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

Seminar 35: Introduction / Experience with M.E.

Dr. Charles Shepherd. Broadcast 25th February 2014

How did you get involved with M.E. (also known as Enteroviral Encephalomyelitis) ?

My name is Dr. Charles Shepherd and my involvement with this illness dates back to personal experience, approximately thirty years ago. Like many doctors of my generation when I was in medical school I was told this illness was hysteria. In fact at the time I was at. medical school a paper came out in the British medical journal describing M.E., Royal Free disease at is was also known at the time as mass hysteria. 

So we left medical school believing that we  weren’t going to see people with this illness and if we did it was all in their minds. And I had personal experience by catching (a PVFS and NOT) M.E. from a patient. I actually got a very nasty dose of chickenpox from a patient who had shingles. 

That changed my mind about this illness. I had all the classic symptoms and yet like many people it took about two years before I got a diagnosis of this illness. During that time I didn’t practice the right management, I didn’t pace my activity, I had problems with benefits  and employment. 

All the problems that people have to go through with this illness. So my views on M.E., especially in relation to management, are very. much based on personal experience. (Through a Herpes Zoster Encephalitis Lens)

What do you do in relation to M.E. (also known as Enteroviral Encephalomyelitis) ? (charity, political, research, services etc)

This is very much based on my experience of dealing with vast numbers of people over the past thirty years with this illness. Either seeing them as patients or as dealing with them in my role as medical adviser to the ME Association which is the major adult support charity here in the U.K.. So I have a lot of if you like clinical experience in dealing with people on a one to one basis, but I also have a lot of experience in many other areas in relation to my charity roles.

I’m involved in research, I have a particular interest in research relating to muscle. abnormalities in this disease. And also the role of vaccinations in triggering this disease. Also within the charity sector we have to provide a lot of information to people with this illness as well as to health professionals. I help to supervise our Ramsay Research Fund which is a major research fund in the U.K.. We’re currently funding researches such as the M.E.  bio-bank, post-mortem research, and muscle research. And we also have a very important role here in the  U.K. in relation to political  activity in this illness. We’re part of the secretariat of the all-party parliamentary group on M.E.. And we also play a very important role in campaigning on benefits, which is a particularly important issue for people with this illness.

Seminar 36: What is the difference between M.E. and CFS?

Dr. Charles Shepherd. Broadcast 25th February 2014

What is M.E. (also known as Enteroviral Encephalomyelitis) ?

M.E. stands for Myalgic Encephalomyelitis. 

And this is a name which came into medical usage following an editorial in the Lancet medical journal in 1956 and it was used to describe an outbreak of this illness that occurred at the Royal Free Hospital in London the previous year. 

The outbreak at that time was being called the Royal Free disease but the Lancet editorial named it myalgic encephalomyelitis. And it was the term that was used because these. patients had muscle symptoms, which is. where the ‘myalgic’ comes from, and they  also had a lot of brain symptoms which is where ‘encephalomyelitis’ comes from. And in medical jargon encephalomyelitis means inflammation which is ‘itis’, within the brain which is ‘encephalo’, and ‘mya’ which means spinal cord. It means in pathological terms inflammation within the brain and spinal cord.

What is CFS? Answer: it's a 'diagnosis of exclusion' criteria based around medically "unexplained fatigue"

Chronic fatigue syndrome is a name that was introduced by the medical profession during the nineteen eighties. Partly as a reaction to the fact that there was renewed medical and scientific interest in this disease, and partly because the medical profession decided that it did not like the term M.E. : myalgic encephalomyelitis, because there has always been and there continues to be a considerable degree of controversy and uncertainty as to whether there is actually inflammation within the brain and the spinal cord. 

So the medical profession in its wisdom decided to rename and redefine M.E. as Chronic Fatigue Syndrome. 

And the way it redefined M.E. as Chronic Fatigue Syndrome, is that it brought in a lot more people under this umbrella of Chronic Fatigue Syndrome who previously would not have met the diagnostic criteria for M.E..

A lot of patients of course dislike the term ‘Chronic Fatigue Syndrome’,  I dislike the term  chronic fatigue syndrome, because I feel we’ve widened the diagnostic net as to who comes under this umbrella of chronic fatigue syndrome. 

And in a way it’s rather like saying that everyone who has some form of headache whether it’s a migraine headache or even a brain tumor headache can be put under an umbrella of a chronic headache syndrome. And so they all have the same cause and they all  have the same form of management. Which clearly isn’t the case? 

What does the combination M.E. and CFS stand for?

The combination-term of ME/CFS is really a messy compromise to try and keep the medical profession on side, who certainly in the UK, and I think this will be true for the USA and many parts of Europe where this illness is recognized; to keep the medical profession on board who wants to use the term CFS, and the patients who not surprisingly-and I agree with 

them-want to use the term M.E.. So we have this messy compromise of ME/CFS. And in actual fact I think what we have also is an umbrella which is covering a wide variety of clinical presentations. And equally it’s covering a wide variety of disease pathways or subgroups. So it’s going back to this headache syndrome or joint pain syndrome. We’re trying to put everyone who has some sort of chronic fatigue under this ME/CFS umbrella.  

And I think we’re very wrongly saying that they  probably all got the same cause, so that they all got the same form of treatment.  

And what I think we’ve got to do, which is I  think what the research community is now taking on board, is to go back several steps and try and subgroup these people who come under this ME/CFS umbrella into clinical subgroups, pathological subgroups. 

