Do MEs cause CFS?

[alex3619]

And then maybe we come back to the same question - what causes the vascular dysfunction? I had been thinking about this particular spaghetti loop and had come to think that at least for MEs the problem is unlikely to START in the autonomic nervous system. The reason for this is that we seem to be dealing with a re-setting of some complex regulatory system. The immune system and the brain are complex enough to reset themselves to a new level through confused internal loops. My guess is that the autonomic nervous system is not quite that complicated - it works like the control system on your central heating and is quite complicated but it may not be complicated enough to reprogramme itself - if that makes sense. Somebody else is re-programming it. You might say that hypertension is a resetting of the autonomic system but I am pretty sure that the real causes of hypertension lie outside and that the autonomic system just resets the way it usually does - although in this case unhelpfully. This may be a confused analysis but it is as far as I have got so far!

(MY BOLDING)


There is a concept in complex systems theory, chaos theory, and catastrophe theory, that these are dynamic stable states drawn to a strange attractor. A strange attractor is a central tendency, the "fixed point" around which the system revolves, but the system is more chaotic and fractal than stable. What happens in some situations is the system becomes highly perturbed. Then it becomes fully unstable, and then resettles back to the strange attractor. Except sometimes the attractor changes, leading to a new stable state that is different from before.

I first came across this in ME from the work of Dr Andriya Martinovic, circa 1993, in connection with eicosanoid regulation in ME/CFS (he used the Holmes criteria mostly). Earlier I was interested in this from the perspective of neural modelling, which I was working on for my PhD candidacy (which ended when I found I could no longer read or even count to 3).

The point is that homeostatic mechanisms are in part from internal settings, and in part from external and internal communication. If its perturbed enough the homeostatic balance can alter. This is less like a thermostat than it is an ecology ... the ecology can find a new balance, but its not the same ecology.

Teasing this situation apart from a causal tangle is difficult, and you always have the possibility that one or more constant external factors are driving the perturbations. That is why we need to untangle the mess, identify key pathways, and then start to think about the dynamics of how it all fits together. The problem is that complex dynamic systems in the real world (and not artificial models) are still largely beyond precise scientific understanding.

That is why basic research is so important. We will never know which study could provide that last vital clue we need until maybe even years after it is done. With so little research into ME biology, relying on serendipity is very problematic.

 

[daisybell]

Is a 'cluster' of antibodies common for autoimmune disorders?

FYI, the symptoms of my hypothyroidism and the symptoms of ME did not wax and wane together. (i.e. the thyroid symptoms did not get worse when the ME symptoms got worse.)

I became hypothyroid due to over-treatment of Graves' disease, and could very clearly distinguish between the hypo symptoms and my ME symptoms (which had been much reduced when I was hyperthyroid). After I took myself off the meds and my thyroid stabilised, the ME symptoms continued progressing...

 

[Jonathan Edwards]

I entirely agree with that Alex. My thought is that brain and immune system are both capable of finding new attractors in a chaotic type of 'internal ecology'. I am prepared to believe the autonomic nervous system has that level of complexity too but my experience of clinical disorders makes me think it is more like the thermostat. There does not seem to be a good reason for the autonomic nervous system to 'learn' new responses to constraints. The brain needs to learn patterns of response and so does an immune system that needs to match responses to pathogens as they come and go. It is hard to see why the autonomic nervous system would learn to change its blood pressure response to standing. So my thought is that the new attractors driving the metastable states of MEs are within the CNS or immune system even if the result is expressed though the ANS.

What I like about the immune system is that we are just beginning to know enough to build detailed systems analysis that one can actually make predictions about new metastable states from. That is what we did for RA. The analysis had 55 steps in the system, four positive feedback loops and lots of negative ones (less interesting). That then led to a generalised version with a key positive feedback loop that actually required only a minuscule perturbation - in theory a single B cell. Brain loops are I think much more difficult but fMRI with this method for looking at pathway activity does begin to look interesting. I know personally a bit about strange attractors in the brain because a member of my family lost her mind after antimalarials due to a loop that was only unwound, and completely effectively, by ECT. That is one reason why I think we should have ME3 in the list, although I doubt that any progress on that front will come from current directions in psychiatry.

 

[NK17]

As always a big thank you goes to @Jonathan Edwards for sharing, for thinking out loud and making the patients on the forum feel less alone and more engaged! This kind of feedback loop is what gives us hope and inspire us not to give up!

