Science for Patients: Dr. Charles Shepherd (Honorary Medical Adviser for UK ME Association) 2014 interview with the Dutch ME/cfs Association : Question & Answer Session

Question & Answer Session with Dr. Charles Shepherd

Friday 28th February, 2014

Question: You are saying that it is uncertain as to whether there is an actual inflammation within the brain and the spinal cord. I think most (99.9%) of the patients didn't get any testing for that. So how can you say there is no inflammation of the brain? I myself feel it every day.

Answer: I am one of the few doctors who is involved in post-mortem research, and the results from a small number of these post-mortems have been published. The bottom line here is that encephalitis (widespread inflammation in the brain) has not yet been found in these PM's. Neither has widespread inflammation in the spinal cord been found.

What we have found is dorsal root ganglionitis - inflammation of tiny nervous structures that lie just outside the spinal cord in the peripheral nervous system and are responsible for processing sensory information like pain and touch.

Question: It can't be found on scans?

Answer: You can make a diagnosis of an "acute encephalomyelitis" through a combination of clinical history, examination findings and abnormalities on neurological investigations, including scans. But you do not see this combination in people with "ME/CFS".

Question: You are saying in your video using ‘opathy’ takes the "heat" out the situation - of course it does, for it still leaves the diagnosis wide open to how you want to choose to interpret it : mental or physical. Because the word ‘opathy’, exactly like CFS, has a dual interpretation : it can be interpreted physically and/or psychiatrically. So how do you make clear which one is which?

Answer: I obviously have considerable sympathy with people who believe this illness should be called "myalgic encephalomyelitis" as my own illness was triggered by a "chickenpox encephalitis". 

But in our current state of knowledge I do not believe that "myalgic encephalomyelitis" is a correct way of describing the pathology. 

This is why I have advocated the use of the term "myalgic encephalopathy" - as this is consistent with the abnormalities that have been published

Question: How can the large differences between patients be explained? Why are some patients bedridden, while others still are able to work and have some social life?

Answer: Nobody has a satisfactory answer as to why some people with "ME/CFS" improve, others remain more static and variable, whereas others become severely affected. Partly because so little research has been done on people with severe "ME/CFS".

The MEA has funded research into factors that may be involved in severe "ME/CFS" and the M.E. (blood sample) Biobank at UCL in London that we are funding is collecting blood samples from people with severe "ME/CFS" to see if there are any characteristic differences in severe cases.

Question: You said you catched M.E. from a patient. Is M.E. contagious?

Answer: I caught chickenpox virus from a patient of mine who had shingles (same virus). The CP virus then triggered my M.E. It is the triggering infection that can be spread to other people. 

There is no evidence that "ME/CFS" can be passed from person to person.

Question: So you mean that M.E. is the outcome of a disease instead of a disease itself. It can have numerous causes?

Answer: A large number of viral infections, including hepatitis, can trigger "ME/CFS". It can also be occasionally triggered by non viral infections (e.g. salmonella) and other types of immune system stressors such as vaccinations. I have a large collection of people with "ME/CFS" who predate the onset to a vaccination - health workers following hepatitis B vaccine in particular.

Question: And is the trigger that causes the M.E. responsible if you get mild or severe M.E.?

Answer: Think of "ME/CFS" as a three stage process involving 3Ps. Genetic factors that Predispose to its development. Immune system stressors (e.g. infections) that Precipitate the illness, 

And a complex range of resulting abnormalities involving brain, immune system, endocrine system that Perpetuate the illness.

Question: Are there perspectives in the development of a medicine or are the researchers groping entirely in the dark where the disease is lodged in the body?

Answer: "ME/CFS" is perpetuated by a complex interaction between abnormalities involving brain, muscle, endocrine/hormone system and immune systems. Until we understand more about these abnormalities and how they interact it is going to be difficult to find a drug treatment that deals with the underlying disease process.

One promising lead which you may have heard about is a drug called Rituximab. This is normally used to treat people with lymphoma - a type of cancer. But some Norwegian doctors have found that it appears to benefit a subgroup of people with "ME/CFS". The reason for this may be due to the fact that Rituximab dampens down a part of the immune system that produces autoantibodies - harmful antibodies that can attack/damage healthy tissues and organs.

Question: Are you cured from M.E. or are you coping? And what is your secret?

Answer: I am not 'cured' of this illness. Like many people I see I have made a degree of recovery but have now hit a 'glass ceiling' whereby I function at around 60% to 70% of my normal healthy self - with occasional ups and downs, often triggered by an infection.

I don't have any secret solution. I don't take any drugs or supplements. The main factor in achieving a degree of recovery has been learning how to correctly pace my mental and physical activity and (I know it's not easy) staying positive. Also having good support from family and friends

Question: What do you think of the use of valganciclovir?

Answer: There are certainly some interesting results from small clinical trials involving valganciclovir and I have been over to America and met one of the doctors using valganciclovir. I have also had a meeting here in the UK with the drug company involved to try and persuade them to set up a clinical trial - but no luck so far.

What we need are some larger clinical trials carried out by other clinicians to see if this drug might be a safe and effective option for a subgroup of people with "ME/CFS", possibly those who have evidence of reactivation of HHV-6 infection coupled with 'infective' type symptoms.

Question: Yes I have heard of it, but it can be dangerous too. Is it possible to try it ? And how do I get it if it is possible?

Answer: Here in the UK doctors would be very reluctant to prescribe an antiviral drug like valganciclovir - unless there was a very good reason for doing so. This is because these drugs can have quite serious side-effects. I suspect that a similar situation exists in other parts of Europe.

Question: Is there any treatment with medication you would advise ?

Answer: In our current state of knowledge I am reluctant to either use or recommend what are best described as speculative forms of drug treatment. Drug treatments do, however, have an important role in helping to relieve symptoms such as pain, sleep disturbance and irritable bowel type symptoms - as well as depression if it occurs.

Question & Answer Session with Dr. Charles Shepherd

Friday 14th March, 2014

Question: I'd really like to know how Dr. Shepherd is at the moment in terms of his own M.E. - and what helped him!