So that we can find effective treatments for these different subgroups under this umbrella, because quite clearly not everyone under this umbrella is going to respond in the same way.

Why do most doctors prefer CFS to M.E. ?

I think the vast majority of my medical colleagues remain convinced that M.E. is not an appropriate name for this illness, largely because this problem with "encephalomyelitis" and the lack of pathological proof or evidence that there is an inflammation taking place within the brain and spinal cord. There are certainly abnormalities taking place within the brain, and we know that from research. But we don’t have any hard scientific evidence to demonstrate inflammation in the brain and within the spinal cord.

"UNTRUE"

What would you call the disease?

My way round this is to propose that we actually rename Myalgic Encephalomyelitis Myalgic Encephalopathy, which would take the inflammation out of the encephalomyelitis and imply that we have an illness here which is affecting muscle and brain function which is what encephalopathy is but without the widespread inflammation. So I have proposed that to some of my colleagues. It is something which is accepted here by the government, then department of Health, NICE but it hasn’t yet achieved any sort of degree of widespread  acceptance. So at the moment we remain in this very unsatisfactory position where we have patients calling the illness M.E., and doctors calling it CFS. 

And those who want to try to make some sort of compromise are calling it ME/CFS.

My preference is to use the term M.E. as myalgic encephalopathy which takes the heat out of the argument and I find when I use this in the presence of my medical colleagues it is accepted normally without any great problem. 

But if I go and talk to my medical colleagues about myalgic encephalomyelitis, instead of actually talking about the illness, talking about how to diagnose it, talking about how to manage it, it just stems back into an argument about the fact that there is no encephalomyelitis. And I think as long as my medical colleagues remain so unconvinced and even hostile to the concept of encephalomyelitis I think we have a major problem. Because all that results in is my colleagues abandoning the term M.E. and using what I regard as this awful term ‘Chronic Fatigue Syndrome’.

(Dr. Shepherd is a 'dishonest' individual.)

Seminar 37: How is M.E. (also known as Enteroviral Encephalomyelitis) diagnosed?

Dr. Charles Shepherd. Broadcast 11th March 2014

What diagnostic criteria are used?

There are a number of diagnostic criteria for both M.E. and chronic fatigue syndrome. 

For M.E. we have doctor Melvin Ramsay’s original description of the illness. We have some criteria called the London criteria, we have International criteria, newly prepared criteria for M.E. 

For CFS we have a range of criteria today. We have Fukuda criteria, we have Australian criteria, we have Oxford criteria here in the UK and we also have NICE criteria in the UK. 

And for both M.E. and CFS these criteria have similarities and differences and even within the criteria for M.E. and CFS there are similarities and differences. 

So this is a picture of great confusion for the average general physician who is presented with a patient in his consulting group who just wants to make a simple straightforward diagnosis of this illness.

So I think most of my colleagues, just like the approach I would take, take a pragmatic view to diagnosing this illness. And we make use of these criteria which I have to say primarily are there for research purposes to identify people going into research rather than clinical purposes. So we make use of these criteria but we don’t stick to them rigidly when we make a diagnosis of this illness.

To make a diagnosis of M.E. or CFS or ME/CFS it is the same process that you go through when you’re making a diagnosis of any illness. You take a history, you examine the patient, you arrange some blood tests which we will come to shortly. As far as the initial part of the clinical consultation is concerned, it is extremely important to take a detailed history from patients with a possible diagnosis of M.E. Because there are many other illnesses which can overlap with this illness and cause diagnostic confusion. So the history taking is extremely important and if there are other symptoms there in the history which are not typical of M.E., they need to be pursued to make sure that you’re not missing some other diagnosis.

It’s terribly important to examine the patients carefully, particularly their nervous system and muscle although on the whole you’re not going to find any particular diagnostic examination abnormalities which are characteristic of this illness. You may find problems with balance, you may find problems with muscle weakness, you may find abnormalities in some parts of the nervous system examination but on the whole, examination doesn’t add an awful lot to the diagnosis of this illness.

Which tests should be arranged when a diagnosis is considered?

When you’re considering a diagnosis of M.E., it’s terribly important to check through a quite comprehensive range of blood tests and some urine tests. These tests are done not to diagnose M.E., because we don’t have a diagnostic blood test for M.E., but they are there to make sure that you’re not missing other conditions.

So you want to check thyroid function, you want to check liver function, kidney function, routine hematological checks, checks of inflammation or infection in the body, a very sort of wide-ranging test is what’s called the ESR. And this list of tests is available, readily available, in all the sort of guidelines that are issued to doctors who are making a diagnosis of M.E.. They’re comprehensively described in the MEA booklets on diagnosis. So those are tests which have to come back as normal before you should be making a diagnosis of M.E..

Now there are also a range of what we will call second line tests, which range from brain scans to immune function tests on the blood, something like even muscle biopsies. Now you cannot arrange to do every single one of these tests in every patient who comes along for this possible diagnosis. It’s not feasible, it’s not workable, it’s just not costable. So with these second line tests you have to reserve which ones you’re going to do on the basis of clinical judgment.

This will be based on whether or not there are symptoms which we might describe as red flag symptoms. So you got a patient who is losing weight, well that would immediately suggests that you need to be looking to do further investigations before making a diagnosis of M.E.. Or they have unusual symptoms, perhaps they have skin itch, skin irritation suggesting that they have a condition called primary biliary cirrhosis that can overlap with M.E.. Or they may have dry eyes, dry mouth, joint pains, suggesting they may have Sjogren’s syndrome, in which you would want to go often do specific immunological tests, anti-auto antibody tests.