Now I have many questions that pop up while reading this thread, the most central one has to do with cases of several people affected by what we can hypothesize ME 1 or 2 etc. in the same family. Specifically what does a case of a mother affected by bona fide ME (diagnosed by CCC and ICC) and her offsprings showing mild symptoms of ME and NK cells dysfunction and a possible subsequent different immune response to endemic pathogens (such as EBV, HHV6, enteroviruses), which are implicated over and over again in autoimmunity? Where do we position ourselves on this? Doesn't it looks like that there is a genetic component? Maybe an epigenetic component too (influence of the environment on the genes)? We know very well that autoimmune diseases tend to run in families (MS, SLE, RA, SjS etc.). What about ME and other autoimmune disorders? What does this tells us? What about starting to study and observe longitudinally parents with ME and their offsprings? I feel like this is still very much overlooked and think that it might open the door to some interesting discoveries and treatments avenues? As far as I know Dr. Kogelnik and Dr. Davis are seriously looking into this and I think they will come up with answers, sooner or later.

@alex3619 following your excellent reasoning, I can't help but think about systems biology, brain kindling and the homeostasis triad between the immune, the endocrine and the nervous systems.

 

[Jonathan Edwards]

Now I have many questions that pop up while reading this thread, the most central one has to do with cases of several people affected by what we can hypothesize ME 1 or 2 etc. in the same family. Where do we position ourselves on this? Doesn't it looks like that there is a genetic component? Maybe an epigenetic component too? What about starting to study and observe longitudinally parents with ME and their offsprings? As far as I know Dr. Kogelnik and Dr. Davis are seriously looking into this and I think they will come up with answers, sooner or later.

Yup, there are genetic factors. We know that for pretty well all autoimmune disorders and also for the 'auto-inflammatory' states like psoriasis. For ME1,2,4,5 there would be genetic factors. We discussed the potential for genome screening at the recent IiME colloquium. I think everyone agreed that it was worth pursuing but it requires a lot of resources. Dr Kogelnik is clearly trying to get it going for certain genes. We just need a little bit more critical mass in the ME research community and these things should get to the top of the agenda fairly soon. Gene screening is in a sense a no-brainer - it's obvious - but it isn't so obvious how best to use resources when there are 40,000 or something genes!

I personally would forget 'epigenetic'. It is one of those buzz words that nobody really knows what they mean by. There are better ways of describing all the things that might come under it I think. Environmental factors can of course operate in families too and one of the most useful recent tools for separating the two is the twin study approach. A twin study for CFS could easily be justified, if it has not already been done. A basic screening study would require little more than the clinical assessment and a good statistician. Twin studies can help separate stochastic causal elements from both genes and environment too - which is clear from diseases like RA.

 

[alex3619]

In complex systems they talk about CCC, and its not Canadian etc. Its command, control and communication, I think, its been a long time. I also have a nagging suspicion they talk about CCCC as well, but I don't recall the last one.

We have perturbations in the hormone, immune and nervous systems. I usually don't talk about endocrine, since endocrine hormones are one class of hormones, and there are at least four classes now. Each of these can imbalance the others, and these can feedback in complicated ways, but there is also positive feedback and negative feedback to consider. Positive feedback is the tendency of something, once activated, to cause an increase in activation. Negative feedback is about decreasing activation. These need to be in balance. The idea of two things in opposite direction being in balance is called an axis, and the point of balance is called the set point.

Autoimmunity has both driving forces, and a failure in braking forces.

If you look at many ME theories, they tend to focus on ONE of these three branches. I try to think in terms of how the three interconnect. The answer could be anywhere, though I think we might be looking at a spread of interconnecting answers, with different individuals having a different mix.

There is no substitute for doing the science. All hypothetical speculation does is help you figure out where to start looking.

 

[Hip]

And then maybe we come back to the same question - what causes the vascular dysfunction?

The interesting thing I observed with the enterovirus that caused my ME/CFS is that, as this virus spread to my friends and family, most people who caught it soon developed what might be termed "ME/CFS-lite". (This virus caused specific physical symptoms, so it was obvious who had caught it). By ME/CFS-lite I mean that they all manifested, on a permanent basis, mild versions of some classic ME/CFS symptoms — like sound sensitivity, increased fatigue, irritability, loss of libido, the "tip of the tongue" inability to remember a word or name during conversation, and in particular, cold hands and feet (Raynaud's), which is a common comorbidity of ME/CFS. I presume this virally-induced onset of cold hands and feet is caused by vascular dysfunction.

