Saturday, July 10, 2021

Three Years later. Loratidine, MCTs and summer cold conundrum summary.

Three years and one bout of COVID-19 and two vaccinations later and I am still trying to understand what happened to me a few years ago and still finding myself perplexed about current symptoms but everyone is perplexed about SARS-Cov-2 now and longcovid is increasingly regarded as a condition potentially related to ME CFS. 

So I continue to think and blog about my own experiences of ME CFIDS in the hope that they will make sense to others and be helpful somehow.

One thing I am sure of now is I am not reacting to salicylates anymore, if I ever did. I can now eat a bowl of cherries, which are chocablock with salicylates, in the middle of the grass pollen season, without any adverse reactions, which is a pleasing state of affairs to be sure, since I do like cherries.

In retrospect I was probably wrong about salicylates and they may have been a red herring. It was hard to see the wood for the trees at the time, I now think what happened every summer for five years was... 

  • a grass pollen allergy, properly diagnosed by skin prick test,
  • was treated with loratidine which I took as an antihistamine and this may have made upper respiratory tract (URT) infection more likely, as this is a known side effect of loratidine.
  • The allergic response to grass pollen may have been made worse by coconut MCTs (medium chain triglycerides, see previous blog article below) which may have made me hypersensitive to allergens and also TH2 shifted.
  • The loratidine related URT infection manifested as a summer cold and may have been exacerbated by MCT related TH2 shift, which would tip the immune system towards allergy and away from antiviral responses.
  • Oedema probably resulted from the proven hypersensitivity to grass pollen and may have been exacerbated by TH2 shift, also possibly URT infection related inflammation.
  • Eating honey may have introduced grass pollen exacerbating inflammation.
  • Eating fresh coconut oil may have exacerbated ongoing hypersensitivity and TH2 shift due to a putative mechanism involving membrane lability due to bilayer membrane molecular kinetics.

This is the most rational explanation I can come up with which explains my experiences and makes the least number of assumptions in accord with Occam's razor.

I have taken steps to treat myself by avoiding MCTs in coconut, dairy and palm oil. Also monitored lipid intake and biased it towards heavier (than MCT) lipids such as one might find in lamb fat and other animal fats as well as plenty of vegetable oils such as sunflower oil for cooking and on salads, walnut oil. 

Also I have of course stopped taking loratidine.

Since stopping MCTs and loratidine and deliberately eating heavier lipids, I have been free of these previously recurring summer colds with oedemas and my allergic response to grass pollen, while still evident, it much less extreme than it used to be. 

Food for thought!

Meanwhile, as part of my struggle with ME CFIDS, I have developed recurring (at least weekly) migraines which are not seasonal but do seem to be cyclical of their own accord as it were, as well as resulting from PEM (post exertion malaise) and influenced by food choices all tied together, it would seem, by histamine. 

Another complex problem I am still trying to make sense of, so will leave discussion to another blog article, considering how confused I got over the summer colds with oedemas. 

I comfort myself that science is mostly about finding out what is true the hard way, by observing phenomena accurately and testing competing hypotheses, at least half of which will be wrong. So I guess being wrong and more importantly being willing to admit you are wrong are a part of what science is all about.

Saturday, October 06, 2018

Coconut - the downside for ME CFIDS patients - possible TH2 shifting.

Further to my previous on problems with food. I have recently chanced upon a research paper which describes a phenomenon which may explain the symptoms I have been getting.

The experiment involved mice being fed coconut oil, which made a significant percentage of them vulnerable to TH2 shift and inflammatory reactions including anaphylaxis.

Dietary medium-chain triglycerides promote oral allergic sensitization and orally induced anaphylaxis to peanut protein in mice.
J. Li et al.


Dietary MCT promote allergic sensitization and anaphylaxis by affecting antigen absorption and availability and by stimulating Th2 responses.
MCT stands for medium chain triglycerides. In this case derived from coconut oil, which is considered a health food and often recommended for ketogenic dieting. The evidence applies only to mice but...

Over the last 5 years I have been suffering from summer headcolds which included severe oedemas in the upper respiratory tract. These may be an exacerbation of a previous tendency to TH2 shift in the summer since ME onset in 1986. The difference between these limited inflammations and the whole body response of anaphylaxis is that these oedemas were localised to tissues where an immune response was ongoing. If a virus is involved it remains unidentified but this condition was accompanied by intercostal cramps and tendency to hives, possibly headaches too and these lesser symptoms are apparently recurrent for me, fit the diagnosis of enterovirus, possibly echovirus which may be recurring like another repeatedly diagnosed virus does for me (HSV2 diagnosed by PCR still recurs 6 to 12 times a year, 32 years after infection, which triggered ME in the context of previous diagnosed EBV). This may be a result of the D in CFIDS (chronic fatigue immune dysfunction syndrome) which causes atypical things to happen with my immune system.

The colds with oedema typically produced pronounced nasal polyps and completely blocked my right ear once as well. The oedemas involved in these headcolds were greatly exacerbated by eating honey and lime and also coconut oil which I construed indicated salicylates, as I mentioned in my previous blog.

Honey and lime drink, which I unthinkingly took for a cold remedy, contains a lot of salicylates from honey but also lime has caused me problems with photsensitivity since and I cant rule that out as a factor and lime and all citrus have been added to my foods-to-avoid list. Honey is also reputed to contain pollen including grass pollen to which I am allergic as proven by a skin test.

Coconut oil, which I was eating regularly over the years this happened, contains salicylates but also MCTs, so this makes it difficult to be sure what has happened, as the MCTs may have exacerbated the oedema by another route as per the paper above, which I may have confused with the effect of salicylates.

I felt the salicylate sensitivity was further corroborated by the fact that I did end up having to avoid green vegetables during oedemas and also afterwards a string of headaches appeared to be triggered by green veg. All low salicylate foods seemed to be more tolerable for me. But green veg may contain potential allergens in the form of lectins which is something I am trying to understand and the headaches were often accompanied by mild asthma which suggests an inflammatory basis but by what route the inflammation occurs I cannot be sure.

So to be honest I would not call this a conclusive level of proof for the salicylate theory. An alternative hypothesis is that I was allergic to the honey and the green veg due to increased absorption of allergens induced by MCTs. However this is why testing food intolerance needs to be based on results and not solely on theory and I continue to test the bounds of my diet to check I am not being neurotic without good reason or making my life harder than it needs to be through lack of awareness.

If a thing makes me ill I need to avoid it, I just need to understand what it is so I can apply the knowledge effectively. There are some things I wont test any more like nightshades and coconut, because the evidence is sufficient for me, the years I ate coconut I got oedema and since I stopped eating coconut the oedemas stopped. Salicylates/lectins sensitivity I will continue to test, albeit very carefully, because it is variable and not as severe if I am not eating coconut.

A reaction to allergens does not rule out exacerbation by salicylates either, which are known to promote oedemas in some people. This is probably not an allergic reaction in itself IMHO, possibly a result of the way salicylates can interfere with prostaglandin pathways etc. This is odd because salicylate is normally regarded as an anti-inflammatory, but salicylates do have a wide range of effects and there are close connections to the inflammatory pathways, not all of which are beneficial. It remains a mystery but if coconut MCTs played a part and altered my reaction to allergens and salicylates combined, then if I do not eat coconut MCTs any more I may be able to tolerate salicylates better.

For me a breakthrough came after noting the long term coincidence in timing of these oedema attacks and my use of coconut oil in cooking, in a concerted attempt 5 years ago to improve my dietary intake of healthy lipids. I decided to stop eating coconut oil last year and this year the headcold with oedema attacks have not recurred, unlike the previous 4 years.

I am still having problems with vegetables and headaches but I found reducing gluten and including apple cider vinegar in my diet seemed to help.

It is my belief that somehow MCT coconut oil was setting me up for inflammatory reactions by some effect comparable to the observed TH2 shifting in mice (TH2 stands for T-helper cell type 2, which is the pro-allergic pathway,) and increased allergen absorption at Peyer's patches and this was behind my apparently new food intolerances.

TH2 shifting is known to be a vulnerability for ME CFIDS patients. Dr Paul Cheney identifed this clinically a long time ago and a recent paper from Maddy Hornig et al corroborates this diagnosis.

Cytokine network analysis of cerebrospinal fluid in myalgic encephalomyelitis/chronic fatigue syndrome.
M. Hornig et al.
Our results indicate a markedly disturbed immune signature in the cerebrospinal fluid of cases that is consistent with immune activation in the central nervous system, and a shift toward an allergic or T helper type-2 pattern associated with autoimmunity.

It occurs to me at the time of writing that its not impossible that the TH2 shift which may apply in my case due to ME CFIDS exacerbated by coconut MCT  might create a situation in which I developed an allergy to a latent virus, hence the strange mix of symptoms I experienced.

Hopefully avoiding coconut will mean I can avoid oedema reactions in future. Though if it is MCTs then its not just coconut as palm oil also has a high fraction of MCTs, though palm oil's capacity for allergic sensitisation has not been specifically tested and probably ought to be. Dairy also has them but I dont eat dairy anyway due to previous problems with it exacerbating summer allergies which I put down to casein at the time but on reflection may have been the same phenomenon.

