A Novel Nutriceutical Treatment of ME/CFS, 2017, Comhaire

[arewenearlythereyet]

thanks, once again, for constructive remarks.

Fatigue is a subjective feeling which is extremely hard to objectivate. Exhaustion, lactic acid accumulation, sleep disturbance etc. can be measured, but the feeling of fatigue can only be estimated by using questionnaires. Patients expressing that they were clearly less tired, and could resume their activity, and in whom the FSS was decreased by at least 15%, were considered responders. If the subjective feeling of fatigue was decreased, but the FSS was not, or vice versa, they were considered non-responders.

Again I insist on the fact that the nutriceutical (food supplement containing vitamins, amino acids, minerals and plant extracts with medical application, in French called ALICAMENTS) are not to be confounded with homeopathy. The effect of several of such nutriceuticals has been proven for the treatment of e.g. male infertility, migraine, metabolic syndrome, hyperlipaemia, and benign prostate hyperplasia. For each of these conditions, specific mixtures of ingredients are being used. I have published the results of trials with these nutriceuticals, both open-label trials and placebo controlled studies. Several of these studies add biological "surrogate markers" to the clinical findings, whenever possible.

I repeat that the prime purpose of treating patients with fatigue is to make them feel better, to increase their "energy" so that they can resume their "normal" professional and familiy life, albeit often with limitations. In general, this is the purpose of medicine.
Now, giving insulin to patients suffering of diabetes does not cure their disease, but improves their health and quality of life. Giving the nutriceutical I have used DOES NOT CURE ME/CFS, but it interferes with (one of) the probable pathogenetic mechanisms, improving the quality of life of a proportion of them. Since the nutriceutical is not toxic and causes no adverse effects, the benefit over risk ratio is positive. Also, the basic ethical rule "first do not harm" (primum non nocere, Hippocrates of Kos, MD, 460-377 BC) is honoured.

Regarding poor studies SUCH as PACE etc. I like to refer to my publication in attachment.

I am a retired professor of internal medicine, endocrinology and metabolic diseases, having published approximately 700 scientific papers, and lectured at 400 congresses and symposia over the world. I have been teaching at Ghent Univesity for 40 years and have personnaly treated several tenthousands of patients. I have organised several multicentre trials in my function of steering committe member of the World Health Organisation. I know the limitations of the present paper, which I clearly mention. So, once again, read the paper for what it contains, and not more nor less.

Thank you for taking the time to reply and to provide more detail on your views on the disease.

I think context is definitely key in terms of claims associated with any nutritional supplement.

I personally take many of these and have got some improvements in symptoms from things like B vitamins and mitochondrial support supplements. However I would say that the use of these are mainly around symptom relief to improve quality of life while I'm sick.

These treatments haven't moved me forward in terms of improving my capability, they have just eased things like brain fog, and reduced the duration of PEM episodes slightly. I am pretty certain that my energy envelope hasn't increased since I've been measuring heart rate activity and steps before and during taking the supplements.

It's really important to stress that this is for symptom relief/ quality of life rather than to give people more energy and feeling less fatigued which could be misleading to many desperate sufferers who are looking for a "cure"particularly with the confusion around the name ( as you mention in your paper).

That is why I hope with future studies you might include the wider aspects of the disease and perhaps use activity and cognitive measurements. It would also be good to see if people's energy envelope did increase or whether it remains unchanged with measures such as constant heart rate monitoring to give an objective measure of activity before and after supplementation. This would also show up PEM episodes so the frequency of these vs activity could then be also captured? I also found that initial supplementation took a while to settle down (6-8 weeks) and in the case of B12 this took a long time (6 months). Longer term studies would be helpful to see what is going on in terms of continuous supplemental therapy. It's also worth noting that pacing activity in a lot of cases will control a lot of symptoms without supplementation so this would need to be a control.

I hope you find these critiques useful and hope you will post some more of your findings.

 

[Valentijn]

I regard a day when my only symptom is "tiredness" or "fatigue" as a good day.

Yes, fatigue is nothing to me. It's not pleasant, but I can ignore it. I can't ignore PEM or more immediate muscle weakness and orthostatic intolerance.

I love it when I get a cold - I feel more fatigued, but my capacity for activity improves a bit, and I can do more than usual. I feel yucky and grumpy due to the cold, but that doesn't stop me from doing anything in the slightest.

 

[Scarecrow]

I was wondering if more measurements than just the FSS scale were being used.

The SF-36 was also used. The author noted:

None of the patients reported adverse events or side effects. In 5 patients (responders; group 1, Table 1) health situation was significantly improved with respect to their physical performance capacity, brain function, and the reduction of muscular pain and exhaustion.

This information could only have come from the SF-36 but I don't know how brain function relates to that questionnaire.