So it seems that ME/CFS-precipiating viruses can cause cold hands and feet even in those who do not have full blown ME/CFS. Though I was the only person to develop mild POTS as well as cold hands and feet. I have a 25 bpm increase in heart rate on standing from prostrate, but when I measured my fellow infectees with the cold hands and feet symptom, none showed any evidence of POTS.

 

[NK17]

Thank @Jonathan Edwards for your clear and straightforward reply and explanation. I'll print it out and leave it around the house for the relatives who still think that I'm exaggerating when I mention heritability and my strong advocacy for strict surveillance on the youngsters. You gave confirmation to the fact that a genetic component is undoubtably real and present.

We need to raise awareness on the subject, we need to clear the jungle of non native species and avoid mistakes that have been done in the past, mistakes which are the product of clear underplay of the severity, chronicity and familiar nature of ME.

 

[Jonathan Edwards]

There is no substitute for doing the science. All hypothetical speculation does is help you figure out where to start looking.

Dear Alex,
Certainly we should do the science - and that is happening. But you do need to know where to start looking! So hypothetical speculation isn't trivial. In my career it was 90% of the battle in getting a treatment tried and proved. Similarly, Fluge and Mella tried rituximab in ME because of a hypothetical speculation. The sort of dialogue we are having on this thread to me is remarkably reminiscent of the lab meetings we used to have at UC on a Friday afternoon with a couple of bottles of wine - which is where the whole rituximab idea for autoimmunity began. The evidence we needed was already there or easy to find, we just needed to argue through how to make sense of it. And we went through the same sorts of argument about how it could be like this - no it couldn't - yes it could - how come - maybe like this - OK maybe it could - but would n't that mean that we'd find this... and so on. In the end it was like we had done the whole jigsaw but somebody had not noticed we had it the wrong way up for the edge bits.

I agree about the three systems all working together - particularly that hormones sort of cut across the other two with molecules that do things in both.

 

[OverTheHills]

@Jonathan Edwards
With your ANA positive ME type 1 - is the titre significant, are you thinking of really high ANA? I got consistently positive ANA after I had had ME for a while but the titres have never been very high. GPs tend to discount positive ANA in the absence of specific autoantibodies but I generally don't find that approach very reassuring ( so often it equates to personal ignorance or research hasn't found the definitive answer yet)

On the POTS angle - what do you think about the anti-phospholipid (Hughes) syndrome connection to POTS described in this article
http://www.dysautonomiainternationa...-should-know-about-antiphospholipid-syndrome/

And like so many others I'd like to thankyou for being here. You have no idea how happy it makes me feel to know that the science brains on here (mentioning no names, you know who you are) are useful in your 'blue sky' thinking. PWME need to feel useful the same as anyone else and we don't get much opportunity.
OTH

 

[Hip]

2. ME2 is due to an oversensitive resetting of cells that recognise what are known as Class I proteins, as in HLA-A, B and C. This includes T cells and NK cells. It probably follows a wide range of intracellular infections. As for ME1 it is in a sense a ‘covert’ form of a recognised illness, in this case Reiter’s disease. It may be more common in men and is likely to occur with sudden onset in early adult life. There may be local joint pains and a rise in CRP level but this may subside leaving persistent fatigue. ME2 and ME1 have nothing in common other than the end result.

@Jonathan Edwards This oversensitive resetting of cells that recognize MHC class I proteins that you mention, could you kindly expand on what you mean by oversensitive resetting.

I have a basic understanding of how MHC I and II work — that they display on the exterior of the cell protein fragments found within the cell, and if any of these protein fragments are recognized as being foreign (such as from infectious pathogens), then the immune system instructs the cell to perform apoptosis.

Do you think your ME2 model might be related to coxsackievirus B, a virus which can form intracellular infections, and which when it infects cells, acts to remove the MHC class I proteins from the cell surface (ref: here)? Coxsackievirus B is of course strongly associated with ME/CFS.

 

[daisybell]

How much work has been done on autoimmune mitochondrial antibodies in ME? Could an as-yet undiscovered AMA be at the root of our troubles?

 

[alex3619]

So hypothetical speculation isn't trivial. In my career it was 90% of the battle in getting a treatment tried and proved.

I agree about the three systems all working together - particularly that hormones sort of cut across the other two with molecules that do things in both.