I count myself lucky the oedemas caused, apparently by infection, when eating coconut were only in my upper respiratory tracts and not in vital organs. But this is a potentially dangerous phenomenon and something I feel its my duty to bring to other peoples' attention, despite the fact my understanding of it is incomplete.

I have now recovered from those episodes but coconut is definitely off the menu.


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Saturday, January 06, 2018

Salicylate intolerance, oedema and headaches in ME CFIDS.

Another chapter in the story of food intolerance linked with the progression of my ME CFIDS has been unfolding in the last few years. I think it is important to blog this in memory of Annabel Senior and her struggle with ME related food intolerance which eventually became so severe it contributed to an early death.

She reached a point where she could not eat anything at all without adverse reactions. Her coroner's report was among the first in the UK to attribute CFS as a cause of death. The following quote is from the National CFIDS Foundation patient memorial.
Annabel Senior, aged 60, died on January 8th after 45 years of CFIDS/ME. Toward the end, she was unable to eat anything due to multiple abreactions. She lasted for nearly 53 days without food, and only gave up water toward the end, because she was too weak to swallow. Annabel was 15 when she became sick and died at age 60. The coroner’s report said, “”Death due to Chronic Fatigue Syndrome…1a. Left ventricular failure, 1b. Occlusive coronary artery atheroma.” She leaves her constant caregiver and husband, Richard. Annabel lived in Conway Valley, North Wales in the United Kingdom.

+URL to a short article entitled Did food intolerance kill Annabel Senior? FYI

Not all PWME become so severely ill in this way but food intolerance is a difficulty for some. I am hoping this is a situation which can be helped by knowledge about foods. So far I have found it best to avoid nightshade vegetables, high amine foods, MAOi foods, dairy and soya and have recently added another to the list, high salicylate foods.

It first began to manifest about five years ago when I began to get a summer cold every year, with very blocked and swollen nose qualifying as nasal polyps.

To put this in context I have had problems with my immune system in summer ever since 1986 immediately after ME CFIDS onset when I started to get chronic recurring virus  accompanied by severe allergic asthma and hayfever every June - July period and an NHS type allergy challenge test later confirmed a grass pollen allergy a decade after ME diagnosis. I had previously been tested in my youth due to chronic asthma which was found to be related to house dust mite allergy, not pollen allergy. I had grown out of the house mite allergy with the help of a lot of rowing, which was a sport which did not bring on attacks, so I was able to get fit and strong and rowed for my school and college. Somehow the allergy returned and shifted to pollen at the onset of ME in 1986 when I was aged 21-22.

As part of this ME CFIDS problem in summer I also experienced a tendency towards developing pus filled cysts and strep type bacterial infections during that summer period of raised allergy. Clearly something strange was happening to my immune system in the summer months. I say this for posterity because even today I have no idea what it is other than it fits the bill for Dr Paul Cheney's observations of ME CFIDS related TH2 shift symptoms.

To add to the summer difficulties over the last five years or so I began to experience a late summer cold every July - August. I discovered by accident that hot honey and lime was a very bad idea as a cold remedy in my case as it made my nose swell up like a balloon (the lime also made my skin feel like it was sunburned when it wasn't, but that is another story). After reading around the internet I realised that honey has a very high salicylate content and that salicylates can cause this kind of oedema reaction and after a few exploratory tests satisfied myself this was a real issue.

I also discovered that loratidine antihistamine can cause upper respiratory tract infection as a side effect. I had been taking it to help with my hayfever but suspect it may have contributed to the yearly summer cold.

Three years ago I started to get a series of headaches. I consulted my food diary and could not believe what I was seeing. I was eating lots of healthy green vegetables like broccoli and peas and lettuce and kale. To my dismay it was these very green and healthy vegetables which were causing the headaches. I soon discovered that these vegetables have high salicylate content and when I switched to low salicylate vegetables, of which there are many, the headaches reduced markedly.

So I am writing this as a simple heads up to say, salicylates can also be a problem with this condition. FYI there is a useful online website detailing salicylate levels in different foods at

I have written this in the hope that PWME who have food intolerance might read this and benefit from my experiences learning to identify the types of food which can cause a problem.

Wednesday, May 10, 2017

No more potatos. Nightshade alkaloid intolerance and exclusion in ME CFIDS in relation to calcium, apoptosis and the mitochondrial pore.

I have heard of more than a few people with ME who suffer food intolerance and for some it can become dangerous. This is a facet of my condition too and I have to avoid dairy and soy for example as well as high amine foods, MAOi foods and other foods which I know from experience repeatedly cause symptoms.

I also now avoid nightshade vegetables; i.e. potatos, tomatoes, chili and sweet peppers, aubergines etc and get iller if I don't. Though stopping eating them was not straightforward and had unexpected consequences, so I thought I should let people know what happened and what I learned from it so that anyone else who is obliged to go down this route can be a step ahead.

I have had ME CFIDS since 1986 but my intolerance to nightshades has been getting worse since about 2010 and I excluded them from 2012 onwards.


It took a while for me to realise it was nightshades. I kept biting the inside of my own mouth and getting mouth ulcers. At first I thought I was being clumsy but then realised the lining on the inside of my mouth was swelling which is why I was biting it by accident. When I took care not to bite my mouth, I still got ulcers anyway and I realised there was some kind of immune reaction involved.

I eventually decided to use the food diary I always keep now after consulting an expert in food intolerance, Prof Jonathan Brostoff who raised my awareness of food intolerance in general, after which I learned how to test for food intolerance with an elimination diet.

So I began to log ulcer incidents and correlate them with foods and after a couple of years found they were happening regularly after eating curry, potato and tomato plus other random looking incidences. I was puzzled but googled these three foods plus mouth ulcers and it spat out nightshades. Once I had familiarised myself with the other foods in this family, a lot of the seemingly random incidences suddenly made sense. So I decided to try excluding all nightshades from my diet and as a result the ulcers reduced in frequency.

It was a bit more complicated as I still got ulcers after eating olives and other foods with alkaloids in them which are not nightshades. I am still unsure about why this is. As a working hypothesis I assumed I had a general alkaloid intolerance and it was causing a hypersensitivity reaction of some kind. It may be more complicated than that, but the point is excluding the high alkaloid foods prevented ulcers and inflammation. However things then got even more complicated.

It took a couple of years for the ulcer frequency to reduce to near normal levels, partly because I was still learning which foods were a problem, but much to my relief the ulcers eventually stopped. However during that time I began to experience changes as follows.

Changes after stopping nightshades.

  • excruciating muscle pain
  • mitochondrial (ATP translocase) blood tests for white blood cells normalised
  • cell free DNA blood test improved
  • viral recurrence frequency increased
I lived with a cricked back on both sides under the shoulder blades and terrible muscle cramp pain restricting my movement for the best part of a year before I finally realised it wasn't going to fix itself and that I needed to try something new. Considering the problem was muscular I decided to try a basic sports science approach and boost mineral supplements to see if I could fix it. Thankfully super-doses of extra calcium over a few weeks did the trick and made the cramps manageable again, though I had to balance calcium with magnesium to keep my heart rhythm stable. (I later found extra sodium salt helped with muscle pain as well FYI.) At the time I had no idea why calcium fixed it or why it had become so severe in the first place though it did occur to me that being on a dairy free diet probably didn't help.

Blood tests on the mitochondrial function of my white blood cells (neutrophils) showed that it was returning to normal from a previous pathologically low state, yet I still had ME. Also my cell free DNA, which measures rate of cell death, was reducing from extremely high to just high.

Both these improvements bode well on the face of it, the only problem was I still felt lousy and still had post exertion malaise and still had regular recurring viruses which are a hallmark of my CFIDS. I recently reevaluated the rate of virus recurrence and found it had increased from 8/yr in 2006 to 13/yr ten years later in 2016. It was a perplexing pattern of observations and painful experiences that made little sense. 

It was several years after giving up nightshades that I chanced upon a research paper which seemed to offer a potential explanation. I hasten to add this paper is proper science but the connection to my own symptoms is not proven scientifically but is highly circumstantial and food for thought, to coin a phrase.
Effect of solanine on the membrane potential of mitochondria in HepG2 cells and [Ca2+]i in the cells.By Shi-Yong Gao, Qiu-Juan Wang, Yu-Bin Ji.

Solanine is the name given to one of the toxic alkaloids present in nightshades (another is chaconine which is thought to be similar in action but I only have research on solanine to draw on). The paper above showed that solanine has important toxic affects on human cells.
  • It opens the inner mitochondrial membrane permeability transition pore,
  • this depolarises the inner mitochondrial membrane,
  • releases calcium,
  • this also increases likelihood of cell death (apoptosis).

All of these affects match the changes after I stopped eating nightshades.

  • My suddenly increased muscle pain was remedied by calcium, perhaps because the calcium previously released by solanines was no longer being released, which meant I needed more calcium.
  • ATP translocase and other mitochondrial activity scores in white blood cells improved, perhaps because solanines were no longer depolarising the inner mitochondrial membrane enabling the membrane potential to drive the ATP translocator enzyme normally.
  • Cell free DNA tests improved, perhaps because cells were not being killed by apoptosis induced by solanines opening the inner mitochondrial membrane pore and so were no longer releasing so much of their DNA into my blood.
  • Viral recurrence due to my ME CFIDS condition got worse and increased in frequency, perhaps because infected cells were not dying as easily due to the lower rate of apoptosis as above.
In addition I have read that nightshades contain an active form of vitamin D called calcitriol which may have been raising my internal calcium levels by taking it from my bones, which isn't so good and makes you wonder about cases of severe ME where people get osteoporosis.