They may have symptoms which are overlapping with multiple sclerosis, which can occur. And sometimes it is quite difficult to differentiate between M.E. and MS. And in that case you want to go off and do brain scans or whatever to look for a possible diagnosis for M.E. So there are a lot of different tests which may be applicable but in certain circumstances. And using your clinical judgment as a doctor that’s the situation when you go often do that sort of tests.

What other conditions should be considered before a diagnosis is confirmed?

Before a diagnosis of this illness is confirmed, as I was saying when we were talking about taking a very careful clinical history from patients, it is important to have at the back of your mind as a doctor that there are a large number of conditions - we list about fifty different conditions in the MEA booklet on this – that can be misdiagnosed as M.E. because the symptoms overlap. So when you’re going through this history, you need to be aware and pick out symptoms which are not quite consistent with the diagnosis of M.E. and then start querying could that be another condition.

Let’s take a couple of examples. You have a patient who comes along who has their fatigue, but also has a lot of bowel problems as well. Irritable bowel typed symptomatology. Now we know that irritable bowel typed symptomatology, bloating, alternating constipation and diarrhea, stomach pains is quite a common accompaniment to M.E. A lot of patients with M.E. do have this. And it is quite tempting to just say well you got M.E. and you’ve got a bit irritable bowel syndrome.

But when you have a patient like that who comes along what should be going through your mind as a doctor is, could this patient also have something like adult onset celiac disease? Which is not uncommon in the adult population, which is treatable to a large degree and can be misdiagnosed as M.E. So you get a patient with fatigue, irritable bowel typed symptoms you should be doing a screening tests to rule out celiac disease at the same time.

Another example might be, you get a patient with fatigue and joint pain. And we have a condition called joint hypermobility syndrome which can overlap with M.E. And again there would be a different form of management if you had someone with joint hypermobility syndrome. Interesting about joint hypermobility syndrome is that these patients often have bruising as well. So that will be another warning sign there. So there’s a lot of different conditions which need to be seriously considered before you come to this diagnosis and say you’ve definitely got M.E..

Who can make a diagnosis?

The diagnosis of M.E. in most cases, I stress most cases, is something that should be capable of being made by a good general practitioner, that’s a doctor in primary care. Where a doctor in primary care is unable to make a diagnosis, then there should be facilities available at the local hospital. Either through an ME/CFS clinic or a specialist at the local hospital who has widespread experience in dealing with this illness, to whom a patient should be able to be referred for a confirmation of the diagnosis.

(A neurologist, if they understood, what they were doing? Sadly that is NOT the case) 

What about the International Consensus Criteria?

The International Criteria is the latest and most comprehensive criteria which aim is to be able to help doctors make a diagnosis of M.E.. It is a very detailed criteria and, as I’ve indicated earlier, I think most of my medical colleagues take a very pragmatic approach to making a diagnosis of this illness, and don’t tend to sit there with a diagnostic criteria especially if it is long and complicated, sitting on their consulting room table.

So I think as an aid to diagnosis this is a very helpful document. But I think to expect that every doctor is going to sit there with this criteria in his waiting room, consulting room and then using it to make a diagnosis of M.E. is probably unrealistic at this point.

(It was a criteria although however 'flawed' that was meant to seperate 'M.E.' from 'miscellaneous' Fatigue Syndromes, which has been 'intentionally' ignored)

Seminar 38: M.E. (also known as Enteroviral Encephalomyelitis) and its triggers

Dr. Charles Shepherd. Broadcast 25th March 2014

What role do infections play in M.E. (also known as Enteroviral Encephalomyelitis) ?

Infections play a very important role in this illness. I think it’s probably helpful just to recap on how this illness probably develops. And I think there are three stages to this illness: there are things that predispose towards this illness, particular genetic factors, there are things that precipitated or trigger it and then there are things that perpetuate it or keep it going.

The role of infection comes into the second stage, things that perpetuate things that precipitate or trigger this illness. And we know that in round about 75% of cases people will predate the onset of their M.E. to a very clear cut infective episode. They will describe an infection. It may be something quite straightforward like a flu-like illness or a respiratory tract infection, gut infection. It may be a rather more specific infection like glandular fever or chickenpox. And they will say “I got that infection and I never recovered from that infection”.

(M.E. is caused by an 'enteroviral' infection NOT EBV or Herpes Zoster)

We know as I say that there are a number of viral infections, particularly viral infections, that seemed to do this. But at the same time there also a number of cases where non-viral infections seem to trigger M.E.. We know that Q fever can cause an M.E. like illness. 

(They are 'misdiagnosed' CFS illness if Q Fever is primary cause)

We know that some people develop M.E. from salmonella infections, although these are rare.

(False, NO evidence and it doesn't even make logical sense)

It is primarily viral infections that seemed to trigger M.E. So that is somewhere where we have a great deal of certainly. Where things become rather more complicated and uncertain and the research evidence is somewhat conflicting, is whether these infections that actually trigger M.E. then go on to persist in the body and play a role in keeping the illness going. In other words do persisting viral infections also play a role. And as I say the evidence here is somewhat conflicting.