 

[Scarecrow]

Yes, fatigue is nothing to me. It's not pleasant, but I can ignore it. I can't ignore PEM or more immediate muscle weakness and orthostatic intolerance.

For me, the problem with ignoring fatigue is that it inevitably leads to even more fatigue and cognitive incapacity and if I continue to ignore that fatigue, then I can add pain and physical incapacity on top.

It's difficult not to see the connection.

 

[Wonko]

For me there is a difference between fatigues.

On 2 or 3 occasions in the last few years I have been well enough to get physically fatigued, presumably the type that most people experience after a few hard workouts or several days hard physical work. I remember it, from when I was relatively "healthy" and could do things that caused fatigue. Of course it doesn't take as long to get there these days but this type of fatigue feels good, at least to me.

Then there's the other type, the ME type.

The problem, it seems to me, is that there is only one word to describe both, and any attempt at finding other descriptors fails because people hear words, their minds drop into the slot marked "fatigue - I know what that is" and never leaves - it's a "new" concept and people don't do well with them, until they experience them personally. This appears to be the way people are, hardwired, new things can only be referenced in relation to old/known things.

Then there is PEM.

If people/researchers/scientists/etc. are simply trying to "fix" the first/normal type of fatigue - this doesn't help us/me, as it's not the problem, it's not what we experience.

 

[Scarecrow]

Thank you all for constructive comments. Yes, this is a preliminary trial. Today, more than 20 patients have been enrolled. The initial cases have taken the treatment during 6 months, and continue to benefit.

All the patients you recruited were ill for more than five years. Of those who you considered responders, have any of them been able to resume their former occupations or studies or are they otherwise engaged in any activities that they were unable to do before treatment?

 

[Scarecrow]

For me, the problem with ignoring fatigue is that it inevitably leads to even more fatigue and cognitive incapacity and if I continue to ignore that fatigue, then I can add pain and physical incapacity on top.

It's difficult not to see the connection.

For the avoidance of doubt, I don't think measuring fatigue is ideal, especially when the treatment isn't blinded but as ME/CFS has pointed out this is a preliminary study.

@ME/CFS, many people have made suggestions about objective measures that you could use in a future trial. Can you say if you intend to incorporate these tools or any others that you may already have been considering?

 

[Trish]

@ME/CFS, thank you again for engaging with us in discussion about your research. I think you are right to remind us that the published study under discussion here is a very preliminary test of concept, not a claim of efficacy. I am interested to hear that you are now doing a second stage trial with a larger group of patients.
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I hope you understand that we are wary of trials where questionnaires are used as the primary, or only, outcome measures.

Fatigue is not the core symptom of ME/CFS. PEM is the core symptom.
PEM is what prevents us being more active, not fatigue.

The SF-36 physical functioning scale is also of limited value, as our symptoms fluctuate, and there is a subjective element in how it is filled in.

Subjective improvement is of very limited value to ME/CFS sufferers unless there is also objective improvement in energy capacity, as measured by either actometer or a biomedical measure of cellular energy metabolism.

We have suffered, as you are aware, from a long history of CBT/GET trials that falsely claimed improvement and even recovery using subjective 'fatigue' and 'physical functioning' questionnaires as primary outcome measures.

It is therefore not surprising that any unblinded trial with subjective outcome measures, whether of a psychological therapy, nutriceutical or drug, will be judged as of very limited value by this well informed, science/evidence focused patient community.

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I do not understand why, when there are objective measures like actometers available, some researchers choose not to use them. We have been hurt badly by this in the past, particularly in the PACE trial, where the approved protocol specified actometers to be worn by patients at the start and end of the trial, and this was dropped by the researchers without adequate justification. (Other smaller trials have shown that subjective improvement was not matched by actometer measured improvement. We suspect this influenced the PACE decision).
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It might help us understand your approach if you could spell out whether you are seeking to develop:

a) a symptomatic treatment for subjectively measured symptoms such as fatigue,

or

b) a treatment that reverses the energy deficit and significantly increases the energy envelope in ME/CFS patients while preventing or significantly reducing PEM.

If it is the former, it is worth being open about this. It doesn't make the treatment worthless as a symptomatic treatment, alongside pain medication and sleep medication that some patients use, but it could not be claimed to reverse ME/CFS.

If it is the latter then it seems to me to be imperative that you use a primary outcome measure that actually measures the patient's ability to make and use energy sustainably and without triggering PEM. Wearing actometers that measure pulse rate and steps throughout the trial seems the logical way to do this. Blood tests to look for alterations in the energy metabolism of cells would add to the strength of your evidence.

Even if in a final stage trial you then move on to using double blinding, the case for your treatment would be hugely strengthened by the use of objective outcomes.

 

[Valentijn]

Regarding poor studies SUCH as PACE etc. I like to refer to my publication in attachment.