In no way is hypothetical speculation trivial, or I wouldn't waste my time. We have been stuck in limited dogmatic thinking. To break out of that, find new research directions, and find new ways to use what we already have, we have to break the box around our thinking. Speculation and debate serve that purpose.

It has some similarity to thinking about conspiracies. Most conspiracies are nonsense. Yet speculating about them keeps society alert, and has people looking. Every now and again they uncover something .Science is similar in that the unknown is what we are looking at, and people only look because they start wondering and need to know, they want answers.

Speculation is not some useless human trait. It is part of what drives civilization forward. What if ....

It is also the basis of science fiction. Indeed, many scientists got their curiously from reading science fiction. We also have words like symbiote, which were a science fiction stuff-up, the original word was symbiont. Since so many budding scientists read the author Hal Clement (a pseudonym) we wound up with the other spelling.

Speculation is also at the core of medical treatment. Doctors have to guess ... a lot. Its an educated guess, and very often right, but its never certain.

The tentative title of the book I am writing is Embracing Uncertainty. Uncertainty is real, its our primary enemy (the flip side of ignorance) but its also an opportunity.

PS ... and of course you cannot have hypothesis generation without speculation. Its part of the never ending circle of the scientific process.

 

[Ninan]

How much work has been done on autoimmune mitochondrial antibodies in ME? Could an as-yet undiscovered AMA be at the root of our troubles?

Have you seen Jonas Blomberg's study? Read about his discovery here (it's in the end).

@Jonathan Edwards comments on this study in the middle of this thread.

 

[Kati]

As I have described ME1 it covers people in whom you can find an ANA, which may be one of the recognised ENAs or an unknown one. People with ANAs with recognised syndromes like Sjogren's can have severe fatigue although I am not sure they get post-exercise malaise. My memory is that they do describe 'crash' type episodes though.

Yes, in ME5 there would be continued antibody production and the target, rather than being a tissue like thyroid or stomach, would be a protein within the immune system itself - so if anywhere in the lymph nodes and tonsils. But aggravating the lymphocytes there would release signals that made you feel fluey in the brain and muscles as well as having a sore throat. And I agree with Alex that this could overlap with targeting microglia directly. Rituximab removes any B cell clones around at the time. As described on the thread with my name on some time back I think in autoimmune disease the cycle is p assed from one B cell clone to another over time by a process of 'miseducation'. In some autoimmune diseases it seems that rituximab can get rid of enough clones to block a furhter cycle of miseducation, although in RA this does not normally occur. The Norwegian data suggest that a proportion of ME responders may get free of a cycle, but it is too early to be sure.

I don't have a good grip on the orthostatic intolerance angle. I hear a lot about it but I am not sure where I think it comes in. I am fairly sure it is going to be secondary to immune or CNS signals in most cases. Of course it occurs acutely in the acute stages of viral illness and it will occur in what is called 'cytokine storm syndrome' which people most often used to experience in a mild form as a reaction to the endotoxin (?or adjuvant) in typhoid vaccine. There might be a different route to orthostatic intolerance through a primary disorder of vascular tone control but I don't understand why you should get all the other features of CFS like brain fog and PEM in that case.

i remember a patient with MS asking me whether the ME/CFS (for lack of better term, widely used ) was the same as MS fatigue. And quite honestly, I don't have a clue because I don't have MS, but my best guess is that we could well feel the same. These patients seem to get stress triggers and need to pace themselves and quite soundedly, they seem to have fatigue. fatigue is the f word that physicians do not like to talk about. Even oncologists cannot explain why some patients don't seem to recover well past their chemo treatments even if their cancer is gone. But is it about the fatigue? Personally I don't think so. i think science and governments can do so much better for us, providing they invest in our disease.

How about stroke patients? how about HIV patients on ART, I have heard a few talking about their fatigue and symptoms of CFS. How about lupus patients?

What I find interesting about your subgrouping @Jonathan Edwards is that there is not one mention of infectious trigger vs gradual onset. I think there are subgroups to be made right there.

Personally, after 6 years of disease I recognize myself in a few categories. (ana, thyroid (I gained 100 lbs) and autonomic) But interestingly I have a high ANA titer since my teens (30 years ago), speckled pattern, which turned homogenous apparently the last time it was tested. i would love explanations about that and my GP is not one to provide any answers.

i am very thankful that you are willing to exchange with patients as community. It's a very good thing all around.