It raises questions, such as why solanines would be toxic to me but not other people. The truth is they are toxic to everyone but most people can deal with them. I don't have a clear answer about my own difficulty but my guess is my body is not eliminating them effectively for some reason. I am now exquisitely sensitive to even tiny quantities of nightshade and they make me far iller than when I was eating them regularly and habituated to them having eaten them all my life.

Another question is why my ME didn't get better when the mitochondrial activity of white blood cells improved. I don't know but recent research suggests there are other metabolic bottlenecks in ME and it may be that just because one metabolic bottleneck due to nightshade toxin improved, did not mean the other bottlenecks or adverse reactions due to ME CFIDS were improved, so these would still cause a fatigue syndrome. Plus my immune dysfunction definitely got worse as the nightshades were no longer helping my white cells out by inducing apoptosis of infected cells. So swings and roundabouts.

My conclusion is that my intolerance of nightshades is a secondary illness brought about by primary ME CFIDS reducing my digestive and other defences. I talked it over with a friendly sceptic who suggested I should check whether the dosage from eating these foods is comparable with the doses in the research paper, before jumping to any conclusions.

Quantitative Analysis.

So I looked for quantitative data for a back of envelope type calculation and found the following report online of an investigation for the Bureau of Chemical Safety of Health and Welfare Canada, presumably sometime before 1993 and sometime after the latest 1990 reference used in the report.
SOLANINE AND CHACONINE Dr T. Kuiper-Goodman and Dr P.S. Nawrot, Bureau of Chemical Safety, Health and Welfare Canada, Ottawa, Ontario, Canada.

I was interested to note that potato flesh does contain significant amounts of solanine. So I made a back of an envelope calculation, as below, using empirical experimental data for quantity, absorption and excretion half-life from human and animal experiments summarised in Kuiper-Goodman, to get a rough idea.

Unless I messed up the maths or missed something important (not impossible considering how befuddled I get sometimes) the figures suggest normal portions of nightshades could provide enough solanines to create concentrations in some human tissues comparable to the Shi-Yong Gao paper, sufficient to have an effect on mitochondrial membrane potential, calcium release and apoptosis rates.

Calculation of approximate magnitude of solanine concentrations in the body from consuming potato.
Using an upper bound figure of 5mg / 100g for potato flesh TGA (total glycoalkaloid) from the Kuiper-Goodman article (table 1), then each 100g serving of potato flesh adds a putative maximum of 5mg which works out at 5,000 µg per 70,000* mL i.e. potentially up to 0.0714 µg/mL, if it is all absorbed, which it isn’t but this is addressed below. This compares to the Shi-Yong Gao paper value of 0.016 µg/mL to produce depolarisation of the inner mitochondrial membrane. *(Assuming about 70L human body volume.) 
The experiments summarised in Kuiper-Goodman (para show figures for rats absorbing 10-22% of total dose with 90-78% excreted within 24 hours in faeces and urine.
Human experiments (para indicate tritiated I.V. solanine is rapidly removed from blood plasma and sequestered in blood cells then transferred to major organs, suggesting measured low levels in blood serum during dietary experiments are misleading.
Excretion had a measured half life of 34-68 days, on which basis 1mg per day regular absorption was calculated to give a 50mg load i.e. 50x the daily dose but this experiment does not take into account biotransformation of the tritiated molecules and the real value for glykoalkaloid load ratio is certainly less than 50x.
So if we guess using the lowest value of 10% absorption for solanine 5mg/100g dose food i.e. absorbtion of 0.5mg/100g; it should result in a single dose of 0.0071 µg/mL for a 70 L adult (a tenth of the dose content) and a putative maximum loading up to 50x i.e. very approx 0.3571 µg/mL. The real load is certainly lower due to biotransformation but since the tritium evidence suggests solanines are rapidly concentrated in erythrocytes and then major organs (leukocytes not mentioned), local concentrations may nevertheless rise considerably higher than the estimate for a whole human body volume, due to sequestration.
The Shi-Yong Gao et all study used treatments with 2, 0.4, 0.08, 0.016 and 0.0032 µg/mL and reported significant lowering of mitochondrial membrane potential (P<0.01) at levels of 0.016 µg/mL and above (p 3363). So the putative average concentration from a single dose of 100g potato is 0.0071 µg/mL, just under half the Shi-Yong Gao lower bound for a single dose. It seems feasible that sequestration could take the local concentration significantly higher in some tissues (eg definitely erythrocytes, liver, kidneys and spleen but I saw no info on neutrophils,) for a single dose and that loading could increase this to values potentially exceeding an order of magnitude higher than the Shi-Yong Gao lower bound. Suggesting a range of TGA concentrations which could account for low function mitochondria and also a raised rates of apoptosis in some tissues.
In the real world the case is strengthened by the reality that portion sizes were often considerably larger than 100g eg a 150g bag of kettle chips or a bag of chips from a fish and chip shop or large baked potato. Also Kettle chips and baked potato can include potato skin which has a much higher value for TGA. A greater sensitivity to processed foods containing potato than to potato flesh could likewise be explained by the likelihood that processed potato probably has higher levels of TGA per dose than the potato flesh value of 5mg/100g because in the food industry solanine levels are apparently considered safe at 20mg/100g ie four times higher, so processed mass produced food is able to reach these levels when skin and green potato (TGA up to 11x more at 220mg/100g) can be accidentally incorporated in bleached potato flour for example or a delay between peeling and processing can raise TGA due to time sensitive injury response in the tuber, especially if TGA is regulated per product mass rather than the incorporated potato mass which could explain my sensitivity to apparently small quantities of potato. So a “safe” 20mg dose of TGA would give 0.0286 µg/mL, exceeding the lower bound of the Gao study even without considering sequestration and half life / load.
PS Allegedly similar values for aubergines and sweet peppers btw.
Soil degradation of glycoalkaloids takes 21- 42 days.

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Monday, May 05, 2014

Why viruses, immunoevasins and mixed Infections may make ME CFS too complex and variable to be easily understood.

I have always believed viruses are important contributors to ME CFS because of my own experiences but to be honest research has not been going smoothly, there have been a couple of high profile disappointments lately but also some good news on the horizon.

In the UK affymetrix studies seeking patterns of gene activation in ME CFS ran into a problem. While discovering real differences between ME CFS patients and normals they also showed that no consistent pattern could be found. The variability between patients seems to have been too great for the small sample size of about 50 patients. But in science a negative result is still a result and people have learned from this. Professor Stephen Holgate since suggested there may be as many as 15 different subtypes of ME CFS. Personally, for reasons set out below, I think that may be a conservative estimate.

The attempt to find a single causal virus was on the face of it set back with the discovery that XMRV was not reliably detected in association with ME CFS, carefully disproved by Professor Ian Lipkin using a double blind experimental protocol. Fortunately Professor Lipkin and colleague Mady Hornig have taken over the reins and are undertaking some very ambitious studies in the USA which have learned from the difficulties with small sample sizes and look very promising with expanded studies in planning. FYI They need and deserve our financial support.


Other fields of virology have also been progressing. Over the last two decades an intriguing picture of how viruses evade human immunity has begun to emerge. As a humble zoology grad I have tried to keep up with aspects of this research which may be relevant to my own condition and I relate discoveries here which are of particular interest to me in the attempt to understand my own illness in the hope that they may be of interest to others.

One of the commonest of the viruses studied is Epstein Barr Virus, EBV for short, which can cause glandular fever aka mononucleosis when contracted in adolescence or later in life and is present in 95% of the population. EBV is a herpes virus which effects different people differently and has frequently been implicated in cases of ME CFS and is known for its ability to persist in and disrupt the immune system causing severe illness in a small number of people (see Dr Lerner on herpes virus induced CFS). It used to be thought that ME CFS was often caused by chronic EBV, but the discovery of ME CFS cases where EBV was apparently not present cast doubt on that interpretation.

There may be more to EBV than meets the eye however since recent evidence (discussed a bit here and in more detail at Simmaron Research) suggests that some ME CFS patients have a compromised immune response to EBV. Somehow their immune cells forget how to mount an immune response to EBV leading to higher rates of latent EBV replication and lowered ability to deal with EBV reactivation. So by some measures (i.e. assessing the immune response to EBV as a way to decide if EBV is present,) it can appear that EBV is not present, when really it is!

In any case, logic suggests that even if some cases of ME CFS are not caused by EBV this does not mean that no cases are caused by it, as one cannot rule out the possibility that EBV causes a proportion of ME CFS and other viruses cause a proportion of other cases. Since XMRV has been disproved, it is easier to say that assuming one singular pathogen is responsible for ME may be a mistake. This may seem a bit vague so one reason for discussing immunoevasins here is to look at why this is a very real possibility.