Answer: Like many people with M.E.. I have hit a 'glass ceiling' where I function at about 60% to 70% of what I regard as ‘normal self' for most of the time. Having tried a wide range of drug treatments over the years I'm sorry to report that I didn't personally find any of them to be effective.

Question: That is my experience too. But what about the key question of whether to exercise, rest, or do some smart combination of both?

Answer: The one thing that has been of more help to me than anything else has been learning to properly pace my mental and physical activities. Trouble is, this has to be done through a combination of personal trial and error and help from a health professional who knows about "ME/CFS" (and is not easy to find!)

Question: Have you ever been bedridden? or at least couch?

Answer: My illness started with a chickenpox encephalitis - which I contracted from one of my patients with shingles - so I did have a period of severe illness (in bed) early on. But apart from occasional relapses, normally triggered by an infection, I am now vertical and mobile for most of the day.

Question: Did you resent him/her for it? ;) and scary occupation you have...

Answer: Doctors do sometimes pick up nasty infections from their patients - that's life!

Question: Dr. Shepherd, in the interview you state that there are no confirmative tests for M.E. Others maintain that they have such tests (e.g. Sarah Myhill and Kenny DeMeirleir). Why, do you think, is there such a difference of opinion among experts?

Answer: I wish we had a biomarker or test (blood, neuroimaging etc) that could confirm that someone has "ME/CFS" but that is just not the case at present. I know that some of my colleagues believe that they have such tests - but this view is not shared by the majority of docs working in this area.

Question: What about De Meirleirs H2S-test?

Answer: I have to say that I am not yet convinced by the validity of the H2S test in relation to "ME/CFS". It is not used here in the UK.

Question: In your talk of 25 February (36), you proposed a new name instead of M.E. or CFS: myalgic encephalopathy, in order to reduce the confusion about the name. But, given the fact there is a lot of research, would it not be wise to wait with a new name until the "final" cause(s) of this illness have been found? A third name can even increase the confusion.

Answer: I proposed a new name - myalgic encephalopathy - at a time when there was tremendous pressure on the medical establishment to get rid of myalgic encephalomyelitis here in the UK, where many doctors just will not use the term M.E. because they do not believe it reflects the pathology. 

Question: If you compare the results of the different researches to "ME/CFS", in what direction do you suppose the cause and treatment of this illness will be found?

Answer: My best guess is that we are going to find the answers through a better understanding of what is going wrong in the brain and nervous system. This is because M.E. involves a combination of central (i.e. brain) and peripheral (i.e. muscle) fatigue and as central fatigue is a dominant feature in a number of other neuro illnesses (e.g. M.S., Parkinson's) I think we are going to find some interesting answers through collaboration with other neurodiseases.

Question: Do you still support the name myalgic encephalopathy, or are you now convinced that M.E. involves CNS inflammation?

Answer: I still support and use the term myalgic encephalopathy in preference to myalgic encephalomyelitis. Whilst I do not believe that M.E. involves widespread inflammation in the brain and spinal cord I do believe that neuroinflammation plays a role - and this is one of the MRC research priorities here in the UK. 

I am one of the few docs involved in post-mortem research and our group have published preliminary results supporting a role for neuroinflammation in "ME/CFS" (i.e. the presence of dorsal root ganglionitis in some cases). 

If you remind me on MEA Facebook later I will give you the reference.

Question: In terms of neuro research are we going to find damage or an ongoing infection do you think?

Answer: In relation to neuro research I would be surprised if we find evidence of on-going infection or significant structural damage. If this was the case I think it would have been shown by now. What is encouraging is that new forms of neuroimaging mean that we can learn much more about brain activity, blood flow etc

And along with info on brain chemical transmitter activity this means that we could get a better understanding of the underlying disease process and effective forms of treatment

Question: Proof of Post Exertional Malaise, PEM, seems to me to be the single most important thing we can achieve to validate M.E., practically for patients & also prevent harm from draconian exercise therapies.

Answer: PEM is a cardinal clinical feature of of "ME/CFS" and it is surprising that it has not been more thoroughly researched. The MEA is funding Prof Jo Nijs (Belgium) and Dr Lorna Paul (Glasgow) to carry out a study that will be looking at the role of immunological and neuroendocrine factors in the causation of PEM.

Question: Do you think the latest findings regarding the role of latent EBV (Loebel et alea) will help explain the pathogenesis of M.E.?

Answer: I suspect that findings relating to reactivation of EBV and HHV-6 viruses are going to be markers of underlying immune dysfunction. You may have seen that the UK M.E. Biobank, which the MEA funds, has been given a $1.5 million grant from NIH to carry out a three year study to look at this aspect.

Question: Dr. Shepherd do you agree with the majority of British doctors, NICE etc and see your M.E. as a pyschiatric or psychological condition?

Answer: I would say that most UK doctors view M.E. or "ME/CFS" a a combination of physical and psychological. 

A minority view it as purely physical and another minority view it as purely psychological. A small number still do not believe that it exists as a clinical entity. 

Question: Does current VO2 exercise testing contain too much of a subjective component atm to be accepted as a biomarker? Because otherwise, it would really help folk to be able to demonstrate that M.E. isn't 'all in the mind' (as was again put forward, w/o evidence, in Spectator today). Sorry, answer other questions first.

Answer: I went to a lecture given by Prof Van Ness a few weeks ago and my view is that the VO2 test is a potentially very interesting and useful finding - but it does need replicating by other independent research groups. We also need results from people who are deconditioned or have a degree of cardia-respiratory failure.

Question: I don't know about anyone else here but I've still to meet an NHS GP who gives me any clear indication that they believe my experience has any pathology in the body, they have ways of indicating that

Answer: Yes, it does. Are you aware of the MEA Guidelines booklet I produce reach year - 52 pages of fully referenced (over 300 key references) info on diagnosis, tests, management and key research findings. We can send a free copy to your GP - see MEA website or Facebook for how to do this.