(Yes, an enterovirus)

The other aspect to infections is that part of the perpetuation of this illness seems to be involving the role of the immune system. On a way that the immune system triggers and kicks in once you have the precipitating viral infection. Part of the immune system disturbance in M.E. may involve what we’ve call reactivation of latent viral infections. So these are infections that you already had hanging around in the body that particularly herpes virus infections like Epstein Barr virus and human herpes virus type 6. And there is certainly some evidence from the research studies that are being carried out, that once the viral infection has taken place, the immune response has taken place, that some of these latent viral infections then become as it were reactivated more active again.

(Yes, this is possible)

So it could well be that the viral infection that triggers this illness off, is not playing any further role in keeping the illness going. But as part of the immune system response to that viral infection there is reactivation of latent viral infections within the body. So it’s quite a complicated picture.

And of course this is something that really does need to get resolved because there are quite powerful anti-viral drugs which can help as a possible form of treatment for this illness, if viral infections are involved in keeping it going. All these reactivated viral infections are involved. And one such drug is called valganciclovir and there have been some small clinical trials taking place. Another one was recently reported from Jose Montoya’s group in Stanford in California suggesting that there may be benefit from giving an anti-viral drug, particularly if you get the right subgroup of patients with the reactivated viral infection, you give them a course of valganciclovir, valcyte. So that is an interesting approach to the role of infection in this illness.

(This drug does not treat Picornaviruses)

Are there other possible triggers for M.E. (also known as Enteroviral Encephalomyelitis) ?

I think there are other things that trigger this illness of in addition to the viral infections that we’ve already been talking about. These are things that we would term immune system stressors. And I have a particular interest in the role of one particular immune system stressor which is a vaccination. Which is essentially mimicking the effect on the body’s immune system of an infection. And we know that a small but significant number of people with this illness will either predate the onset of their illness to a vaccination, although they describe a very significant exacerbation of symptoms, or a relapse following a vaccination.

(Yes, an enterovirus, post-vaccine)

It’s quite interesting when you look at reports from people who describe the onset of their M.E. following a vaccination, that there is certain vaccinations which seem to be heavily weighted in this respect. One vaccine in particular is Hepatitis B vaccine which seems to be a trigger factor for this illness. Quite a considerable number of people that I’ve collected over the years. So whether there is something slightly strange about Hepatitis B vaccination in relation to M.E., we’re not quite sure at the moment, but it certainly has been linked to the onset development of other autoimmune disorders such as SLE in the medical literature.

(Many cases of M.E. post-Hepatitis B vaccination)

Having said all that I think it’s important also note that in addition to all 75% of people who predate the onset to a fairly clear cut infection or perhaps a vaccination, we have a group of a significant minority who develop this illness in a rather more gradual fashion and do not predate the onset of their illness to any particular event whether it’s infection, vaccination or whatever. They may describe a series of infections after which they become more and more unwell and eventually if you like slip into a ME/CFS like illness. But they don’t have a clear cut factor which seems to be triggering their illness.

(a chronic enterovirus infection, is possible?) 

Can a trauma be a trigger?

Trauma can occasionally be a trigger factor in the development of this illness. And just like infections and vaccinations it can sometimes cause a major relapse or exacerbation of pre-existing symptoms. So we do have a small number of people who will predate the onset of their illness to perhaps a major road traffic accident. Another form of physical stress if you like which sometimes is described as an onset to this illness is in people who undergo major surgery general anesthetics. So I think you could bring those people into this group as well.

(a enterovirus being present at the same time is possible?)

Seminar 39: M.E. (also known as Enteroviral Encephalomyelitis), exercise and the mitochondria

Dr. Charles Shepherd. Broadcast 7th April 2014

What are the effects of exercise on someone with M.E. (also known as Enteroviral Encephalomyelitis)

The effect of exercise on people with this illness is very characteristic and it is really a diagnostic key, a diagnostic feature of the illness. So that when people exercise their muscles run out of energy, they run out of the capacity to perform exercise. So what we term exercise induced muscle fatigue is, I believe, what is probably the hallmark of this illness.

Interestingly enough, when people exercise beyond their limitations they will also get what we call post-exertion malaise, post exertion fatigue. This can sometimes be delayed for several hours or even 24 hours. So they go to the point to their exercise tolerance and stop, but the following day perhaps, they then feel that they’ve got an exacerbation of their symptoms because of this symptom of post exertion malaise.

What is exercise tolerance time?

Exercise tolerance is a term that we would normally apply to exactly how long someone can exercise for before fatigue sets in, quite often pain sets in and then if they continue after that actual weakness and unsteadiness of the muscles will occur. It’s a very variable factor with people with M.E.. So someone at the mild end of the spectrum with this illness they may be able to go for a walk for half a mile, perhaps even longer before they’re starting to feel fatigue and weakness. Whereas someone who is more moderately affected may only be able to walk perhaps a hundred or two hundred yards. An absolute maximum before they reach the point at which they cannot carry on any further. And of course people at the severe end of the spectrum, who are wheelchair bound, bed bound and house bound, they would have very very limited tolerance for any form of physical activity or exercise.

The other, I suppose, characteristic of this is it depends what sort of exercise activities are being undertaken. If it’s a short burst of terribly strenuous or physical activities like saying trying to go for a ride on a bike or a run or something which someone with M.E. would not be able to do, but if you put someone with M.E. through that sort of exercise their ability to sustain that form of high-intensity exercise will be very very short. Whereas if it’s low-intensity exercise, walking for instance as I say, there would be a wide variation in the tolerability as to how far someone would be able to do that.