In the intervening period since ME CFS research turned away from chronic EBV, research of EBV which is also implicated in cancer and autoimmune disease has uncovered how EBV can evade the human immune system by making products which jam our defences. These products are called immunoevasins and we are still learning how they work. We have also learned that other viruses can likewise make comparable immunoevasins which attack the same weaknesses in the human immune system. Below are discussions of two examples, EBV's viral version of interleukin-10 and EBV's BNLF2a gene, an antigen processing blocker.

To be clear, the suggestion I am making is that ME CFS cases could look similar because they have one thing in common, us, human beings. ME CFS patients are all human and we have the same weak points in our immune system. Viruses would naturally evolve to exploit these weak points and where they succeed, different species of virus could cause similar types of problems in the immune system of their host. This is a different way of looking at ME CFS from the search for one causal virus such as XMRV and after the results of XMRV tests and the CFS Research Foundation's analysis of Dr J Kerr's results, it needs to be considered.

I must stress at this point, proof conclusively linking or debunking the action of immunoevasins in relation to ME CFS symptoms has not been acquired, this blog is speculation. However the known effects of some of these immunoevasins bear comparison with ME CFS symptoms. Thus far, the more we learn the more credible the scenario is becoming not only that a virus like EBV could cause the primary immunological symptoms of ME CFS but that other viruses and possibly biotic bugs can too, by attacking the same weaknesses in human immunity.

Viral Interleukin-10.

One of EBV's immunoevasins, a secret weapon which has been known about for over two decades now, is a molecule which mimics a human immune messenger molecule called interleukin-10 or IL-10 for short. Viral versions are known as viral interleukin-10 or vIL-10.

After much careful research we now know EBV's version of vIL-10 can effect the human immune system and release cytokines which encourage allergic and autoimmune reactions as well as reduce antiviral activity (as linked above). This matches the TH2 shift observed by Dr Paul Cheney in his ME CFS / CFIDS patients, which people commonly report as part of their ME and which has experimental corroboration. Dr Cheney has specifically discussed the way in which pathogens mimic IL-10 as a possible cause of TH2 shift in ME CFS patients.

The main effect of EBV's vIL-10 is to change the activity of defensive white blood cells making it easier for EBV to survive. EBV predominantly survives as a persistant infection inside white B cells which by means of other immunoevasins it activates and transforms prematurely into long lived memory B cells inside which it can persist, though it does infect other cell types. This is interesting because these are the very same B cells which are wiped out by rituximab treatment which we know helped some ME patients in Norway.

On the other hand vIL-10 makes NK (natural killer) cells less active. NK cells are an important immune defence against many pathogens and they have been shown to be less active than normal in some CFS studies (eg Brenu). vIL-10 also decreases the activity of CD4+ T helper cells which normally produce cytokines which activate NK cells.

If EBV reactivates and infects new cells it produces more immunoevasins including vIL-10, which must pass into the intercellular medium to have its effect and in so doing can spread around the whole body causing system wide changes. EBV is using vIL-10 to prevent NK cells from destroying the cells it has infected. By doing this it also makes its human host more vulnerable to other bugs which NK cells would otherwise kill.

This is a wide range of bugs including yeasts and biotic infections because NK cells are thought to be essentially innate killers, not specifically attacking a particular type of antigen like B cells or T cells, they simply eat anything which is not showing "self" antigens. So NK activity is stopped by a self antigen not started by a bug antigen. Not surprisingly the immune system has a failsafe to regulate NK cell activity to stop it accidentally eating its owner's body and that failsafe is IL-10. vIL-10 can do many of the same things as IL-10 and as a result NK cell suppression occurs with every reactivation episode of EBV. Each cycle the host immune system would be laid low for a while as is often reported in cases of ME and yet different aspects of the immune system like B cell transformation can be stimulated by the very same virus. I can only speculate at this stage that where EBV reactivation was continual, NK deactivation probably would be too. Alternatively both could vary in intensity over time through periodic bouts, which matches the experiences of some patients.

Speculatively speaking this fits some aspects of the altered immune response in ME CFS I have experienced which has been corroborrated anecdotally by many other people; i.e. a poor response to some biotic infections at certain times, vulnerability to virus infections and an altered inflammatory response to them, also raised allergies and tendency to rheumatic joint pain, which could all be explained by the effects of vIL-10.

TAP inhibitors: how EBV's gene "BNLF2a" silences infected cells.

Another more recently understood secret weapon of EBV is made by a gene called BNLF2a. Once inside the cell, one of the first things EBV does, as well as making vIL-10, is making the product of the BNLF2a gene which stops the cell being disposed of by white cells. These particular white cells for the record are CD8+ killer T cells which, unlike NK cells, can target specific bug antigens presented on the outside of cells and select infected cells for demolition.

To do this EBV exploits an Achilles heel of the immune system which is that an infected cell must alert white T cells waiting outside to consume infected cells. It may seem a bit burocratic, but unless the infected cell reports properly the white T cells cannot sense what is going on inside the infected cell because the cell membrane gets in the way. The infected cell makes its report by moving virus antigens inside the cell through the membrane to the outside, to act as flags, using a special "transporter associated with antigen processing" or "TAP" for short. EBV's secret weapon, the BNLF2a gene, "turns off" TAP and prevents flags from being raised, so the CD8+ killer T cells outside cannot tell anything is wrong.

Its like a baddie in a movie kidnapping someone and tying a gag over their mouth so they cannot cry out, in this way the EBV can hold a cell hostage and live inside it for a long time, occasionally reactivating to provoke another "bad patch" and infect more cells and other people. This allows these viruses to maintain an infection in a host for longer and thereby spread themselves to others. This is probably why NK cells continue to be useful in the immune sytem's evolutionary arms race with pathogens, as a failsafe, since a cell which does not have functioning TAP will also not present the self flags which appease NK cells, so NK cells should eat them once their existing self flags are recycled. But this failsafe relies on active NK cells and as already mentioned EBV does its best to deactivate NK cells with vIL-10.

Viral Evolution.

So EBV inflicts a double whammy on the immune system, disabling key defences both inside and outside cells, which is probably why it is such a common virus. Luckily for us a virus as successful as that evolves over time by natural selection to become less fatal, simply because if it kills its host it dies too and cannot spread. That doesn't stop it making the host very unwell, but it might explain why a host with ME CFS could be so unwell for so long and yet not die. Viruses would evolve to do exactly that.

Again EBV is not the only virus which can turn off TAP. For example the common herpes simplex viruses HSV I & II make ICP47 (1 & 2) both block TAP inside the cell. Cowpox virus CPXV12 blocks TAP, so does US6 from human cytomegalovirus, so does UL49.5 from varicellovirus. All of these viruses can disable TAP, yet the less closely related species of virus evolved convergently to do it in different ways suggesting that disabling TAP is highly advantageous to viruses and implying that TAP is both a central mechanism in anti-viral defence and because of this also an Achilles heel, a key weakness in our immune defence like IL-10, only inside cells instead of outside them.

It takes little imagination to conceive that the combination of vIL-10 and TAP inhibitors could be very disruptive to the effective clearance of infections by the human immune system resulting in the kind of ongoing low level infection which could cause chronic immune activation which is typical in ME CFS cases.

Personally I think this really is relevant because of my own experience with ME CFS, which began some time after a severe adolescent EBV infection and yet involved other recurrent viruses which were not EBV itself.

Are Immunoevasins the answer?

Its too early to say. If we learned anything from XMRV surely it was to be cautious about this kind of complex biochemistry and raising hopes without quadruple checking the evidence. Experiments are needed to prove or disprove any hypothesis. Yet the discovery of these immunoevasins has the potential to explain many perplexing yet common ME CFS (CFIDS type) symptoms in one go, so they need to be looked at and understood better.

However its worth pointing out that if we hypothesise immunoevasins may play a part and accept the apparent absence of EBV in some cases of ME CFS might be misleading, looking for one single virus to blame for all ME CFS would still be a mistake. The reality emerging from immunoevasin research is that EBV is not alone in using viral Interleukin-10 or TAP inhibitors to trick the immune system.

Cytomegalovirus for example also produces a viral version of Interleukin-10 (as does Orf Poxvirus which humans can catch from sheep and so does equine herpes virus type 2 "EHV-2" for short, see paragraph 3 of the introduction). They are probably not alone because IL-10 represents a weak point in human immune defences as it deactivates key immune responses. CMV also produces a TAP inhibitor and is not alone, (as linked above see fig5 p578).

It makes sense that any viruses which acquired a copy of the IL-10 gene or of a viral forgery would tend to survive and remain with us. In evolutionary terms the selection pressure favouring the use of vIL-10 is very great. This might also apply to some biotic infections which could also benefit from making counterfeit IL-10 because of the way it reduces NK cell activity. Likewise any virus which can disable TAP has an advantage and will persist better than one which cannot. This implies there may be more viruses using these tricks and that a range of different infections could impact our immune systems in similar ways ie deactivating NK cells, activating allergies, promoting autoimmune disease with persistent relapsing remitting intracellular infection causing periodic or chronic immune activation. In a nutshell, ME CFS.