Question: "Replicating by other independent research groups" - Can the MEA do this?

Answer: Yes, a vital part of the research process is replicating other people'e research. This is why we need further trials into Rituximab. The MEA Ramsay Research Fund is happy to consider such proposals and we would certainly be interested in one relating to the VO2 exercise testing.

Question: What is your opinion about cognitive behaviour therapy and get? Is it possibly helpfull, not helpfull or even destructive?

Answer: The form of activity management that I advocate is pacing - the problem with GET is that it is too inflexible and fails to take account of stage and severity of the illness. In patient UK surveys around 50% of people report being made worse by GET.

Question: What is your opinion of something like the Lightning Process?

Answer: I have been very critical of the Lightning Process and have reported a number of LP practitioners to the regulatory authorities here in the UK. The MEA position on LP is summarised in the Alternative and Complementary treatment section on the MEA website.

Question: Have had M.E. for 15 years and have been on calcium channel blocker for increased breathlessness for some years. Syndrome x has been mentioned - is this seen often with or even associated with M.E. Currently seeing immunologist at Newcastle and clinic for M.

Answer: Yes, syndrome X has been associated with "ME/CFS". As you are in the UK I suggest you order a copy of the MEA purple booklet - where it is discussed in the research section.

Question: Also low dose naltrexone (LDN) has gained a little popularity. I've found it great for my strange neurological morons such as muscle solidness, spasm, twitches, involuntary leg jerks… yet there seems to be little awareness about it. Also gave me incremental improvements in functioning. I just thought I'd make it known, that depending on your symptoms, there could well be an existing medication that's good for M.E., as well ad other conditions. But typically it's on private prescriptions.

Answer: There is quite a lot of anecdotal support for naltrexone here in the UK but some people also report that it has made them worse, In the absence of results from a proper clinical trial this is not a drug that I would use or recommend in our current state of knowledge.

Question & Answer Session with Dr. Charles Shepherd

Friday 28th March 2014

Question: My "ME/CFS" was probably triggered 13 years ago due to being pregnant. After 1 1/2 year I felt better, but always very tired. It never went away. Inflammations. Is this also known as a trigger for M.E.? What do hormones have to do with it? Now that I am 44 years old, there is a new inflammation of M.E. since 1 year. Do hormones maybe play a role again?

Answer: A number of what we call immune system stressors can trigger "ME/CFS" - one of which is pregnancy. The explanation probably involves a combination of immune system and hormonal changes that occur in pregnancy. Also interesting to note that a significant number of women with M.E. improve when pregnant.

There is also some research information (paper in The Lancet from gynaecologists Studd and Panay) to indicate that changes in female hormone patterns can affect "ME/CFS" symptoms.

It's referenced in the MEA purple booklet: Studd J and Panay N. Chronic Fatigue Syndrome. Lancet, 1996, 348, 1348.

Question: How do pregnancies usually progress for women with "ME/CFS" ? How common is it that there is an improvement? And does this improvement last after the pregnancy? And are there risks?

Answer: Most (but not all) women notice an improvement (sometimes quite significant) during pregnancy. Unfortunately, many then return to their normal state of "ME/CFS" once the baby is delivered and life gets more physically and mentally demanding! Are you involved in getting pregnant when having "ME/CFS" ? A good review of what happens to women with "ME/CFS" during pregnancy you’ll find in this paper - Schacterle RS and Komaroff AL. Archives of Internal Medicine, 2004, 164, 401 - 404.

Question: In your college you mention several possible causes of "ME/CFS". What do you think of the role of ongoing stress? Can it be a cause of "ME/CFS" ?

Answer: To clarify: I am saying that there are a number of factors that involve a stress on the immune system response which appear to be involved in triggering "ME/CFS". 

Infections (viral more than bacterial) are the most common - but other triggers include vaccinations, trauma, operations, pregnancy and pesticide exposure. 

Mental and/or physical stress can be an important factor in both helping to trigger "ME/CFS" when, say, you have an infection. On-going stress can also be an important factor in preventing or delaying any natural recovery process that may be taking place. And this is why stress management (through relaxation, meditation etc) is an important part of management if/where stress is playing a role in maintaining the illness.

Question: In your college you mention a large number of possible causes. How is it possible that so many various illnesses all can cause the same illness M.E. in the end?

Answer: There isn't a single underlying problem in "ME/CFS". The illness is maintained by a complex interaction involving a number of brain abnormalities plus abnormalities in the immune system, hormones and a biochemical deficit in the way the muscles produce energy.

Question: Do I understand well that physical stress has the same impact on the brain as other stress, such as fright?

Answer: There are similarities and differences as to how the body responds to physical and mental stress. With mental stress part of the nervous system called the autonomic nervous system goes into overdrive with the production of chemicals (e.g. adrenaline) that produce symptoms such as raising the pulse rate and sweating.

Question: Is it possible that the hormonal changes during the menopause cause less bowel problems due to "ME/CFS", such as chronic diarrhea?

Answer: I don't think you can easily link hormonal changes during the menopause to the very common irritable bowel type symptoms that occur in "ME/CFS". This is more likely to be due to a disturbance in a part of the autonomic nervous system that controls the emptying activity in the bowels. Changes in a chemical transmitter called serotonin may also be involved in the irritable bowel type symptoms that often occur in "ME/CFS"

Question: Do the hormonal changes during the menopause commonly cause no changes in "ME/CFS" symptoms?

Answer: Hormonal changes that take place during the menopause can cause a number of symptoms that also occur in "ME/CFS" (e.g. sweating, fatigue, problems with memory and concentration) So it is quite common to find that women going through the menopause report an exacerbation of their "ME/CFS" as well.

Question: What is the SMILE-trial actually about?

Answer: The SMILE trial is a UK trial that has been looking at the feasibility of using the controversial Lightning Process as a form of treatment for young people with "ME/CFS". The MEA opposed the trial for a number of reasons and argued that if a trial was going to take place it should involve adults, not children.

Question: Is the main question: where do the abnormalities start, in the brain or peripheral?