What is the effect of M.E. (also known as Enteroviral Encephalomyelitis) on the muscles?

The effect of M.E. on the muscles is this symptom which I already described of exercise induced muscle fatigue. So we have this range of muscle symptoms which develop progressively after someone has been doing any form of activity. So fatigue will set in in the muscle, pain will probably set in in the muscle - but not always - and then if the activity is pushed on beyond the persons limitations, actual weakness will occur in the muscles.

How can one avoid exerting oneself too much?

To avoid getting these muscle symptoms and overexertion, to a certain extent it requires a process of trial and error. It’s something that people with this illness learn to develop and the way which we try to make people understand the best way to cope with this key symptom of M.E. is through a process what we call pacing. This involves very careful management of activity and rest or relaxation.

So what we would advise patients with this illness to do is to pace their activities. So that they are not exceeding their limitations, they are dividing their physical and their mental activities into little small chunks, so they do a little bit of physical activity within their limitations. They then have a period of rest or relaxation. Perhaps after a bit of physical activity they might do a bit of mental activity, and then they have a period of rest or relaxation.

What is important not to do is, and this takes people into what we call a boom and bust cycle, is to push on to the point of physical exhaustion, fatigue and then stop because then you’re just going to get a prolonged period when you’ll not be able to do anything and return to activity. So it is very important to try and pace activities, with little bits of activity, gaps in between, followed by little bits of activity.

What’s the difference between pacing and GET?

The difference between pacing and graded exercise therapy very much depends on who is recommending the particular form of treatment. But in very simple terms pacing is living within your limitations. But at the same point within those limitations, given the fact that you are having little gaps, little periods of rest or relaxation between activities, gradually trying to increase the amount of time you are spending on a physical or mental activity. But certainly not pushing yourself beyond your fatigue barrier.

Graded exercise is a rather more structured and pro-active form of activity management in which people are, if you like, often encouraged to push beyond their boundaries and not necessarily take a rest when you would be taking a rest during pacing. Our experience, certainly in patients surveys, is that 90 % of people who respond to patient surveys on activity management find that pacing is a very effective form of activity management. Very few people report any sort of adverse effects to it. Whereas if you look at patient opinion on graded exercise you will find that up to about 50% of people in these surveys report graded exercise actually makes them worse. But there is a small number of people who find graded exercise to be helpful in their management.

I suspect this reflects the fact, going back to my previous points about this big umbrella of people that come under this term chronic fatigue syndrome, that there are people who have an illness of one end of the spectrum which may well be more of a psychiatric type of illness who respond to this type of approach. Opposed to the people at the other end of the spectrum with very much a physical M.E. type illness, who are much more likely respond to pacing.

How to deal with relapses while pacing?

The way to deal with relapses in relation to pacing is first of all to try and make sure that you can recognize as soon as possible that you’ve got an exacerbation of symptoms going on or that your illness is going into a relapse phase. To a certain extent this is fairly recognizable because most of the things that we know cause M.E. are also the sort of things that tend to cause a relapse. So relapses are in particular caused by infections, sometimes they can be caused by vaccinations, stress seems to play a particularly important role in causing relapses and sometimes a physical trauma. We talk about road accidents, we talk about surgical operations could cause a relapse. So if you are aware that any factors are going on, like an infection, that is likely the cause of a relapse, you need to modify your pacing program to take that into account.

So you would drop the degree of activity you were doing, both physical and mental within those little chunks, to a lower level. You would decrease the time you were doing involved in those activities and you would at the same time extend the period of rest and relaxation between your activities. So it’s a very careful balance that has to be struck, and again as we are learning how to do pacing, it’s very often a question of trial and error before you actually pick up and learn how to do it properly.

What role do the mitochondria play in M.E.?

The mitochondria play a very important role in M.E. Mitochondria are tiny little, what we call organelles within the muscle and they’re rather like Duracell batteries within the muscle. They’re the places where chemical reactions take place which break down sugars, which were taken from our diet to actually form energy in the form of something called ATP.

We know from our work. Actually the very initial stuff on mitochondrial dysfunction in this illness was done on some of my own skeletal muscle, this was done over thirty years ago, and the results were published in the Lancet. We demonstrated with someone called professor George Radda from Oxford the fact that when I exercised there was an abnormal increased amount lactic acid being produced in the muscle. Which is indicative of a problem within the mitochondria.

At the same time some research was being done by a colleague of mine, professor Peter Behan up in Glasgow which was actually again taking little bits of muscle and looking them up under the microscope. These experiments under the microscope show that there were actual structural changes in the mitochondria.

So we have evidence of biochemical abnormalities in the mitochondria from the magnetic resonance spectroscopy studies at Oxford, and structural abnormalities from the electron microscopy studies that were being done in Glasgow.

So we know that this seems to be a problem with mitochondrial function in M.E. Which may play a very important part in explaining why people have this very characteristic symptom of exercise-induced muscle fatigue, and sometimes pain in this illness.

Seminar 40: M.E. (also known as Enteroviral Encephalomyelitis) & possible treatments

Dr. Charles Shepherd. Broadcast 21th April 2014

What are the most common symptoms in M.E. (also known as Enteroviral Encephalomyelitis) ?

