would say 'Wow we must do a trial'. But there are no known BRIM receptors yet.

 

[Sasha]

@Sasha,
Do you have an example of the sort of thing you are thinking of?

Not specifically, but I'm once more at the stage of casting about for new and reasonable things to try and was wondering what would make it potentially a useful experience for everybody else if anything worked for me.

There is a sort of Catch22 in the way you have described this. If there is an 'intervention' that yo have 'high hopes' of then presumably someone has either proposed this intervention as a therapy or someone has a theory that suggests its use. The person is likely to be a medic or scientist? In which case they should be doing a trial anyway. They are 'the right researchers' - already there.

That's a very good point!

What seems much more relevant is reporting the existence of an intervention option that gives rise to high hopes for some theoretical reason to the science community - which is us here - for debate. If anything actually sounded worthwhile to researchers then we could almost certainly get the message through to people who might try it.

The trouble with trying it as a one off is that we simply do not have objective markers that would provide additional evidence of any weight. If you were able to say 'I got much better and look, my BRIM receptor levels rapidly normalised from 76.3 to 12.2 over the period of treatment' then researchers would say 'Wow we must do a trial'. But there are no known BRIM receptors yet.

I agree that that's a problem, but possibly less of a problem if the effect is huge - as per the Fluge and Mella patients. Going from bedbound to fully recovered in a patient who has been ill for years with little change should carry some weight, I think, in the absence of biomarkers.

 

[Kitty]

Going from bedbound to fully recovered in a patient who has been ill for years with little change should carry some weight, I think, in the absence of biomarkers.

That should at least prick up ears, specially if it happened in a dozen people who'd been severely ill for a long time.

I'm not really expecting to hear about it, though; if a drug were capable of restoring 60% of function long term, we'd have found it by now. Maybe an uncommon pairing of drugs is less likely, but enough people have been ill from teen years to retirement age, with all the combinations of infection, accident, disease, surgery and treatment they'll encounter between them, that the odds are still on it surfacing.

I think my ten bob's on no useful drug being available because no one's ever tried to drug whatever's gone haywire.

ME is quite an unusual combination of bad luck. No outwards signs of the sins of our fathers to identify us, no magic lantern to reveal the worm inside, no medieval concoction offering a clue to what might help...

 

[Creekside]

Going from bedbound to fully recovered in a patient who has been ill for years with little change should carry some weight, I think, in the absence of biomarkers.

The problem there is "Did they actually have ME?" Without biomarkers, we don't know for sure. It might have been some other medical problem that produced similar-appearing symptoms. Even if it was ME, it could be a possibly rare subset in which patients are unusually sensitive to effects of viral infection or whatever, so the treatment might work for 15 people in the world, but not for any other PWME.

no medieval concoction offering a clue to what might help...

Any treatment that works for someone is a clue to what's going on inside. The problem is that there aren't any really useful clues. The treatment might work on some downstream effect far from the root cause, or it might work only due to some epigenetic combination unique to that individual. Someday, when ME's mechanism is understood, maybe there will be an answer for why cumin cured me of PEM, but the fact that cumin worked for me isn't a clue that would likely lead to the secret of ME.