Answer: I think the sequence of events is that a triggering infection causes an abnormal immune response (possibly involving over-production of chemicals called cytokines) which then affects various parts of the brain and the brain-hormone systems (especially hypothalamus and cortisol production)

Question & Answer Session with Dr. Charles Shepherd

Thursday 10th April, 2014

Question: Can you tell me exactly what the problems are with the mitochondria?

Answer: The mitochondria, which are the batteries in cells that help to produce chemical energy in the form known as ATP are not doing so in an efficient manner. It is possible that the initial viral infection, or other immune system stressor, has affected the way they work.

Question: In the overall mitochondria or just those of infected tissue?

Answer: Mitochondria are present in almost all tissues in the body - they are not just producing energy in muscle cells. Liver has a lot as well - but we have concentrated research efforts in relation to muscle mitochondria.

Question: Are the problems with mitochondria measurable/provable?

Answer: Yes, you can look for evidence by taking a sample (biopsy) of muscle and looking for structural changes under the microscope. Professor Mina Behan has done this - including using some of my own muscle!

You can also look at changes in the way chemical reactions are taking place, including the excessive production of lactic acid, using what is called magnetic resonance spectroscopy (MRS). This has also been done on my own muscle - with results published in The Lancet!

Question: Will there be a test available in the near future to show one has problems with the mitochondria?

Answer: As I said earlier there are tests available - electron microscopy and MRS - that can show abnormalities in the mitochondria, or biochemical changes, that are consistent with mitochondrial dysfunction.

Question: I understand the tests are there for research purposes. But we need them to be on the common laboratory list of our GP's so they can ask for it.

Answer: I'm afraid these are research based investigations at present. Until the situation becomes more clear, and mitochondrial dysfunction is accepted by the wider medical profession, these tests are not going to form part of routine cynical assessment/diagnosis of "ME/CFS".

Question: Is there a linear connection between the severity of the problems with the mitochondria and the severity of the fatigue, pain and other complaints?

Answer: The research that has been published so far has only involved small numbers of patients, and tended to avoid those with moderate or severe "ME/CFS". So we don't have any clear evidence of a link between severity of findings and severity of symptoms.

Question: Is there a link between the increasing of the variable personal boundaries, the fatigue attacks, the muscle fatigue and the shortness of breath, dizziness, headache (orthostatic intolerance)?

Answer: Yes, all these problems are probably interlinked. I went to a really good physicians workshop on OI (causes, investigation, self-management, drug management) given by Professor Peter Rowe at the IACFS conference in San Francisco. I am currently writing this up for a website report.

Question: How come that the fatigue/exhaustion sometimes takes place a day or 2 days later? (I find this most unfair of "ME/CFS", one moment you're busy, and a few hours later or the next day it turns out to have been too much again anyway).

Answer: The reasons why people have post-exertional malaise and symptom exacerbation are complex and were discussed in some detail in San Francisco. They probably relate to a combination of metabolic/chemical, immune system and possibly blood flow changes to skeletal muscle.

Question: For very severe cases, pacing is nearly impossible because they exceed their limitations by doing almost nothing. I'm almost always in PEM and I get worse and worse. Do you have any suggestions how severe M.E.-patients can try to stop deterioration? I can understand if you don't have answers.

Answer: I'm sorry but it's not really possible to go into how pacing should be applied to people with severe "ME/CFS" in just one line…The bottom line is that any sort of physical and mental activity has to be very low grade (keg passive exercises with a physic) and increased at a very gradual rate.

Question: But why is PEM sometimes 2 houres and sometimes 2 days later?

Answer: The simple answer is that we just don't know. The research that Professor VanNess et al has been doing (the double dose exercise test measuring Vo2 max) is shedding some light on what may be happening. The MEA is funding Prof Jo Nijs to carry out research into the cause of PEM.

Question: Why do you not mention HPV vaccination as a trigger for "ME/CFS" while you’re mentioning many other vaccinations? Don’t you known any cases that HPV is the trigger? Or are there other reasons or don’t you acknowledge that HPV vaccination may be a trigger?

Answer: I have covered HPV in more detail on the YouTube video page for the mitochondria video (n39). I have a number of cases where HPV appears to have triggered "ME/CFS" but the MHRA here in the UK came to the conclusion that there is no link with this vaccine. I am sceptical about this conclusion.

Question: What do you think of oxygen therapy? Can it help with muscle pain or the problems with acid in the muscle?

Answer: Although there is evidence of hypoperfusion (low blood flow) in certain parts of the brain in "ME/CFS" I'm not convinced that oxygen therapy is of any value. There can also be dangerus in giving oxygen to people who may not be breathing in a normal manner. Evidence was presented in San Francisco that some people with "ME/CFS" have very shallow and low oxygen intake breathing because they do so via the abdomen instead of the diaphragm at the base of the chest. You can check your breathing by lying flat on the floor and observing whether it is diaphragmatic or abdominal - shallow or deep. Then try breathing in deeply for three seconds through the nose using the chest and diaphragm - the correct way to do so. 

Question: How do you explain that the Japanese all of a sudden find evidence of inflammation, have pet-scans gotten better? And how would for instance scans of peeps with mild flu look like?

Answer: The Japanese are not the only research group to demonstrate what is called neuroinflammation. My post-mortem group here in the UK have evidence of what is called dorsal root ganglionitis in "ME/CFS" in tissue from people who have died. This finding has also been published.

The results we have published relate to 4 or 5 cases - would need to check with the paper for precise numbers. I have been discussing this post mortem research and the Japan research research on MEA Facebook if you want to follow it up. An abstract from our paper on DRG is there as well.

Question: Have you heard of stealth viruses?

Answer: Yes, stealth viruses were implicated in "ME/CFS" many years ago - but the virologists eventually came to the conclusion that they were not relevant.

Question: Do you think these viruses are relevant?

Answer: A wide variety of viral infections are capable of triggering "ME/CFS" and there is some evidence (from Dr. Chia in California in particular in relation to enteroviral infection) that there could be "persistent viral infection" in some cases - as enteroviral infection persists in stomach tissue.