Experts like Dr Jonathan Kerr and Prof Stephen Holgate have stated that there are probably many subtypes of ME based in part on empirical evidence from affymetrix studies as well as clinical experience. Certainly there is a lot of variation between different cases which I discuss in more detail in a section below but this makes it all the more plausible that vIL-10 producing pathogens may account for some ME CFS subtypes.

Speculation on Mixed Infections.

Immunoevasins are significant for mixed infections because they explain how two or more viruses might interact with each other inside their host, raising the possibility that more than one kind of virus is involved in individual cases of ME CFS through unfortunate combinations. (Something I have tried hard to understand because of my own case history involving mixed infection with recurrent viruses.)

One study on both EBV and CMV provides an example of how viruses can interact with each other, showing that where elderly people have both EBV and CMV they are more likely to experience inflammatory disease  from their EBV infection if CMV is present. This suggests EBV and CMV interact within the patients' bodies making the combination more harmful than either one on its own. The same may be true of interactions between other viruses.

At this point, what we know raises more questions than it answers. A finger of suspicion points at EBV because of the way that it can make itself at home in B cells and turn their activity to suit itself using immunoevasins.

But 95% of the population has EBV and they dont all get ME CFS. We know that if you get it young it barely causes a snuffle, but in your teens it can put you in bed for months because you are better able to fight EBV the younger you are. It also varies for individuals, some people are not badly affected by it, others are. Broadly speaking the fact that EBV does affect people so differently makes it more plausible that it could be behind some cases of ME CFS.

We also know CMV's immunoevasins grant it some abilities similar to EBV's, enabling it to disable the immune system and become a persistant infection. Again it is a common virus and not everyone with it has ME CFS but these are two viruses we know more about than many others so are good examples to discuss, even though we are left wondering what else is going on and how many more can do likewise.

The possibility worth exploring is that where one virus like EBV or CMV can disable the NK response, other viruses which can't do this themselves can take advantage of that to infect cells elsewhere in the body in different tissues, to which they are specifically adapted.

This alone could make mixed infection more severe than you would expect judging by the sum of the affects of individual viruses. One reason for this is that viruses adapt to their host and a successful virus does not kill its host as this reduces the time they have to spread themselves. Viruses tend to evolve to balance their "aggression" to be sufficient to survive and spread and no more. It is only when viruses switch hosts that they tend to become lethal plagues until the virus evolves and its lethal affects attenuate.

However where a virus is disabling an aspect of a host's immune system not targeted by a second virus which is sufficiently aggressive to survive in a healthy person, the second virus may prove overly aggressive for an immune system already compromised by the activity of another virus. So a combination of viruses may cause greater debility than one virus on its own.

Evolutionarily speaking this could happen and keep on happening where mixed infections of a particular combination which is unfortunate for the host are relatively rare events compared to the total number of infections by those viruses in the whole population. This is because a virus will primarily evolve to suit the most common infection scenario, since that is the way it will normally spread.

What we may be seeing with the rising incidence of ME CFS like illness is a reflection of the increased chance of getting an unfortunate mixed infection in the modern world. This could be due to increase in travel, especially air travel as well as the total size of the human population of the world.

A further discussion, which is speculation at this point, is that where secondary viruses can disable TAP, the compromised cells may become a refuge for any viruses which can infect them including vIL-10 producing viruses. This might allow this kind of illness to become not only persistant but progressive, acting like a ratchet of infection, claiming more and more host cells for the viruses to live in as the infection continues. This deserves consideration with respect to more severe ME CFS cases.

I believe this line of thought could be significant for understanding ME CFS because of my own experience with at least two viral infections which I believe interacted with each other resulting in ME CFS with recurrent viruses.

There are other alternative hypotheses. For now they are all just hypotheses. There could still be one virus like the one we hoped XMRV would be, but then you have to explain the wide variation in gene activity seen in the London affymetrix studies. The cause of ME CFS might even be a new kind of disease, like prion disease, which we simply haven't encountered before. We still can't rule these out but for now the interaction of viruses using immunoevasins is a sufficient hypothesis, employing facts we do know and the best I can currently find, to explain what happened to me, though it remains to be seen if this is the real cause for the millions of people who are afflicted around the world.

Speculation on Variability in ME CFS.

The variation among ME CFS patients presents a puzzle which mixed infections and their immunoevasins might explain, but for now we don't know for sure what proportion of variation this would account for.

vIL-10 suppresses NK cells, stimulates B cells and has the potential to encourage autoimmune illness which could cause even more clinical variation in symptoms between different patients, even when caused by the same infection, because antigen specific immune reactions are by their very nature a dice throw and so if they happen to cause autoimmune disease can affect any part of the living body due to the way the immune system creates random antibodies in its search for a way to destroy invaders.

There is a theory that EBV in particular contributes to autoimmune disease by making autoimmune cell lines of B cells, which should die off, into long lived memory B cells. These normally act as parent cells to clones of cells intended to fight specific pathogens. Where the B cell is accidentally attacking the body it is normally disposed of, but if infected by EBV they can be incorrectly confirmed as a bonafide defender leading to the production of a clone army of B cells causing autoimmune disease in whatever tissue they happen to be specific to, which is completely random. This might contribute to autoimmune reactions in some ME CFS patients, as the Norwegian rituximab trials suggest it does.

This implies there may be at least two sources of variability involved in ME. Firstly a large number of different virus combinations, secondly the random chance of autoimmune reactions. This is without considering the genetic variability of individuals, which constitutes a third kind of variability which could alter the course of the disease.

Timing is also known to make a difference to the course of viral infections. As previously mentioned, EBV for example is often much more severe when contracted by a teenager than by a baby. When an individual contracts viruses, relative to life history and events like contracting other viruses, may make all the difference in how mixed infections play out for different individuals.

Besides this the disease itself is known to change over time both in the long term and for some people in the short term creating cycles of fluctuating illness. So the assessment of patients and their biochemistry can show variability for that reason as well, making it all the more difficult for clinicians and experimenters to spot patterns and join the dots.

Solving the Riddle.

The implication of viruses evolving strategies which converge on weak points in the human immune system and the possibility of mixed infection in ME CFS is that epidemiologists studying outbreaks may be looking at intricate complexity, not necessarily a simple disease caused by a single infection. For example when looking at an ME outbreak they may be looking at the intersection between epidemics of two or more different viruses, each seeming relatively innocuous on its own, in the context of individual differences in susceptibility caused by genetics and timing.

It is possible to conceive that we are in a situation where variability means that two patients with exactly the same condition might provide different biochemical results at any given moment in time despite having comparable clinical histories. This would imply that in order to understand ME CFS, which we don't, we need to discern relevant patterns of biomarkers for the disease over time as well as between different subtypes. It may be one of those situations where small efficient studies really won't get the relevant information and bigger really is going to be better.

Noone does bigger better than the USA and Prof Lipkin and colleague Mady Hornig are already embarked on this process (as linked above).

This will hopefully lay the groundwork for identifying and characterising immunoevasins and the way they affect our human immune systems and in my opinion this will eventually lead to an understanding of ME CFS.

If there is anyone who can make headway in this field of study it is Ian Lipkin (wiki) the professor who proved that XMRV was not the answer to ME CFS. He and his expert team have a good reputation for using effective biochemical analytical tools, using careful experimental protocols, to identify viruses involved in epidemics.

He is already working on identifying viruses in white blood cells in ME CFS, which is good news to say the least and has suggested a worthwhile next step on the journey to understanding ME CFS, along with many other human diseases, would be to map the molecular fingerprints of the human microbiome, all the microscopic symbionts and pathogens which live within us, which we know very little about.

He has made a heartfelt plea for ME CFS patients to support this ambitious project to sequence the entire microbiome in order to lay the foundation for future research.

Its a big project and needs at least a million dollars to get it started. By crowdfunding standards this is very achievable, if 100,000 people gave $10 each that would do it! Once completed it would put him and the rest of the scientific community in a better position to detect immunoevasins and other patterns of activity in pathogens linked to disease of all kinds.

Considering the realpolitik of ME research, supporting this project would also make a visible statement, that the ME CFS community are self-empowered, are serious about finding out the truth and want to help those who want to help us. By funding this work we can not only advertise our cause but we can ensure that this knowledge is applied as quickly as possible to understanding ME CFS. Besides enlightened self interest this work will benefit all humanity and noble as that is, it also lays down a marker in an important conversation about enlightened mutual interest and why the disabled and impoverished ME CFS patient community has been left to fend for itself when a percentage of all healthy people in the developed world will be joining our number every year until the cures are found.

It is an historic opportunity for the ME CFS community to contribute to their own future and the future of humanity. Like the sequencing of the human genome, it is a great undertaking which will help spur advances in technical know how and understanding benefiting medical research across the board and far into the future.

If we are remembered for nothing else, completing this project would be something to be proud of.

To quote Eleanor Roosevelt, "it is better to light a candle than to curse the dark." Lets beat this thing together, it has got to be worth $10.

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Friday, December 24, 2010

Neurological Illness in ME.

In chatting to online friends with ME, I end up repeating the ideas which have helped me to live with ME again and again, so I thought I would write them down.

Lack of diagnosis coupled to a desire to do my bit and push through ME contributed to a push crash cycle of relapse in my case, which not only hindered convalescence but caused deterioration. I hope this advice can prevent that happening to others.