I didn't realize the file you uploaded was a different study you co-authored. I appreciate that you seem to view ME as an immune disease and reject the psychosomatic paradigm and treatments. Though I don't think your beliefs regarding the influence of psychosocial factors such as stress, emotion, profession, socioeconomics, personality, education, or stress management skills are supported by quality research:


I'm glad you reject CBT, but I think you overestimate the role which stress-management can play as a treatment:

Adaptation of the way of life, and the family, social and professional environment is necessary in order to reduce stressful factors to such an extent that the limit of the capacity of stress adaptation is not exceeded. The stress management skills can be improved by means of techniques of relaxation and meditation such as Zen-yoga, transcendental meditation, autogenous training or mindfulness [122,123]. In the long term, mindfulness seems to be more beneficial to patient well-being than cognitive behavioural therapy (CBT) [124,125].

And exercise of any sort is rarely helpful, especially as patients by definition must have exercise intolerance. If that exercise intolerance is noticable enough to be diagnosed, they probably don't have spare energy for swimming or other activities. Any exercise added comes at the expense of other activities, typically ones essential for daily living. If I were well enough to do water aerobics at all (I'm not), it would mean I wouldn't be able to cook dinner, shower that weak, or sit down on one of my garden beds to do 10 minutes of weeding. I also note a lack of citations to support your following statements:

Aside from the recommendations concerning a “healthy life style” dietary prescriptions should be given, tobacco use must be prohibited, alcohol consumption should be limited, and moderate exercising should be encouraged. Many patients experience benefit from wateraerobics (aqua-gym) which they prefer to “graded exercise therapy” (GET).

You also use that paper (described as an opinion piece) to market several supplements from a single website. Some already exist, and apparently the new one is to be called "Improve". Looking at the ingredients from other supplements there, algae does indeed seem likely to be the secret ingredient not mentioned in your newer paper

This is an extraordinary claim, and I have seen no evidence at all to support it any of it:

In our experience the combination of the adaptation of the way of life and the diet, together with mindfulness, nutriceutical food supplementation, and water-aerobics is well-accepted by the patients, and commonly results in a sufficient recovery to allow for the majority of patients to resume work, albeit commonly in a part-time mode only.

 

[TiredSam]

Adaptation of the way of life, and the family, social and professional environment is necessary in order to reduce stressful factors to such an extent that the limit of the capacity of stress adaptation is not exceeded. The stress management skills can be improved by means of techniques of relaxation and meditation such as Zen-yoga, transcendental meditation, autogenous training or mindfulness [122,123].

@ME/CFS are you working on anything to help ME sufferers whose stress management skills are just fine, who like the occasional glass of wine, and who avoid all exercise so that they don't make their condition worse? That would be great.

By the way, I have absolutely no interest in mindfulness, Zen-yoga, Zen-anything, transcendental meditation (is that the one where you bounce up and down and delude yourself that you're levitating - seriously? For ME sufferers?) or positive thinking or anything else like that. I have a fairly grumpy outlook on life. I hope this doesn't reduce my chances of benefitting from your research. It's certainly never stopped my bones mending, colds going, or any other ailments getting better.

 

[Sid]

I'm surprised to see water aerobics recommended for ME/CFS. Personally, no activity makes me weaker and more orthostatically challenged than being in a bath, jacuzzi or swimming pool, presumably due to vasodilation and thus severe worsening of orthostatic intolerance, a very common and disabling symptom of ME/CFS.

 

[Perrier]

The problem with this is that we don't care about "fatigue". Fatigue isn't what disables us, or makes our lives more unpleasant. When we initially go to a doctor, it usually isn't because we are fatigued. It's because we're disabled, in pain, can't stand up without getting light-headed, or a dozen other symptoms. And if we had a list of symptoms we'd like to go away, fatigue probably wouldn't make the top 20.

There's a reason patients hate the name "chronic fatigue syndrome", and it's because we aren't particularly fatigued. We're sick and disabled. The primary source of our disability is post-exertional malaise, where we get very sick after activity, lasting for days or weeks. PEM involves a variety of symptoms, primarily the exacerbation or onset of neurological, immunological, and muscular symptoms. PEM is what keeps us housebound, bedbound, or unable to live like we used to. Accordingly, it's typically the symptom which we care about the most, and would find most indicative of actual improvement or worsening.

Even if a treatment doesn't help with PEM, it might be helpful if it impacts upon another symptom, especially if it improves our quality of life with regards to sleep, pain, etc. But if your work remains focused on fatigue, it's of little value to us. It's especially problematic if a treatment makes patients feel more energetic with no corresponding increase in activity capacity, as it can push us into over-exerting and crashing and being less functional, all while feeling less "fatigued".

This is well articulated. Fatigue is NOT the central symptoms. Doctors please take note.