But I'm not convinced there is any link with stealth virus infection...

Question: Is ampligen dangerous?

Answer: Ampligen has side-effects, some of them can be unpleasant, but I would not say it was a dangerous drug. This is based on my reading. Ampligen is not available/licensed for use in the UK and I do not have any personal experience involving its use.

Question: Are you aware of the study of the University of Nijmegen where they are going to give the immunosupressant Anakinra to ME/CFS patients? What do you think of this?

Answer: I wasn't aware of the clinical trial you refer to but I do want to see trials involving drugs that can dampen down the immune system - because there is growing evidence of what we call immune system activation, and cytokine production, in M.E.

One of the drugs that would fit into this category is "Etanercept" - which is used to dampen down activity in autoimmune disorders. I will need to translate the drug you refer to - it may be very similar.

Question: But wouldn't it be dangerous if people are not screened for infectious diseases like lyme? I hope they'll have mirtazapine on their hands to treat PML which might occur.

Answer: Yes, you have to be very careful about the sort of "ME/CFS" patients you use in clinical trials that involve drugs that can produce serious, or very serious side effects. The same logic applies to "Rituximab" - which can (rarely) cause a fatal allergic adverse reaction.

Question: Dr. Shepherd, I'm deeply concerned about "ME/CFS" discussions in the UK. How can the research collaborative be effective when members hold diametrically opposed views on what makes good science? (e.g. PACE)

A: As you know I am a member of the UK "ME/CFS" Research Collaborative. I take the view that there is a case for having a forum where all sides of the "ME/CFS" debate can meet and discuss where we agree and disagree. We cannot go on with a situation where everyone sits in their own separate tents.

Question: I found the Stanford & IACFS/ME conferences very inspiring; How long do you think it will be before we see a break-through in "ME/CFS" research?

Answer: Yes, there was a lot of good clinical and research information presented at San Fran - some of which has real practical implications for patient management. I was so inspired that instead of rushing out a report (7,600 words!) I've been spending the last week or so getting it right. I would not want to use the words breakthrough or cure but I think we are heading towards some significant steps in understanding the underlying causes of this illness. The work on neuroinflammation was particularly interesting and I am now discussing how we might try and replicate these PET scans here in the UK - a major hurdle is that these scans are very costly to do. And if we are dealing with a disease involving low level inflammation then we really need a trial of drugs that can dampen down this over-activity - in the same way that they are used to dampen down disease activity in rheumatoid arthritis etc.

Question: I'd love to read your conference report; I hope it'll be on the MEA website.

Answer: it is being prepared for the MEA magazine but I hope we will be placing it on the website as well for the benefit of non-members.

Question: Lately a MMA test showed a huge shortage of B12. Is there any link to M.E.?

Answer: We discussed B12 in San Francisco. There is no firm evidence of vitamin B12 deficiency in "ME/CFS" and no firm evidence of benefit from B12 injections. However, there are plenty of anecdotal/patient reports of people gaining benefit and one report demonstrating lowered levels in spinal fluid.

Question & Answer Session with Dr. Charles Shepherd

Thursday 24th April, 2014

Question: In your webinar you mentioned several symptoms of M.E. But you did not mention problems with the stomach or the bowels. Don’t you consider problems with them as symptoms of M.E.?

Answer: Yes, irritable bowel type symptoms are very common in people with "ME/CFS" and I have just produced a new information leaflet on this subject for people in the UK. However, it's also important to exclude other possible explanations - such as coeliac disease. Although very common I would not regard irritable bowel type symptoms as being a key diagnostic feature of M.E. or CFS.

Question: Do you have personal experience with alternative treatments or did you hear of them from patients? What is your opinion about them?

Answer: There is a limited role for alternative treatments for bowel symptoms. One product that may be worth trying is a probiotic such as Activia - where there is some research evidence of benefit for constipation and pain. Ginger and acupressure at the wrist can also help where nausea is a problem.

Question: What is Activia, is it a medication?

Answer: Activia is a probiotic supplement that contains bifidobacteria - and it may help where there is constipation and pain.

Question: Do you know a treatment for problems with the bowel? (and coeliac disease is excluded)

Answer: After excluding other possible explanations most doctors would recommend a symptomatic approach using drugs that can reduce constipation or diarrhoea, colic pain and wind/bloating. Changes to diet can also be very helpful in some cases, especially for wind and bloating.

Question: I saw a video of Teitelbaum who, like you, said that if you don't have problems with sleeping you don't have M.E. Don't most of the criteria mention "unrefreshing sleep", which imo is something different?

Answer: I would regard "unrefreshing sleep" as a key diagnostic feature of "ME/CFS". Disturbed sleep can take several forms in "ME/CFS" - in the early stages there is often an excessive sleep requirement - known as hypersomnia. Later on people may have difficulty getting to sleep, or just very erratic sleep.

Question: Teitelbaum also said that something like 90% recovers, doesn't he mean they manage it with diets and pills?

Answer: I would not agree that 90% of people recover from "ME/CFS". A lot of people make some improvement (as I have done) and learn to manage their symptoms and disability. But that is not the same as recovery. A significant minority - perhaps as high as 25% - are severely affected and remain so.

Question: Once an orthomolecular doctor noticed that my system had shortage of hormones from the adrenal cortex like DHEA. He suggested to take medication containing those hormones. Would you give such treatment? Can it possibly harm the whole system?

Answer: There is plenty of good quality research evidence to show that people with "ME/CFS" have slightly lowered output of the hormone called cortisol - but clinical trials have not shown that taking cortisol is a safe and effective form of treatment for "ME/CFS". There is no sound research evidence to show that people with "ME/CFS" have lowered levels of DHEA and there are dangers in taking DHEA if it is not needed by the body - so I would not recommend this approach.

A research study from Cleare et al. in 2004 reported that DHEA levels were actually raised in "ME/CFS" - suggesting that DHEA supplementation was both unnecessary and possibly harmful.