One of the hardest things I had to deal with was not so much the muscle pain and weakness but the derangement of my nervous system so the first topic concerns what I have understood about managing your nervous system with ME.

Neurological overactivity paradox.

ME is considered by the World Health Organisation (W.H.O.) to be a neurological disease and while I might differ about its underlying nature (which seems to be immunological in my own case) there is no doubt the nervous system is often seriously affected by ME.

Contrary to the outward appearance of ME patients who are usually obliged to restrict their activity, ME can sometimes lead to febrile (feverish) mental activity which prevents sleep and contributes to emotional lability, cognitive impairment and sensory hypersensitivity.

Severity of symptoms can range from feeling a bit wired to mind altering psychosis but can spiral out of control (especially if not recognised) for reasons I will try to explain.

Why overactive?

Dr Paul Cheney who lives and works in the USA is an experienced ME clinician who understands well that many ME patients he has treated have increased nervous system sensitivity. For example it is well known that people with ME are often hypersensitive to light and sound and smells and other sensory stimuli. ME related cognitive difficulties and sleep disturbance etc could also be ascribed to the same kind of problem.

Neurological overactivity in ME is real, so something is causing it. Dr Cheney explains this as the nerves reacting to the harm caused by ME and becoming more active. He noticed that this also happens in cases of physical injury and suggests it may be a general response to any kind of nerve damage (not necessarily due to an immune response) possibly to assist organisms in becoming alert and avoiding further damage. Speaking as a zoologist it makes sense to me that in our natural environment we evolved to become more alert if something is harming us.

Vicious spirals in ME.

We don't know how this increase in nerve activity comes about as yet (¤). However it happens, PWME (people with ME) still experience stress like anyone else, if not more so due to their increased sensitivity, which activates their nervous system even more via stress hormones eg adrenalin and cortisol and this kind of stress response is well known to spell disaster for people with ME. This is probably because stress hormones prepare people for action and so not only activate the muscles and nerves using up the limited available energy thus causing an energy crisis, they also suppress the immune system as well, to divert energy away from immunity and towards muscles and nerves to prepare for action. This is unhelpful since immune mediated ME appears to involve persistent viruses and a suppressed immune system can permit a viral episode to commence. This is one potential vicious spiral. You feel ill, so you try harder stressing you more, making you iller etc etc.

(¤)(It is worth remarking that the mysterious ciguatera epitope detected in ME patients is one line of investigation which might relate to nerve activity in ME, but we don't know enough about it and there may be more to it than that. It certainly deserves more research.)

What I must state for the record is that I dont agree with the tacit assumption made by some with limited experience of the condition that the kind of ME which I and many others experience begins as a vicious spiral between behavioural stress responses and immune system. I cannot speak for all CFS patients but ME is far too pernicious for that explanation in my own case and I have much personal evidence that virally initiated immune disease is the primary cause of ME which then greatly increases vulnerability to secondary illnesses which can include vicious spirals involving stress as well as other kinds of factors. While these can be significantly reduced by careful management the primary cause cannot currently be treated, hence the Glass Cage effect where one is stuck between a rock and a hard place and full recovery is not achieved despite long periods of convalescence. (See also "Seven Distinct Subtypes" below for discussion of the different types of ME).

Another vicious spiral occurs because ME involves inflammations with low energy levels in cells which makes them prone to damage leading to nerve activation as mentioned above. Hypersensitive nerve cells use more energy not less, when nerves use a lot of energy anyway. When a cell is low on energy but using more energy it is more likely to be damaged leading to even more activation, lower energy etc etc. If Dr Cheney is right, this implies a potential vicious spiral where energy depletion with increased nervous sensitivity leads to more severe energy depletion and potentially nerve cell damage or death, leading to increased nervous activity etc etc. This matches my experiences pretty well and there is plenty of evidence that brain structure changes in ME, so it is my current working hypothesis to account for secondary neurological illness on top of immunological ME, which is what I believe the W.H.O. classifies as a neurological disease.

It strikes me that evolution would tend to find a way round the particular problem that nerve stress leads to a vicious spiral of nervous overactivity in an immune crisis and it may be that brain fog and the sense of fatigue that many people with ME (PWME) experience are the body's natural way of countering this and telling us it has made a deep physiological choice which means it is best if we use less energy and work with our immune system rather than struggle against it and damage our health in the process.

Unfortunately in ME the immune activation is chronic and while our workaholic modern industrial culture grudgingly allows for the need to deal with a bout of illness, the attitude towards chronic illness is even less patient and pressurises people, both those with chronic illness and those in positions of authority over them, to deny that it is really necessary to rest all the time when sometimes it really is. So people with ME are bound to experience conflict here which doesn't help and IMHO this cultural dimension may contribute to the problem, I feel it did in my case. People with ME need to be empowered to listen to their bodies and react as nature requires.

Secondary neurological illness.

The vicious cycle of energy depletion people with ME suffer is just the tip of the iceberg and beginning of secondary illness. Dr Cheney observed that over longer periods of time further interactions within the brain lead to the decrease of stress hormones. It is viewed as depletion but it may just be a necessary reduction which the body makes to try to keep nerve activity balanced, as it would counteract the two vicious spirals mentioned above by minimising both immunosuppression and nerve activation. We don't know enough at this point. However the clinical result Dr Cheney observed is that this makes people with ME mentally unable to deal with stress and complexity. This is like a double whammy of confusion on top of sensory hypersensitivity which magnifies the slightest disturbance out of all proportion whether you like it or not and leaves a proportion of ME patients with a condition comparable to shell shock. In addition there is evidence that physical changes in brain structure associated with longer term ME may result in cognitive impairment. Add to this combination physical pain and weakness caused by the same flu like immune reaction and you begin to get the picture, but it doesn't stop there.

Commonly reported is the subsequent destabilisation of midbrain functions causing problems with temperature control in the hypothalamus, emotional lability in the limbic system, blood pressure, balance and assorted neuralgias. These knock on affects in turn exacerbate the vicious cycle ongoing in the nervous system and if unrecognised can add major stressors from within the patient to those coming from the outside world, potentially pushing an ME patient's nervous system into very vulnerable states.

The degree of severity for any individual is variable in the first place but the good news is that good management can reduce the tendancy for  secondary illness to become more severe. Management in turn depends on the standard of advice available to patients which in turn depends on understanding the principles behind the illness. Here science has only scratched the surface but knowledge is not the only obstacle, there also needs to be a political will to offer good advice to patients and let them rest appropriately. Let us not forget how and why this basic decency was denied to patients for so long. To that end accurate diagnosis remains a priority for ME research.

Most patients, even when undiagnosed as I was for 10 years and left without advice, eventually learn from the nightmarish experiences and injuries secondary illness can bring about to manage their energy balance carefully. But this does permanent damage and it doesn't have to be this way. We can all benefit from giving appropriate moral support and recognition to empower ME patients to rest appropriately and so prevent more severe secondary illness while science seeks a cure.

How does that happen?

Something is harming the nervous system in ME and setting off the neurological overactivity spiral. It could be inflammation which is often reported by PWME in conjunction with allergic and autoimmune symptoms, probably as a result of the TH2 immune shift (see below), but there is more to it than that.

People with ME (aka PWME) are known to have increased levels of lactic acid in their brains (300% of normal according to Shungu's SPECT scans) and indicators of high levels of apoptosis (cell death) in their bodies, which is something Gow and Kerr have detected with their gene assays. These are indicators of physiological stress accompanying immune activation, corroborated by Klimas' analysis of cytokine activity in CFS.

As stated above, the problem with increasing nerve activity as a response to the harm done by ME is that it will produce even more lactic acid in the nervous system. Lactic acid is a sign of metabolic stress and normally increases when healthy people do exercise e.g. athletes doing endurance training. This is known as the oxygen debt and it arises from using food to make energy without using oxygen which is termed anaerobic respiration. Paying back the oxygen debt usually happens naturally when people stop exercising and get their breath back.

PWME produce lactic acid without exercising which suggests they are respiring anaerobically like an athlete even when they are not doing any exercise i.e. they feel like they have just run a marathon, all the time. This implies that mitochondria (cell organelles where aerobic respiration normally takes place,) are not working normally in ME and a paper from Dr Sarah Myhill et al on mitochondrial dysfunction in CFS supports this idea.

Why this should be the case remains a mystery. For my own part I contemplate the evolutionary perspective and wonder if mitochondrial shut-down might be an adaptation to stop viruses exploiting the concentrated energy that aerobic respiration produces around the mitochondria. Instead PWME's cells may be switching to the more distributed but less efficient energy produced by anaerobic respiration in the cytoplasm to deprive viruses of concentrated energy and slow down their reproduction to give the immune system an advantage. If this is the case mitochondrial shut-down with anaerobic respiration like this constitutes an immune defence mechanism, like running a temperature. In that scenario it wouldn't matter what strain of virus you had, as the ME, like running a temperature, comes from the patient's own body trying to beat the virus i.e. this might be the same response which makes people feel tired when they have the flu for example which is chronically activated in ME for some reason.

Seven Distinct Subtypes.