The most common symptoms in M.E. are I think grouped under three main headings: the brain symptoms and in particular here we have what we call "cognitive dysfunctions". This is problems with normal mental activity, problems with short term memory, concentration, attention span, being able to process new information and retrieve information.

Balance problems are a characteristic feature of this illness. People don’t describe this as sort of feeling dizzy, spinning round, but they say that they feel as though they’re constantly unsteady when they’re walking along. As though they might be walking on rubber or so they probably had too much to drink. We know that the balance centers in the brain may be disturbed in this illness.

A third part of the brain abnormalities in this illness causing brain symptoms, is what we call symptoms relating to the autonomic nervous system. In medical jargon we call this orthostatic intolerance. This is problems related to being able to stand up for a long period of time. Or symptoms relating to changing posture from being flat or lying down to standing up. In which case there may be a change in or lowering of blood pressure causing what we call orthostatic hypotension; fall in blood pressure when changing posture. This causes problems such as feeling faint, sweating or even feeling sick.

So we have this group of important neurological symptoms, which I think fully justifies this disease being called a neurological illness by the WHO. We then have the very characteristic muscle symptoms which I already described, the exercise-induced muscle fatigue, pain which can be very severe in some people. It’s not always present as muscle pain but muscle pain can be a very major feature of this illness.

We then have what I call the infective immunological type symptoms; a feeling as though you got a sort of ongoing flu-like illness which may be accompanied by feelings of sore throats, enlarged glands.

And then finally, I think the other key symptom of this illness is the sleep disturbance. So I think you cannot have this illness without some form of sleep disturbance. It’s interesting that in the very early stages this sleep disturbance may be an excessive requirement to sleep what we call hypersomnia, particularly in the early post viral stage. Then this quite often moves on to another type of sleep disturbance where people have either difficulty initiating sleep, getting off to sleep, they have erratic sleep, they wake up early in the morning. But they’re no longer having to sleep 12-14 hours a day. Whatever type of sleep disturbance they have, they will describe the fact that they wake up and feel unrefreshed, they have unrefreshing sleep whatever type of sleep disturbance they have.

So those I think are the key cause symptoms of this illness. There are many other symptoms which are associated with it: increased sensitivity to light and noise, increased sensitivity to alcohol is a very interesting symptom which I think is diagnostic of this illness. But I think the brain, the muscle, the infective and the sleep symptoms are the core ones you would make the diagnosis on.

Which symptoms can be treated?

The symptoms that can be treated, and I think really should be treated by a doctor when they occur, are pain and sleep disturbance, and if it actually occurs as part of the illness then obviously any sort of depressive component.

So as far as pain is concerned there are a number of drugs which doctors can consider prescribing when ordinary types of pain reliever like aspirin, brufen and paracetemol are found to be ineffective. And we have a, if you like this, step ladder of pain killing drugs available on prescription which could be considered when these sort of ordinary pain killers aren’t working.

Examples of the sort of drugs which might be used, there is a drug called Amitriptyline, which is a sedating tricyclic anti-depressant drug, which is used at very low doses, not used as a depressive, the sort of dose you would use to treat a depression. It’s used at a very low dose and at the very low dose it can help with pain, it can help with muscular pain, neuropathic nerve pain, and it can also - because it has a sedating effect - help with sleep disturbance. So that is one drug that can certainly be discussed with the patient.

If pain is more severe then there are other drugs which pain relief doctors who are specialized in this type of medicine might consider using. One of which is called Gabapentin. This is a drug which is actually normally used to treat epilepsy, but it’s also been found, again as a different type of dose and regime, to be very helpful and sometimes in pain relief particularly pain relief when that involves nerve pain.

There are various drugs which can help with sleep disturbance in addition to possibly Amitriptyline. There are groups of drugs which can help people, there are short acting drugs, they can help people get off to sleep and they are just used for a very short period of time.

There is also some evidence that the drug melatonin, which is used to help people cope with jetlag, can be helpful in some people with this illness. And people with this illness who have a very disturbed form of sleep disturbance, sometimes they gather a complete reversal of sleep rhythm, that is something that could be considered in those circumstances.

And as I say if someone has a clinical depression with this illness, and a clinical depression is something that can occur with any long-term illness, especially when you’re having all the problems that you’re having with an illness like M.E., then that always has to be taken seriously. Because we know that sadly some people with M.E. who are very upset because of all the things that are happening around them, do actually contemplate and just occasionally even commit suicide.

So depression, clinical, true clinical depression as opposed to just feeling fed up with this illness must be taken seriously. And again if necessary treated with antidepressants.

Sadly at the same time we have groups of symptoms which are not amenable to drug treatment. One example there would be the problems that people have with cognitive function, problems with memory, concentration and it would be wonderful if we as doctors had some sort of drug that we could help people with that type of symptom cope with better.

What other treatment suggestions can you give?

Other treatments in addition to the key aspects of management which of course are activity management and pacing and dealing with symptoms such as pain and sleep disturbance are, I think that any doctor who is dealing with this illness has to deal with the many practical aspects that this illness creates for their patients.

So I think they have to be very pro-active and supportive in relation to things like helping them with their benefit applications, giving them a suitable advice on what they should do in relation to work and employment. And in the case of children and adolescents helping them with their education which might involve trying to get home tuition, if a child is able to do so, and integration back into school at a very gradual level if the child is well enough to start returning to school.

What help can be given to very severe M.E. (also known as Enteroviral Encephalomyelitis) patients?