Question: I have been an "ME/CFS" patient for about 30 years and my question is: I’m reading regularly that the pituitary gland probably plays a role in "ME/CFS". The pituitary gland controls the thyroid gland. Could it be that a thyroid abnormality is an effect/symptom of "ME/CFS" ? Or vice versa, that "ME/CFS" is an effect/symptom of a thyroid abnormality, like for example subclinical hypothyroidism?

Answer: We know there is a disturbance in the hormone regulating pathway that starts in the hypothalamus gland in the brain, the pituitary gland (which lies beneath it) and the adrenal glands (that produce cortisol). But there is no sound evidence of a similar disturbance taking place in the thyroxine pathway.

So doctors should not be prescribing thyroxine to people with "ME/CFS" - unless they also have abnormal blood tests (T4 and TSH levels) that are used to measure thyroid gland function.

Question: Can alternative treatments in general cause harm to "ME/CFS" patients?

Answer: I would not say that alternative treatments cause harm to people with "ME/CFS", but they have to be used with care, especially if you are going to take large doses of supplements or vitamins or plant based remedies.

And if you have faith in things like acupuncture (especially for pain) or homoeopathy then I think they are well worth trying.

Question: Is there a relationship between "ME/CFS" and a Vitamin B12 deficiency? I have both an elevated TSH value as a far too low Vitamin B12 value. I am recently treated with Vitamin B12 injections and Thyrax.

Answer: Having an elevated level of thyroid stimulating hormone (TSH) normally indicates that your thyroid gland isn't working as effectively as it should be. Thyroid disease and vitamin B12 deficiency can sometimes be linked through autoimmunity - where the immune system attacks the body's own tissues.

Question: Are you familiar with low dose naltrexone? What do you think of?

Answer: Some people in the UK are prescribed LDN and we receive very mixed feedback from them. The problem is lack of evidence from a clinical trial to show that it is a safe and effective form of treatment. So in our current state of knowledge I do not use or recommend LDN. There has been a small clinical trial using LDN in fibromyalgia (Younger et al, 2013) which suggested that it provided some benefit in pain relief.

Question: Big compliment btw for the video on exercise (and mitochondria).Iif anyone ever starts again about treadmills I'll show it to them!

Answer: Thanks for the comment on the activity management video. There is a new research study out confirming that the VO2 max test is a useful tool for clinical assessment in "ME/CFS".

Question: Speaking of videos, last time I mentioned a pressure in my brain after antibiotics etc. It sometimes moves to my eyes (they tremble, which can also be felt from the outside) and for instance my throat/thyroid, which "plops", also noticeable by others and I filmed it. Would you care to watch it? A neurologist said they‘re muscle contractions, but as far as I know I don't have muscles in my brain.

Answer: Ah, but you do. There are lots of small muscles controlling movements in the face, eyes, mouth etc. A spasm in the muscles that open/shut your eyelids is called blepharospasm - and I think it's quite common in people with "ME/CFS", especially when they are tired. 

Question & Answer Session with Dr. Charles Shepherd

Thursday 15th May 2014

Question: You spoke about 'post exertional malaise' in M.E. following physical exercise. What about 'PEM' after mental exertion and after sensory 'overload'? For me the effects are the same.

Answer: Actually, I think "post-exertional exacerbation of symptoms" is a better description. Although this primarily follows physical exertion, it can also follow mental exertion. The MEA is currently funding Prof Jo Nijs et al to try and get a better understanding of what causes PEM/PEE.

Question: You mention that it may be possible to take medicines in order to reduce cytokines with as result less problems like flu, sore throat etc. But would it not be a danger to become overactive when you do not feel the symptoms any longer?

Answer: There are a number of drugs that can help to 'dampen down' immune system activation and over-production of cytokines. One such drug is Etanercept - and there is already some limited evidence from a small study in relation to "ME/CFS".

I think you have to be fairly cautious for a while about physical activity levels, and to some extent mental activity levels, once symptoms have either stabilised or there has been a significant degree of improvement/symptom reduction in "ME/CFS".

Question: Does the fact that the MRC decided to finance the research mean that your Government recognise M.E. (CFS) as a biomedical disease?

Answer: The MRC have fully accepted the need for funding biomedical research (which they are doing) and have highlighted the need for research into neuro inflammation in particular. However, the UK government position still remains rather neutral in that while they fully accept "ME/CFS" to be a genuine and debilitating illness, official bodies like NICE (who control what doctors prescribe) view this as an illness that involves both physical and psychological causation.

Question: In webinar 36 you talk about dysfunctions of the brains which are measurable. Which dysfunctions, and are they measurable, in the sense that in that case we patients can effectively confront our GP’s with them when consulting them?

Answer: I'm afraid that all these sophisticated (and often quite expensive) tests that can measure aspects of brain dysfunction are hospital based - so you are not going to get them through primary care or a GP. Most are also research based rather than being available for routine clinical assessment of patients. One possible exception is tilt table testing - which can be very helpful in assessing people who are having blood pressure and pulse rate problems when they move from lying to standing - what is called orthostatic hypotension (fall in blood pressure when standing up) or POTS (postural orthostatic tachycardia syndrome).

Orthostatic intolerance/hypotension causes symptoms such as feeling faint or lightheaded when staying up - along with nausea, sweating, reduced concentration, blurred vision…….it is very common in "ME/CFS" but often unrecognised and not managed properly by doctors!

Question: So by taking those medications to dampen down the cytokines we can get rid of the everlasting flu-like symptoms, but we must still remain cautious with activity. To me it seems difficult to find a new measure for activity, as it is now given by sore throat etc.

Answer: There are now a number of investigations, neuroimaging in particular, that can demonstrate abnormalities in the way that parts of the brain control the output of hormones (low cortisol in particular), blood flow (SPECT scans), cognitive function (functional MRI scans) and activity in what is called the autonomic system.

Question: Is it common with brain-fasciculations to have neurotransmitters coming out of your ears?

Answer: I'm not quite sure what you mean about having neurotransmitters coming out of your ears! Fasciculations can refer to visible twitching or trembling of muscles. 