This may explain why Dr Jonathan Kerr found seven distinct subtypes of CFS which he regards as seven different diseases but each having comparable energy symptoms which leads to them all being classified as CFS. Which one of those seven is the real "ME" I just don't know, I think they probably all need new names. In my own case the cause is definitely immunological related to viral activity and that might be a defining attribute of one kind of CFS. But that situation may not be the same for everyone with CFS as mitochondrial function might also be impaired by factors other than immune (and maybe also auto-immune) diseases, such as toxicity. In addition different viruses and different combinations of viruses might produce different kinds of immunological CFS with different degrees of debility and prognosese. It seems likely there is much to be discovered about this.

Taking both papers together (seven subtypes and mitochondrial dysfunction,) illustrates the likelihood that CFS is not one disease but a new field of medicine with clinical causes for the several subgroups of patients being related to mitochondrial dysfunction but with different initial causes for different subgroups. In other words, although they may seem similar at first glance, you cannot put all cases of ME in the same basket. For now, when I write about ME I am referring to the immunological variety which I experience and I hope that anything useful I have learned might be broadly applicable to other subtypes, but I fully recognise that not all PWME experience the illness in the same way and will not find all I have learned about my situation applicable to theirs. I expect the current naming convention (or lack of one) to change as we learn more about the different subtypes, which should make things easier for everyone.

Anaerobic respiration would explain a lot.

Lactic acid production in ME patients implies intracellular acidosis. Dr Cheney has suggested the acidic products of anaerobic respiration inside cells are responsible for the well known problem of magnesium depletion in ME, because some of these like citrate can take magnesium with them when they are excreted.

Dr Cheney measured poor oxygen transfer in his patients (corroborated by more recent research) who were experiencing breathlessness and observed their blood becoming more alkaline (i.e. extra cellular or blood alkalosis) which he suggested was due to increased bicarbonate content. He hypothesised this was the body's way of neutralising the acidic products of anaerobic respiration and it strikes me it may also inhibit viral growth, constituting yet another anti-viral defence mechanism and I can see no reason why it should not do both at the same time. Bicarbonate in the diet is potentially helpful and probably should not be avoided entirely however it is well understood that blood alkalinity interferes with oxygen transfer making it less efficient and in ME this exacerbates poor aerobic energy production which constitutes another vicious cycle and a distinct aspect of secondary illness in ME. The blood chemistry involved is related to the problems caused by hyperventilation, though in ME blood alkalosis is not caused by hyperventilation. In my opinion this might explain why some PWME experience a "toxic" feeling of anoxia and breathlessness which cannot be relieved by taking deep breaths, indeed that can make it worse and it also gets worse when one has excess alkaline drinks or foods with bicarbonate in (like certain mineral waters, certain cakes and confections. In my own experience this can sometimes be exacerbated by ingesting salicylate containing foods so that salicylate levels rise above a certain threshold, as this can also inhibit oxygen transfer (and for some people can also trigger nasal polyp inflammation which adds to breathing difficulties). Proper management is as ever, a question of balance.

The upshot of all this is that many symptoms of ME and generalised CFS are explicable as the result of a prolonged and systemic bias towards anaerobic respiration in patients. This pathological kind of fatigue can lead to nerve activation which can then result in a negative spiral and this is why (as ME patients typically learn from experience) there is a need to restrict both physical and mental activity to prevent more severe illness.

( ☼ It is worth noting that immune mediated ME also involves symptoms such as an allergic tendency and recurrent viruses, which Dr Cheney recognised probably result from a TH2 shift. His description matches my own experience and explains why immune symptoms so often accompany the plethora of additional ME symptoms. This is a very important insight and explains another major cause of suffering for ME patients and mystification for general practitioners but as a topic is distinct from neurological illness so I will limit discussion here.)


From my personal experience I can say that when I first got ME it felt as though my brain began to work differently from the way it had before. The disturbance seemed to affect my entire nervous system and subjectively it spread to every part of me, changing who I was subtly but profoundly. I experienced changes in vision and everything seemed painfully bright and more colourful. Odd events like sleep paralysis on waking and lucid dreaming, which had not been a feature of my sleep before, began to occur more frequently, almost regularly. I also began to suffer from hyperacusis (sensitivity to sounds) and was much more sensitive generally, including my awareness of other people. I was less able to clear my mind of the impressions other people made on me and forget them once they were no longer in my presence, the perception of others would linger far longer and ramify more deeply in my own consciousness compared to previously. Added to which I was much more easily confused and upset, clumsier and accident prone.

Fog and Quicksand.

As a consequence of the evidence and my experiences I see the cognitive dysfunction most PWME experience as part of a systemic dysfunction of the nervous system rather than a localised response, affecting most if not all mental faculties. As I mentioned above the fogginess may be a protection mechanism against psychosis, to damp down nervous overreactions which might lead to psychological or neurological damage. It follows you should not try to push through this, it will only make things worse. I say this having tried and suffered as a result.

The whole situation is counterintuitive compared to "normal" life without this kind of disease. You can't clear your mind or get things done by trying harder. Instead, like someone stuck in quicksand, you have to stop struggling as that only drags you in deeper. You have to stay calm and float to the top. If you try harder you only increase the amount of lactic acid in your system, use up precious energy reserves which can end up in an energy crisis and cause a relapse.

Besides this when fighting anything including ME you release stress hormones which temporarily suppress the immune system. This is not helpful when you consider viruses probably cause ME. In addition, some viruses are triggered to replicate by stress hormones, as they have evolved to take advantage of the opportunity which human stress represents to evade the immune system, to reproduce and transmit themselves to new hosts. As a result ME related immune reactions can be more severe after stress, in addition to the depletion of energy and increase in products of anaerobic respiration. In other words, if you push, you crash.

So you have to rest and not push. This can be amazingly difficult and frustrating in a culture dedicated to pushing people to achieve. For willing participants it can seem disheartening if one is used to the emotional rewards of activity and can no longer enjoy the satisfaction of the accomplishments one used to take for granted. This restriction combined with the dismay of other people one might have to disappoint can make adjusting to ME a doubly difficult experience, undoubtedly more stressful than a house move or a divorce or even grieving a bereavement, which I mention since these are said to be the most serious stresses that most people will normally experience. This stress of course increases the severity of the syndrome, but the long and the short of it is that while there is no cure, one has to adjust priorities as well as activity and find one's peace anew in a gentler pace of existence because high levels of activity are simply not sustainable when you have ME.


Everyone has to find their own way through, but the bottom line is that if you have ME and you try to push, you crash. Most people I know with ME tend to compromise and sometimes endure a crash in order to get something important done in the short term. But it is not advisable to push it too far, as you can damage yourself both mentally and physically.

A comparable example is the case of athletes who are advised not to train while they have a virus, as it can be damaging to the heart and muscles. People with ME seem to be in a similar situation, only there are variations among patients and its likely there are several related but different syndromes all being called ME at the moment. For some it is a perpetual illness while for others the condition can eventually respond to convalescence with some degree of recovery. Either way, you have to take it gently to recover and to avoid doing damage to yourself and to get the best out of the life you have and survive until treatments are found, which one hopes, with good reason, are probably only a matter of a few years away.

To pace effectively its helpful not only to moderate physical activity but also to try to stay balanced emotionally and psychologically, stay calm and not get into stressful situations or cycles of thought. Its not always easy when your nervous system is overactive.

Useful Supplements.

Living with ME is in my view all about keeping an even keel which includes balancing your mind as well as body. But what I have learned from ME is that my mind is part of my body, what happens to my body effects my mind, especially what I eat but also infections and immune reactions. While this is a liability in certain circumstances it is also potentially a tool which can help.

To that end there are a few things that one can take to change the situation and help calm an overactive mind, which are appropriate for ME patients.

Magnesium: Is one of the most important. It naturally calms the nervous system and counteracts oversensitivity to an extent. It is commonly reported that PWME are low in magnesium. This is not surprising if it is true as Dr Cheney has suggested that some of the acidic byproducts of anaerobic respiration (marathon runners and ME patients alike) take magnesium ions with them when they are excreted. As I understand it, its important to get enough magnesium to assist this process and also other critical bodily functions which depend on magnesium. However there are a couple of catches.

Firstly magnesium supplementation displaces calcium which can lead in the long term to osteoporosis and weakening of bones and joints. Since living with ME is all about the long term you cannot afford to ignore this and must take calcium supplements if you are taking magnesium supplements.

The second problem with magnesium is that it is hard to absorb in large quantities and in my experience it is often quite tricky to find a supplement which can provide it without disturbing the osmotic balance of the gut and inducing diarrhoea. While epsom salt (magnesium sulphate) is very helpful in bath water as it is absorbed through the skin and a little pinch in drinks can be helpful and harmless, taking it internally in higher concentrations is not so good and quantities approaching one or two teaspoons in a glass of water will usually induce diarrhoea in 3 to 6 hours and lesser quantities can still loosen the bowel content quite a bit. The same goes for magnesium citrate.

However I have found magnesium glycinate does not cause this kind of problem though it is best if buffered with an acid buffer to balance out the pH. It is slightly alkaline and since PWME tend to have problems with blood pH (which Dr Cheney considers is usually too alkaline in PWME) this can cause problems of its own unless buffered. Another one worth mentioning is magnesium orotate which is pH neutral and does not seem to cause a problem.