 

[alex3619]

What I like about the immune system is that we are just beginning to know enough to build detailed systems analysis that one can actually make predictions about new metastable states from. That is what we did for RA. The analysis had 55 steps in the system, four positive feedback loops and lots of negative ones (less interesting). That then led to a generalised version with a key positive feedback loop that actually required only a minuscule perturbation - in theory a single B cell. Brain loops are I think much more difficult but fMRI with this method for looking at pathway activity does begin to look interesting. I know personally a bit about strange attractors in the brain because a member of my family lost her mind after antimalarials due to a loop that was only unwound, and completely effectively, by ECT. That is one reason why I think we should have ME3 in the list, although I doubt that any progress on that front will come from current directions in psychiatry.

I am a big fan of systems biology. During a two year improvement in my ME I went back to uni to finish my biochemistry degree and add it to my informatics degree. Bioinfomatics and what is now called systems biology is what I was interested in as a career. I realized in 1986 that complexity, and operating with incomplete information, are the big challenges facing us now, and not just in medicine.

I am really happy you were able to find answers in RA. I am hoping that experience will help shorten the time for scientists to find answers in ME. We need to deal with the complexity and uncertainty, but we cannot throw out empirical evidence and rigorous testing and analysis in the process. Modern systems biology seems to be about forging this path.

 

[Marco]

@alex3619

The idea of a phase transition ocurring in complex chaotic systems such as human physiology is strangely attractive and something that we've discussed here on a few previous occasions. It also seems to tie in with our personal experiences. While symptoms may wax and wane, few of us (as far as I can tell and more of this below) are ever symptom free. There also seems to be a pattern where many of us report some initial benefit from some treatment or another (and I'm pretty sure we've all been through enough repeated cycles of optimism and disappointment to be pretty resistent to any placebo effects) but end up being dragged back to the same state of unwellness. Anecdotally, until the last few years, I used to have one or two strange experiences per year where for no apparent reason I'd suddenly feel well for a few hours. Not just better but 100% normal. Of course then I'd run off and do something enjoyable and end up overstimulated and in a crash for days after. That seems conistent with a temporary switch away from a aberrant basin of atttraction.

My thinking about the available evidence has led me to believe that the primary 'loop' may be in the brain's immune system which has become primed and over-sensitised (which I think conversely results in a response to external stressors that is inappropriately inflexible and unresposive). This is somewhat analogous to what is found in various chronic neuropathic pain states and similar to Prof Edwards' ME-5. Interestingly, recent experimental evidence suggests that central sensitisation in neuropathic pain states may depend on ongoing nociceptive peripheral input rather than being self sustaining. Basically, in an animal model, they induced central sensitisation by inflicting a peripheral injury and the central sensitisation was found to be able to be suppressed by local anaesthesia of the peripheral injury.

That being the case what might be the ongoing peripheral stressor in ME/CFS. A chronic low grade infection could do the job but I don't believe the preseence of a pathogen is at all necessary. When you look at what stressors tend to increase symptoms in ME/CFS it a very long list indeed from physical or mental exertion, psychological stress, heat or cold environmental stress, common infections, food and chemical sensitivities (incidentally alcohol intolerance is another symptom we share with post concussion syndrome) light and noise sensitivity, widespread diffuse pain without apparent tissue damage etc. Basically it boils down to the 'stressors' everyone encounters on a daily basis and while I'm sure people with other chronic illnesses also find coping with daily stressors challenging, we seem to be particularly sensitive to even trivial levels of 'stress'.

In short I'm suggesting that via toll like receptor signalling of 'alarmins' (or the cell danger response if you like) to primed and sensitised immune cells in the brain, that everyday signals of cellular/metabolic stress are the ongoing peripheral stressor which triggers glial activation and a cascade not only of the perception of illness but also secondary ANS dysregulation etc which results from this immune activation.

A remaining question is why only a minority of people exposed to the same stressors develop these mulitsytem syndromes? If 'CFS' then is a state of glial priming and activation - the 'ME' could be various 'defects' that allow for or promote chronic brain immune activation (there could be a long list here which could include autoimmune mechanisms).

As regards sudden/viral onset it could well be that this is the initial trigger for glial activation (and doesn't need to be a neurotropic virus) but its also well known that glial priming/gliosis increases with age and the elderly have a disproportionate immune response to common bugs (and other 'stressors' such as falls and injuries). Its also possible then that the 'flu from hell' that many associate with the initial trigger may in fact be such a disproportionate immune response that 'unmasks' pre-existing glial priming (by whatever mechanism). In this context its worth remembering that the Dubbo studies found that those who went on to develop ME/CFS after exposure to common viruses were those who had the strongest immune response (and a history of vigorous exercise).