In "ME/CFS" it is sometimes seen in the tiny muscles that control the eyelid movement - something called blepharospasm.

Question: Mere muscle contractions don't cause high-ness or things "breaking" in your brain?

Answer: There isn't any evidence to show that these visible muscle contractions/fasciculations are causing harm or damage in the brain - even though they are very annoying.

Question: How did you motivate the MRC to decide to pay the research? Or in other words: what can we learn in other countries from your approach?

Answer: About 5 years ago the MRC was persuaded by politicians and patient groups to address biomedical research - so they set up an MRC Expert Group on "ME/CFS" research. I was a member of the group. The Expert Group then listed a number of biomedical research priorities. The MRC responded positively by providing £1.5 million of ring-fenced funding for biomedical research on our priority list. Five studies - central fatigue biomarkers, immunological activation, autonomic system, mitochondrial function and sleep intervention with sodium oxybate - were accepted and these are all now in progress.

Question: Your answer makes clear the important role of organised and joined patient groups!!

Answer: Here in the UK we have an All Party Parliamentary Group on "M.E." at the House of Commons - it is a very useful way of making sure that Ministers and senior officials from MRC, NICE etc. have to come and answer difficult questions. Do you have anything similar with the Dutch politicians?

Question: I know the different patient groups in the Netherlands already know the need of attention by politicians and journalism. And I thank them a lot for doing so!!! But your words make clear once again the importance of doing so and trying to improve.

Question: Is there something in general to tell about problems for M.E.-patients with their weight?

Answer: Weight gain is very common in "ME/CFS" but when this occurs it's worth having thyroid function checked if this isn't adding to the problem.

Unfortunately, there is also evidence to suggest that being overweight can have an effect on the underlying disease process in "ME/CFS" because it is now known that fatty tissue is a source of inflammatory immune system chemicals - which may help to explain why heart disease and diabetes are more common in people who are overweight.

Question: Elsewhere in the webinars you talked about the hypothalamus. What’s the impact of the hypothalamus with M.E.-patients?

Answer: Hypothalamus is a tiny pea like gland in the brain that helps to control temperature regulation (which probably explains why people with "ME/CFS" have problems with high/low temperatures). It also send messages to all the glands in the body that produce hormones - which may be involved with lowered output of cortisol.

Question: Are there any drugs or supplements to regulate the functioning of the hypothalamus?

Answer: Unfortunately, we don't have any drugs that are really useful in helping to reset the hypothalamus when it's not functioning properly.

Question & Answer Session with Dr. Charles Shepherd

Thursday 22nd May, 2014

Question: I am thinking of trying LDN. What is your opinion on LDN?

Answer: We receive quite a lot of anecdotal information about LDN. Some people say it helps; a significant number report no significant benefit and a few say it makes them worse. It is not a drug that I would want to recommend or use until we have sound evidence of safety and efficacy from a proper clinical trial. I would add there there is evidence of some benefit from using LDN in a small clinical trial carried out in patients with fibromyalgia.

Question: I have also neuropathic pain (allodynia/hyperesthesia). Is LDN tested for this condition?

Answer: I don't think there is any sound evidence relating to relief of neuropathic (nerve) pain from clinical trials for LDN. But there are some useful drugs of proven benefit for nerve pain - examples include gabapentin and pregabalin.

Question: In your college you mention that a very important step forward would be to find a/ some biomarkers. Could cytokines be usefull as biomarker?

Answer: Yes, it's possible that cytokines, or a combination of cytokine abnormalities, could act as a diagnostic biomarker for "ME/CFS". And there is some evidence that this is the case from Jose Montoya's research group in Stanford, California. This work was presented at the IACFS/ME conference in March. I have done an on-line 16 page supplement report on the conference. 

It can be downloaded from the MEA website: www.meassociation.org.uk⁠

Question: Is it a requirement for new research that that patients that are exemined are diagnosed according to the International Consensus Criteria? Are they assumed to be the point of departure?

Answer: I don't know of any research groups who are currently using ICC for recruiting patients into research studies. Most studies are still using Fukuda or Fukuda + Canadian criteria - which is what we are doing for recruitment into the M.E. (blood sample) Biobank in London.

Question: You spoke earlier about the 'encephalomyelitis' in the name M.E. and the lack of evidence for using this name. It seems that some studies, like the recent study (Watanabe et al.) using PET scanning did show that neuro-inflammation is present in patients with M.E..

Answer: Yes, the Japanese study indicates neuroinflammation - as does the post mortem studies I was involved with where dorsal root ganglionitis was found in some of our post-mortem cases. But neuroinflammation can occur in a variety of conditions that are not even classified as neurological (e.g. lupus).

So the presence of neuroinflammation does not automatically mean that someone has an encephalitis - which would mean a more severe and widespread inflammation of brain tissue and would be found at post-mortem.

Question: Do you still want to use 'Encephalopathy' instead of 'Encephalomyelitis'. Despite the fact that there's been a study in Japan that shows that in every M.E. patient that was participating there was inflammation of the brain.

Answer: We have NOT found "encephalitis" or "myelitis" (= inflammation in the spinal cord) in any of the post-mortem cases. So I still think that "myalgic encephalopathy" is a better term to use. "Encephalopathy" is also a term that most doctors are willing to accept, including those who will not use "encephalomyelitis". 

Question: There is recognition that the severe patients need specialised facilities. Does that mean that this kind of assistance is already organised and operational?

Answer: I'm afraid there is very little in the way of in-patient hospital based services for assessment and management of people with severe M.E. here in the UK. And there aren't any domiciliary (home visiting) services either. This is an unacceptable gap in health care for people with severe M.E.

Question: Would it not give much more clarity if only the ICC-diagnosis was used for research?

Answer: It would add much more clarity if researchers agreed on a single case definition for "ME/CFS". As Prof Lenny Jason pointed out in San Francisco we now have over 20 case definitions and no real agreement on which one to use.