Taurine: is a simple supplement which is a natural component of bile which protects cells from oxidative stress and stabilises membranes, thus reducing damage and it also calms the nervous system. Best taken before bedtime when required as it can assist other methods of calming the nerves to stop a crazy patch in its tracks so you can get some sleep and recover. It is available at sports supplement stores. It is completely innocuous though it tends to result in a slightly firmer stool so one should moderate doses accordingly. It works well as a one off dose.

Melatonin: I find helpful for getting to sleep at night. It also helps to reset a disturbed sleep cycle and people commonly use it for jet lag. It is very important to get good sleep in ME because this is when the body heals itself and among other things it is when growth hormone is released which supports healing and immunity and also the activity of the liver which is important in digestion and cleaning our blood.

Not everyone finds they respond to melatonin in quite the same way but fortunately for me and a majority of people, one 3mg tablet is enough to make the difference between another sleepless night and a full night of sleep and this makes the difference between a downward spiral versus a steady convalescence. While that is not the same as recovery, it is better than getting worse. Melatonin does not cause the same interactions as other drugs, such as tricyclics like amitriptyline which can disturb heart function, because it is a natural hormone we have evolved to process. A dose of melatonin just gives a little boost to levels of naturally occurring melatonin in our brains, enough to help us zonk out.

In the UK it is a prescription drug. If you have your doctors agreement you can get it online as well. You should not take it if you are driving in the near future, allow at least 6 hours.

Triple Whammy: I find taking all three of magnesium, taurine and melatonin has a more beneficial effect than any one on their own or the sum of the three taken individually.

Zinc: when neurological difficulties are associated with signs of allergy I find zinc has a beneficial effect, reducing the allergic tendancy a little and calming nerves.

B Vitamins including B2: aka riboflavin, this vitamin supports the activity of enzymes which remove stimulants from the blood. Having tested this myself quite a bit I am adding it to the list as it is very real even if I dont quite know how it works. If you have brain buzz due to something you ate B complex including B2 is the first thing worth taking to help and it also helps with calming natural stimulation such as that which is due to adrenalin etc. See the discussion of amines below for more information.

Foods worth avoiding.

Caffeine: top of the list, but it is very much an individual thing, some people don't seem to have a problem with it and others sometimes have a problem depending on the fluctuation of their illness. Others like myself avoid it entirely because it has harmful affects. This is understandable since it stimulates the nervous system and could potentially set off a vicious cycle of overactivity and fatigue, though the situation may be more complicated than that as it may involve histamine content and/or release and the allergic immune shift which may be behind ME in some patients.

Amines: of which histamine is but one are very common in our foods. Not all amines are equal and according to advice received from Professor Jonathan Brostoff (author) and subsequently in my experience, some of them act as stimulants on the nervous system in a manner comparable with caffeine eg tyramine. This is obviously a problem if you have an overactive nervous system in the first place.

Coupled to this PWME tend to have reduced liver activity for a number of reasons and this means amines are not cleaned up as quickly as they should be (see also the MAOi subheading below). So amines can build up and some PWME tend to be sensitive to these in a way which exacerbates mental overactivity. For those affected it is well worth being careful about what types of food you eat and when.

Some foods naturally have a high amine content, the avoid list is the same as the avoid list for those taking medical MAO inhibitors (see below). Many foods tend to produce amines as they age and deteriorate under bacterial action so as a general rule fermented foods and aged foods and foods past their sell by date will have high amine contents. If it disturbs your sleep to eat strong cheese or spinach for example, now you know why. Individual sensitivities seem to be personal so its a question of recognising foods that cause you mental activity and working out how to manage them. e.g. Avoid them in a bad patch and also be aware that accumulated small doses which would not normally cause a problem on their own can add up to cause a problem.

It is worth adding that you can theoretically support the activity of the enzymes which get rid of amines (monoamine oxidases or MAO's) by taking B vitamins, in particular B2 aka riboflavin, see link and FAD. Most B vitamin supplements should offer plenty of this. I have tried using B vitamins including B2 as a therapy for food related mental stimulation and I have found it helpful, depending on the type of stimulating food involved.
MonoAmine Oxidase Inhibitors - MAOi's : as the name suggests these inhibit monoamine oxidases or MAO's. The activity of MAO's matters to PWME because they not only break down amines (as mentioned above) peripherally in the cells of the body by oxidising them, they also break down our natural stimulating hormones like adrenaline which, if they are not broken down like this, can build up and create high levels of stress and anxiety by overstimulating our nervous system and gut activity and suppressing our immune system. Obviously imbalance in any hormones is not good.

Some relatively common foods and spices contain naturally occurring MAO inhibitors (MAOi's), so one needs to be aware of these as our livers may not clear them up as quickly as normal and doses may accumulate (eg nutmeg, tumeric, onion, olive oil, black pepper which contain myristicin, kaempferol, quercetin, curcumin and piperine). A combination of high amine foods and MAOi foods can be double trouble which lasts for days, as the dual dose can lead to high levels of stimulating amines and also prevents the natural cleanup method from working properly and also allows the build up of adrenergic stimulating hormones, which can lead to serious head-buzz. Which can be very difficult to live with if you have no idea of what is happening to you. Here is a google page with lists of foods to avoid when taking artificial MAOi's, the same logic applies when you want to avoid mixing natural MAOi containing foods with high amine foods.

MAO's occur as type A and type B. Type A remove food derived amines and both type A and B remove natural hormones. Different MAO inhibitors can target different types of MAO. In my personal experience some MAO inhibitors can result in mental overactivity and IMHO may play a part in IBS. The pattern I have noticed is that too much MAOi can cause the squits and its sudden absence when you are used to its presence can cause constipation. So again its a question of balance and consistency. I was surprised to discover foods like olive oil and pepper contain MAOi's. But it makes sense now I know. I find a little pepper on my food when necessary can help move things along, for example. But when I deliberately stopped eating MAOi's I was constipated for a while until my body adjusted.

It is also worth noting that low MAO-A activity (i.e. leading to high levels of amines) has been experimentally associated with increased levels of aggression. It strikes me this might contribute to emotional lability in people who get a bit grinchy, as I know I do, as part of their ME symptoms, so its one to watch out for IMHO. Also of interest is the fact that MAO's are predominantly found in mitochondria, the organelles where aerobic respiration normally takes place. Its probably not a coincidence that they seem to show (in my personal estimation) reduced activity in my experience of ME but it is probably a secondary 'knock-on' affect rather than causal.

Nutmeg:  believe it or not contains a psychotropic mix of MAO inhibitors, which is stimulating, alters mood and in my estimation contributes to emotional lability in even small quantities. What some readers may not realise is that nutmeg is a common ingredient in premade foods containing spices such as many brands of premium and budget sausages. If you find yourself getting stroppy after a few sossys now you know why. Another one to avoid if it causes you a problem.

Nightshades: since I first wrote this I have discovered that I have a real problem with nightshade family foods, including potato, tomato, eggplant, sweet and chili peppers, goji berries, huckleberries which cause an increasingly bad reaction for me involving malaise and mouth ulcers. It took a while of keeping a food diary to cotton on the real cause. Nightshades are food plants which are relatives of the deadly nightshade and so produce small amounts of toxic solanine molecules which can end up in food products obtained from them in varying concentrations. These are usually handled by the digestive system, liver and immune system without harmful affects in healthy people but appear to be enough to cause a problem for someone with a weakness in that regard. The result of eliminating nightshades from my own diet has been a measurable reduction in cell free DNA in blood tests which correlates with the mechanism of action of solanines. Unfortunately this didn't reduce the CFS/ME itself which suggests that as with other food intolerances the difficulty in tolerating nightshades is a symptom of long term ME and not a cause. For those who have food intolerance accompanying ME, eliminating nightshades and other potentially toxic foods may be worth researching and testing.

Personal: on a personal note, I suffered for many years (1986-1996) with undiagnosed ME involving diagnosed and unusually severe recurrent virus, severe raised allergies and high levels of mental overactivity and cognitive problems including serious perceptual dysfunction which I was lucid enough to know were very wrong but which I was powerless to prevent. After diagnosis in 1996 and since understanding the above I have been better able to influence the secondary symptoms and break the cycle of mental and physical overactivity which once lead to push-crash and serious relapses.

For this reason I think it is very important that diagnosing ME, which some doctors percieve as a stigma and dead-end diagnosis, is seen as a positive step because with early diagnosis of ME and a sincere attitude there is much that can be done to assist convalescence and prevent deterioration today. Even a tentative diagnosis would have been much more helpful to me than the wall of silence I initially encountered (for ten very difficult years) despite consulting several mainstream medics, because diagnosis constituted a form of recognition which gave me licence to behave appropriately despite the conflict this created with other priorities. Prior to diagnosis I had no choice but to attempt to continue normally, to my detriment.

Recent research has done a great deal to improve the credibility of the diagnosis by showing the reality of the ilness involved and further research will hopefully provide effective empirical tests and therapies to assist doctors in making effective diagnosese and offering helpful treatments with appropriate advice.

Future advances aside, I hope that what I have written above can help a few people to live more comfortably with ME and help inform anyone who chooses to care for someone with ME.