Apologies for the (not wine assisted) rambling. Just tossing in a few thoughts which may apply only to a sub-set.

 

[Jonathan Edwards]

@Jonathan Edwards
With your ANA positive ME type 1 - is the titre significant, are you thinking of really high ANA?

On the POTS angle - what do you think about the anti-phospholipid (Hughes) syndrome connection to POTS described in this article
http://www.dysautonomiainternationa...-should-know-about-antiphospholipid-syndrome/

If the ANA titre is 1/1000 and you have CFS I find it hard to believe the ANA isn't causing the CFS - or at least a sign of what is - for me that's ME1. The difficulty with ANA is that standard assays tend to be done in a way that gives a 1/10 positive in maybe one person in twenty or something like that. So that is regarded as 'in the normal range' because normal ranges are defined statistically. Moreover, there do seem to be a lot of people with 1/10 ANA who are perfectly well. So maybe we should think of it as 'normal'. I suspect we should but it is worth remembering that at least one person in twenty has a blood pressure of 160/95 and feels perfectly well but a blood pressure like that needs treatment - it is not 'normal' in the sense of healthy.

So I think a 1/10 ANA is probably not telling us much. The question then is at what level it does. I think it will depend on the lab but I tend to think that anything more than 1/10 is probably relevant to symptoms. The absence of any 'specific antibody' on further analysis is not a sign that the ANA is less important - just that it is not one of the ones put in the kit. We know of lots of specific ANAs relevant to disease that do not get put in the routine kits. And I guess that for ME1 we would expect the ANA not to be in the kit because it is not one that goes with a well described 'autoimmune rheumatic disease'.

It is hard to convince most of the medical profession to take autoantibodies seriously unless they fit into some convenient pigeonholes they understand. I think this is short sightedness, but until we have more evidence it is hard to argue. We need to get the evidence.

I think it is possible that antiphospholipid antibodies and orthostatic intolerance are linked in a few people but I am not quite sure what to make of it just yet. The site on the link does not actually tell us much about the association.

 

[A.B.]

@ Jonathan Edwards I had anti-thyroglobulin antibodies of 19 UI/mL, with normal value being < 4.1 according to the lab. I've heard different opinions on whether this is significant. What do you think?
Also adrenalin below the detection limit in two separate 24 hour urine catecholamine tests, low insulin, reactive hypoglycemia, low FH and FSH.

 

[justy]

Yup, there are genetic factors. We know that for pretty well all autoimmune disorders and also for the 'auto-inflammatory' states like psoriasis. For ME1,2,4,5 there would be genetic factors. We discussed the potential for genome screening at the recent IiME colloquium. I think everyone agreed that it was worth pursuing but it requires a lot of resources. Dr Kogelnik is clearly trying to get it going for certain genes. We just need a little bit more critical mass in the ME research community and these things should get to the top of the agenda fairly soon. Gene screening is in a sense a no-brainer - it's obvious - but it isn't so obvious how best to use resources when there are 40,000 or something genes!

I personally would forget 'epigenetic'. It is one of those buzz words that nobody really knows what they mean by. There are better ways of describing all the things that might come under it I think. Environmental factors can of course operate in families too and one of the most useful recent tools for separating the two is the twin study approach. A twin study for CFS could easily be justified, if it has not already been done. A basic screening study would require little more than the clinical assessment and a good statistician. Twin studies can help separate stochastic causal elements from both genes and environment too - which is clear from diseases like RA.

I have another angle to add to twin studies. We have M.E in three generations of females in my family: My mother, a maternal cousin, myself and my daughter with an M.E like illness. The point being that I was adopted at 6 weeks and my brith mother with an M.E diagnosis never saw me, or even held me after birth, and yet the genetic susceptibility seems to exist within our family.

My birth mother also has the hypothyroid issues and I now have positive ANA (speckled) my presentation was gradual and I have had onle long remiison for several years to near normal. My daughters presentation was sudden onset.

Anyway, very interesting discussion, so much I would like to say about the science, rather than just personal anecdote, but i'm afraid that my brain does not work in the way it used to and I find it very hard to take part. But I thank @Jonathan Edwards very much for being here to take part in and initiate these discussions.