Question: Last time you told that many M.E.-patients have overweight. Is this just due to the fact of lack of exercise or doe other factors play a rol in this?

Answer: There are a number of factors that are probably involved but lack of activity combined with no change in diet must be a major factor. It's very important that people who are gaining weight with M.E. should have their thyroid function checked - because low thyroid function can cause weight gain.

Question: For very severe cases, pacing is nearly impossible because they exceed their limitations by doing almost nothing. I'm almost always in PEM and I get worse and worse. Do you have any suggestions how severe M.E.-patients can try to stop deterioration? I can understand if you don't have answers.

Answer: I'm afraid I don't have any simple answers regarding the problems facing people with severe M.E.. What I will say is that progressive deterioration is unusual in "ME/CFS" and where it occurs there should always be a thorough clinical reassessment to make sure that nothing else medical is being missed.

Question: The situation in the Netherlands for severe patients is not better then in the UK. Improvement will come from recognition, based on research. So please continu all the research you planned to do!!!

Answer: There is also a major problem in the way that people with severe M.E. are not being involved in research. But things are changing…..

The M.E. Biobank in London is actively recruiting volunteers with severe M.E. to give blood samples. And Prof Julia Newton, in Newcastle, who is appearing next, has been given a grant from MERUK to carry out a study on people with severe M.E. This will involve visiting these people at home.

Question: Last time you asked if we have in the Netherlands a similar system of the All Party Parliamentary Group on M.E. I'm not sure, but I do not think that we have such a Group. But it seems to me a very significant way to influence and inform the Government. Thanks for the idea!

Answer: Regarding all Party Parliamentary Groups - I suggest you see if a similar system operates in the Netherlands. If it does, you need to find a friendly MP who is interested in "ME/CFS" and set up a group - which can then question ministers, civil servants, health authorities etc.

Question: How come that side effects of regular meds like antibiotics, inflammatory agents etc are becoming more invalidating throughout the years?

Answer: I'm not sure if I understand your question about antibiotics and the way you are using invalidating. Do you mean the side -effects are becoming more prominent?

People with "ME/CFS" are certainly more sensitive to some types of drugs, especially those like antidepressants and some types of painkillers that act on chemical transmitter systems in the brain. But the reasons why remain unclear...

Question: Let's take the side-effects first. They tend to become worse throughout the years, aren't they?

Answer: I'm not sure that the actual side-effects of established drugs have become worse. I think there is increased recognition that people with "ME/CFS" are more likely to experience side-effects with some types of drugs. On the other hand, people with "ME/CFS" who use drugs like amitriptyline for pain relief or sleep disturbance often report that side-effects tend to gradually diminish as time goes on.

Question: With triptans their condition can get worse, isn't it? Also with benzodiazepines, but that's due to habituation?

Answer: Yes, there are some drugs, including benzodiazepines like Valium, that came make people with "ME/CFS" feel worse. Statins for lowering cholesterol also have to be used with care because one of their side effects is to cause muscle damage/pain.

Question: Also I hear complaints that a certain med has worked for years, and then all of a sudden doesn't seem to have its desired effect anymore. Is that explicable?

Answer: The fact that some medicines become less effective, or ineffective, over a period of time is not something that is unique to "ME/CFS".

Question: Would you suggest to use only the ICC?

Answer: the ICC has some advantages as a clinical definition but I sense there is great reluctance amongst international researchers to move to using either this, or the Canadian Criteria.

What we have to work on is international agreement on a research definition that EVERYONE starts to use? 

It makes no sense whatsoever to have over 20 different case definitions for "ME/CFS" in use - especially when it comes to trying to compare the results of different research studies on the same subject but where different types of patients have been used.

And I am not blameless here having helped to produce and revise the London criteria for M.E.

Question: So all researchers need worldwide consensus criteria. Is there a leading group/researcher that can propose criteria and convince everybody to use them?

Answer: I hope you have heard of Prof Lenny Jason from Chicago - who is the real expert here. If everyone would listen to what Lenny is saying, which includes constructive criticism of several case definitions, things would really start to improve….

Lenny Jason has a wonderful powerpoint slide showing a house of playing cards crumbling because the foundations are unsound. The same applies to "ME/CFS" - unless you have a sound foundation of an agreed case definition everything else that relies on it - cause, management, epidemiology - will fail. 

Question: Do you know if there are plans to r replicate the PET findings of Japan somewhere around the world?

Answer: I am currently discussing with some of my neurological colleagues whether we can set up a UK study that would aim to replicate the Japanese findings. A major problem here is cost - this type of PET scan is extremely costly.

Question: Do you have a patient organisation on brain problems? Those organisations sometimes have the money.

Answer: We don't have any 'brain organisations' or brain charities here in the UK that would be sympathetic to funding a neuroimaging study in "ME/CFS".

Question: Is drug clearance less in people with M.E. due to liver cytochrome P450 system or kidney function or maybe methylation problems? Or do people need lower blood values for drugs to work?

Answer: I don't think there is any sound research evidence to show that people with "ME/CFS" have problems with metabolism of drugs in the liver or their excretion/removal via the kidneys.

Key

Myalgic Encephalomyelitis (also known as Enteroviral Encephalomyelitis)

Myalgic Encephalomyelitis = acute onset Enteroviral Encephalomyelitis NOT Myalgic Encephalopathy as Dr. Charles Shepherd suggests

'Nightingale Research Foundation Definition' (2007 & 2016) defines Enteroviral Encephalomyelitis

'International Consenus Criteria' (2011) overlaps closest to Enteroviral Encephalomyelitis

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The Canadian Consenus Criteria (2003) is a conflation of the terms M.E. and CFS and an admitted error by Dr. Bruce Carruthers

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Chronic Fatigue Syndrome

Holmes Definition (1988) overlaps "Abortive Polio" onset symptoms and "Enteroviral Encephalitis"

Fukuda Criteria (1994) is a minimisation of the Holmes Definition (1988)

SEID (2015) is a futher minimisation of the Fukuda Criteria (1994). 

Diagnosable diseases are excluded