Help for people with severe M.E. is very sadly lacking, certainly here in the UK, and I suspect the same picture applies throughout the rest of Europe. Many of these people who are wheelchair bound, house bound or bed bound have no access to medical services. They are unable to get to hospital clinics for appointments obviously and at the same point we have a number of specialist referral hospitals based services here in the UK now, but these clinics by and large are not providing home visiting domiciliary services for people with severe M.E..

So there is a major problem for this group of patients in accessing medical services and it is something that really should be addressed as a matter of urgency. We have tried to do that through the all-party parliamentary group on M.E., but it very much relates to the willingness of physicians and people looking after patients at a hospital based level to try and set this in motion, And sadly that is not happening.

Seminar 41: Promising discoveries and research

Dr. Charles Shepherd. Broadcast May 5th 2014

Which are the most important discoveries of last years regarding M.E. (also known as Enteroviral Encephalomyelitis) ?

When it comes to important discoveries in the past few years I think, apart from the very interesting results from the clinical trial of the drug Rituximab, it is very difficult to isolate anything and say that is a major breakthrough in our understanding of this illness, that is a major piece of the M.E. jigsaw fitting into place. I think what we are seeing at the moment is a number of small pieces of this ME/CFS jigsaw starting to fit into place. So these are pieces of information, such as I say, rather like pieces of a jigsaw in relation to what is going on in the brain.

And in particular here I think I would like to highlight the work of Professor Julia Newton up in Newcastle here in the UK who has done some really solid work on the role of what we call this autonomic nervous system, this division of the nervous system that helps to control blood vessels. It also has a role in gut activity, bladder activity and even blood supply to the skeletal muscle. And it may well be that the disturbance in autonomic nervous system activity, and the results of the research that is going on in Newcastle, is going to help us get a much better understanding of what may actually be going wrong in skeletal muscle and also possible blood supply to the brain and the way in which perhaps decreased blood supply to the brain because of the autonomic nervous system dysfunction is causing these symptoms like cognitive dysfunction with short term memory, attention span and concentration being very poor in these patients. Because that is an area where we really do need to make some headway.

In addition to that, other pieces if you like of this jigsaw which is starting to fit into place, is the role of the immune system. And I think we are starting to change our mind about the role of the immune system in this illness. There used to be a feeling that the immune system abnormalities, which have not always been consistent or robust, were pointing to some sort of immune system deficiency in this illness, a defective immune system response. 

Whereas the sort of picture that is now emerging is of an immune system which may be, as a result of this viral infection that triggers the illness off, acting in a rather overactive state. So that there is in medical jargon low-level immune activation taking place.

And one result of this is the production of immune system chemicals called cytokines. 

These are the immune system chemicals that you normally produce when you’ve got an infection, a flu-like infection that make you feel so grotty. It is not the virus itself that makes you feel flu-like, it’s the cytokines. And it is possible that these cytokines being produced at a long going basis as a low-level of producing these sort of ongoing flu-like symptoms, malaise and everything else that goes with having M.E.. At the same time we now have drugs and this is taking us on to possible forms of treatment which can actually dampen down this cytokine activity.

So I think by piecing these bits of muscle, brain, immune system, genetic factors together, we’re starting to build up a more solid picture of what is going on in this illness. And I don’t think we’re going to find in the future that there’s going to be some sudden breakthrough, a major piece of research which suddenly explains all this. It is going to be very much a question of providing further bits of information, further bits of this M.E. jigsaw and putting them into place and fitting them together. Because all these different abnormalities are probably interacting to a certain degree.

What is the MRC and what is its research program?

The MRC or Medical Research Council is the government body here in the UK that sits on a very large pot of money for medical and scientific research. And, as I’m sure is the case in many other European countries, there has been considerable criticism from the patient community and also from politicians about the lack of research into the biomedical causes of M.E..

Now up until recently the Medical Research Council I have to say took very little notice of these complaints and concerns, but about 3-4 years ago it decided it would set up an expert group on ME/CFS research and I was a member of this group and it was a very welcome move. It was something that I would certainly recommend to people who are campaigning to try and get government-funded research elsewhere.

So we had an expert group with a remit to identify a list of high-priority and medium-priority research items which it was felt should then be encouraged from the point of view of getting researchers to submit research applications to the MRC. So we identified these research priorities involving muscle, brain, immune system, sleep disturbance, genetics and one or two other subjects and invited applications from the research community.

And what was so welcome about this process was that we didn’t expect that many research applications to come in. But in actual fact we got far more research applications than there was money available for.

A total sum of about 1.5 million pounds of ring-fenced money was made available for these research grants. And with very few exceptions these were very high quality research applications. In addition to that many of them involve people who were totally new to this subject. So it was I think a very welcome and very productive exercise. And in the end 1.5 million pounds of government research money was distributed to five projects and we have five projects now underway.

There is a study on sleep disturbance and also a drug treatment is being trialed for use in sleep disturbance in M.E. as part of that study.

We have a study at the University of Liverpool which is taking forward the research on mitochondrial disturbance in skeletal muscle. We have a study looking for biomarkers, is there a biomarker, a blood abnormality which can be related to debilitating fatigue. And this is starting off using patients with a very well-defined condition called Sjogren syndrome in which central fatigue is often very prominent feature and it has a number of overlaps with ME/CFS.