 

[ME/CFS]

when reading further comments, I notice that everyone is looking at his own story. I have given general recommendations based om my clinical experience in a rather important number of patients, many of whom I follow and try to help since several years. The nutriceutical suggestions made in my previous paper (on Systemic Immune Disorder) do NOT concern the new development described in my recent paper. It is hard to discuss if the commentators do not read the publications carefully.

 

[Wonko]

@ME/CFS

It's hard to read the publications carefully. and I presume you also mean understand them, if cognitive impairment is an issue, which it is, for many.

It is not currently possible for me to read either of the papers posted, either by Trish, or by you, they may be the same paper, they may not, I cannot determine even that ATM. From a quick visual scan neither is particularly friendly from a cognitive point of view.

So I am forced to go off what others say about it, this is not unusual, either for myself or for others on an ME forum.

We have some members who do not have as severe cognitive issues, they dumb things down for me, and others, so we can get an idea of what's going on.

I wouldn't let it discourage you

edit - they are not the same paper.

 

[Trish]

Hi @ME/CFS, I think you have to allow us a bit of leeway. We are, after all, individual patients who have close knowledge of our own story and like to share this. That's the nature of patient forums.

We also, as ME sufferers, have limited ability to concentrate and read scientific papers.

Any thread in the forum is open to any member to comment in any way they like, it is not a controlled discussion between scientists.

Some members have scientific training, and vast experience of reading ME research papers, others are not scientifically trained or have less knowledge of how science works. We try to help and support each other in learning together.

We are always grateful when scientists join us in discussion, but hope they will understand both our wide variation in experience and our limitations.

 

[TiredSam]

when reading further comments, I notice that everyone is looking at his own story.

Filling in a subjective questionnaire is just someone looking at their own story. Collecting lots of subjective questionnaires is collecting a lot of own stories. If you assign numbers to a lot of people's subjective reported feelings and then perform operations on those numbers it doesn't raise anything above the level of a bunch of subjective own stories.

Once you start making objective measures you can start taking the scientific high-ground if you like.

I have given general recommendations based om my clinical experience in a rather important number of patients, many of whom I follow and try to help since several years.

Without objective measurements that is a subjective interpretation of a bunch of annecdotes.

And really, the fact that you have recommended transcendental meditation in any paper does affect how seriously readers of any of your other papers are likely to take you.

This is not medicine:



It is a belief system.

Surely you don't recommend that any ME patient should ever try this:



Because it wouldn't relieve stress (on the offchance that ME patients need to, which I don't accept), it would make them crash.

As a result of the feedback on this thread, can you tell me which objective measures you'll be planning to use in your future studies? It really is a kind of pre-requisite.

 

[Hoopoe]

I know the limitations of the present paper, which I clearly mention.

Are you able to document improvement of PDH or mitochondrial function in responders? There's a device called a Seahorse flux analyzer which has been able to show abnormal energy metabolism in ME/CFS, and I'm guessing that some university in your area might have one.

 

[Barry]

The problem with this is that we don't care about "fatigue". Fatigue isn't what disables us, or makes our lives more unpleasant.

Agreed. In my wife's case a key symptom that I observe in her is lack of power - energy not available to her at the rate her body needs it to be delivered at; like a car with a partly blocked fuel pipe. She can walk slowly, for a while, but gets slower and slower the more she tries. There comes a point if she isn't careful, she doesn't have energy enough left to stand. Through all this process she goes from her "best", of feeling unwell, to much worse, feeling horribly ill. She then needs a day or two to recover again.

It's not necessarily walking that does it of course. We had our daughter and grandchildren with us recently, which was wonderful, but no matter how careful we tried to be, there were a few days my wife ended up feeling really ill, because her normal pacing routine was disturbed.

And this is real physical function I'm talking about here, (i.e. as measured objectively), not perceived physical function (i.e. subjective), which PACE, GETSET, etc glibly and misleadingly refer to as "physical function".

 

[Barry]

This information could only have come from the SF-36 but I don't know how brain function relates to that questionnaire.

Trouble with the SF-36 is it only deals with subjective measures, even though naming conventions seem to imply otherwise. e.g. Physical function subscale sounds like it closely reflects actual physical function, but it is of course perceived physical function. The PACE FOI data showed, unsurprisingly, a huge disconnect between the two, but failed to aknowledge that. It would be good for any further trials to not fall into the same trap.

 

[Scarecrow]

Trouble with the SF-36 is it only deals with subjective measures,

Yes but that's the nature of self-reports.

The phase III rituximab trial also relied on subjective reports but people were generally happy with the design because the treatment was blinded.

This is a preliminary study so there isn't a placebo. However, the results help inform the investigators in future trials.

I don't think we should get too hung up about what we perceive as flaws in this research. Yes there is a patent pending but nothing is being sold off the back of this initial study. Let's see what happens in the future.