And then we have a study on immune system functioning in M.E. and this goes back to the point I was making about immune system activation in this illness and the production of these immune system chemicals. We know that when people with an illness called hepatitis C are treated with interferon, which is one of these immune system chemicals, they can actually develop an M.E. like illness as a side effect. So this study on the immune system function and possible low-level activation of the immune system in M.E. is going to look at this group of people who are being treated with interferon for hepatitis and see what differences there are between the group who do not develop ME/CFS-like symptoms and the people who do develop ME/CFS-like symptoms when they are treated with interferon.

And then the final study is a further study on autonomic nervous system dysfunction. This is this part of the nervous system which controls blood flow, blood vessels, pulse, heart rate, and this will take forward some of the very important research that professor Julia Newton and her colleagues in the university of Newcastle are already doing in this area. So that’s five very important studies now being financed by the Medical Research Council here in the UK.

Seminar 42: State of affairs regarding M.E. (also known as Enteroviral Encephalomyelitis)

Dr. Charles Shepherd. Broadcast May 19th 2014

What will help to get recognition of M.E. (also known as Enteroviral Encephalomyelitis) as a biomedical disease?

There are two important things that we need to do in order to get proper recognition from the medical profession for M.E. being a biomedical disorder. The first thing is that we have to identify some robust and consistent, what we call biomarkers, to make a diagnosis of this disease. As I’ve been saying earlier, we don’t have blood tests which you can diagnose M.E. through. If we can get some biomarkers of abnormalities in the blood in relation to the immune system or the endocrine, the hormone producing system, or any other system which are consistent in people with M.E., which are not found in people who are normal and healthy, are not found in people with other diseases, then we have evidence of this being a physical disease.

The second thing that we must have is consistent evidence of abnormalities in the muscle, the immune system, or the brain which are consistent with symptoms. Because at the moment we have a number of abnormalities which are quite clearly described in the literature, but they don’t necessarily are linked to symptoms. We can make assumptions that they may relate to symptoms just like we can say that low blood pressure, low blood volume to the brain may be causing cognitive dysfunction. But we haven’t proven that. And until we can come back to the medical profession with firm evidence in this sort of area and say here is a abnormality in the brain, it’s clearly linked to that particular symptom, then we are going to make real progress in persuading sceptical medical colleagues of mine that this is a real physical illness. 

Which current developments are hopeful?

Current developments which I think are really helpful in taking this illness forward from the research point of view, certainly in addition to the research initiatives that I’ve already been describing from the MRC and bodies such as that. But I think the real positive aspect of research at the moment is the way that people are cooperating, starting to cooperate on an international basis. Because up till now we’ve had a lot of different people in different countries getting on with their own research.

But I think we are now reaching the point where we are meeting together, discussing research that’s taking place and cooperating on research. Certainly one example of this is the way that the biobank that we set up at UCL is cooperating with the Norwegian biobank.

We’re using similar types of protocols, we’re using similar types of criteria for diagnosing the people who are giving the blood samples. 

And one aspect to this that I think is very encouraging is the work that Dr. Andy Kogelnik over in the States is putting into this, and the Open Medicine Institute, the OMI. I was lucky enough to be invited to go over to New York last year, to participate in the two, three day meeting that we held. This was a round table meeting of experts. Researchers and clinicians from all parts of the world who just got together, we were cocooned if you like, in a hotel for three days and we just discussed research. Tossed around a lot of ideas and came up with things which really needed to be done and needed to be funded. And it wasn’t just talk. Andy is gone off and put these ideas out on the internet and money is starting to come in, and people are starting to discuss and cooperate as a result of that.

I think another important development in a similar way but within the UK is the development of what we call the UK research collaborative, which is an offshoot of the MRC expert group on ME/CFS research. And this is an umbrella organization that is bringing together existing researchers, new researchers, people who are interested in getting involved with this research, charities, people who are funding research like the MRC and the NIHR, as well as - and this is very much a missing link in research at the moment - the pharmaceutical companies.

So we’re all meeting together as one body to discuss research. We’re planning a major two day conference next year, to take this forward. And I think that’s again something that people in other countries could look at and perhaps do something very similar to bring everyone together within a country, who’s involved in any sort of research or funding research to actually meet and discuss what’s going on. 

What hope can you give to the most severe M.E. (also known as Enteroviral Encephalomyelitis) patients?

I believe there is real hope now for the people who are at the most severe end of the spectrum of this illness, who are bed bound, wheelchair bound or house bound. Firstly because, as I’m being saying, we are starting to make real progress in piecing together what are the various aspects that are causing this disease. As we understand more about what is causing this disease, we are now gonna start looking and we are looking at treatments like Rituximab, and things, drugs which actually act on the underlying disease process. It’s opposed to just trying to patch things up by treating symptoms.

At the same time I know progress is very slow and there is an urgent need to make things much quicker. But there is a recognition from the people who are working in the clinics, the hospital based clinics, that the severely affected are not getting a fair deal. That they need to provide some sort of specialized inpatient facilities where people with severe M.E. can be looked at in a sympathetic environment where they can be properly assessed, where any management interventions could be looked at in a careful and sympathetic way.

And where this is not possible that there needs to be domiciliary home based services where the hospital goes out to the person with severe M.E. and deals with them at home. Because it is clearly just not acceptable that a whole group of people with this illness are just totally divorced from the normal health service and social care services that are available to everyone else in this country. And to whom people with severe M.E. have paid for and they're now getting absolutely nothing in return.