The Komaroff Lecture

[Guest guest]

The Komaroff Lecture

http://home.vicnet.net.au/~mecfs/general/komaroff.html

This address was given on 18th November 1995 in London by Professor

Komaroff, Professor of Medicine at Harvard Medical School,

Boston, USA.

(Ed: This talk was also given as the Melvin Ramsay lecture at The

First World Congress on CFS and Related Disorders in Brussels on 9th

November. Here Professor Komaroff refers to CFS as M.E., for benefit

of the UK audience. This is the first part of Dr Komaroff's address.

The second part will be printed in a future edition of 'Emerge').

" I will try today to summarise some of the most important and

provocative research that has been done on what in the States we

call CFS and you call M.E., in a way that everyone here can

understand. In the last two years there has been research reported

from the UK, Europe and the United States showing new lines on this

illness. They satisfy my bias as a clinician studying this illness

for 15 years, because they point to the role of infectious agents,

and also to the possibility of abnormalities in the brain.

Patients say their illness was often triggered by an infection, and

many of the symptoms they've had would seem to involve the brain;

and yet this illness is defined by a group of symptoms - symptoms

are entirely subjective, anyone can claim them. But science regards

it as proof only when there is objective measurable evidence of

abnormalities. In my view one of the most important things that has

happened in the past few years is that such objective evidence has

increasingly materialised.

First - studies that have identified the frequency of this illness.

This is a study conducted by our group (slide) on patients seeking

care for any medical problem at all - not just for fatigue. We

concluded that about one out of every hundred people, or 1,000 in

100,000, meet criteria for M.E. Another study we published several

months ago, did a random survey of 4,000 people, regardless of

whether they had sought medical care. The estimate was that 98 per

100,000 in the US meet criteria for this illness. Many more complain

of debilitating chronic fatigue, but do not meet the criteria. For

now, we can say with some certainty that 1 in 1,000 people in the

States has this illness, which makes it as common as MS or Lupus.

Several things struck me when I was first seeing patients with M.E.

many years ago. First, unlike people who seek medical care because

of fatigue, in most of our patients their fatigue began suddenly

with a flu-like onset, they were saying 'it all started with that

virus'. The second thing about the illness was the phenomenon we

call 'post-exertional malaise'. After modest physical exertion, and

typically not while the person is exercising, but the next day or

two days later, there is a flare-up of fatigue, weakness, difficulty

thinking, sore throat, fevers, in the majority of patients - as if

physical exertion was provoking a response that affected the whole

body. We think it may involve an unusual response of the immune

system to exercise, and are currently studying this.

Thirdly, there's the possible involvement of the brain. Most

patients complain of difficulty with concentration and memory, of

other symptoms that suggest brain involvement, such as tingling and

numbness, transient periods of weakness, photophobia or

hypersensitivity to sound. Those symptoms are experienced, in our

study, by the majority of patients. A small group had symptoms that

clearly indicate a disorder of the brain - periods of total

disorientation or confusion, seizures in patients who never had

seizures before, ataxia - difficulty with balance, weakness of one

side of the body, blindness, and one sided sensory deficit, meaning

numbness or tingling sensations. This is a small group from a much

larger group of patients, but they do suggest there's a process

involving the brain.

Physical examination abnormalities are largely absent, with the

exceptions - swollen lymph nodes in the back of the neck; and two

tests of balance (part of neurological exam) are abnormal in a

substantial fraction of patients. We did a study with physicians who

did not know if they were examining a patient with M.E. or a healthy

individual, and identified that these abnormalities were present

more often in M.E. patients than the healthy population.

Recently we've completed a study to show how badly debilitated

patients with this illness are. The most widely used measure to

define functional capacity in various diseases is called the SF36.

This test has subscales - physical function, general scores in

thousands of healthy Americans - you can see the relatively high

scores here (slide with graph). We also studied patients with heart

failure, and major depression, and they are shown here in the

middle. But patients with M.E. had scores that are lower on all

except the mental health scales, where they have far better scores

than the depressed patients. So by these measures, M.E. is a

terribly debilitating illness, and M.E. patients are more

functionally impaired than patients with congestive heart failure,

major depression, and many other diseases.

In my mind there are two basic controversies about this illness. Is

it all imaginary? Is there anything there that says 'this person is

sick'? The other question is - is M.E. a psychological illness? Many

people ask 'why isn't M.E. or CFS just depression or some other

psychological illness?' That way of asking the question says the

asker doesn't take psychiatric illness seriously - it is diminished

and trivialised that way. Depression is a serious illness, just as

M.E. is, but I don't think they are the same thing. These are the

reasons why:

First, there are a group of symptoms in M.E. - sudden onset, lymph

gland swelling, this post-exertional malaise, and night sweats. None

of these symptoms reflect psychiatric illness. Secondly, there is a

whole series of good studies that find abnormalities of the brain in

the hypothalamic-pituitary axis, different to what one sees in major

depression or other psychiatric illness. Third, there is the failure

of this illness to resolve fully with psychiatric therapy. In my

experience, many M.E. patients do develop psychiatric illness, and

the depression responds to appropriate therapy. However, not once,

has anyone's illness gone away with psychiatric therapy. There was

an important paper presented at the Brussels conference, that used a

treatment for depression called Prozac; in a randomised trial they

found absolutely no benefit to M.E. from Prozac. And then there is

the failure to find evidence of psychiatric disease, either before

or after the onset of M.E., in a large fraction of our patients.

To summarise an important study of this hypothalamic-pituitary-

adrenal axis that I mentioned - the hypothalamus makes hormones that

affect the pituitary, and the pituitary makes hormones that affect

the adrenal gland. In healthy people a normal amount is made by each

of these glands. In major depression, you see a very hight amount of

these chemicals made by each organ; but in CFS/ME what you see is

the opposite from major depression - an underproduction by the

pituitary of ACTH, which leads to an underproduction of cortisol by

the adrenal glands. This objective measure in M.E. is different from

healthy people and even more different from major depression.

Another test of the hypothalamus is a study from Behan's group at

Glasgow. They looked at a hormone called Prolactin, after giving a

compound that affects the brain chemistry called Buspirone. In

healthy individuals, and patients with depression, you see a slight

increase in the level of Prolactin when you give Buspirone. And in

CFS or M.E. you see a very striking higher rise in the prolactin

level following giving this compound.

So the simple answer to the question 'why isn't it all just

depression or some other psychiatric illness, is because it's not!

When we looked with our psychiatric colleagues we could not find

evidence of psychiatric illness in the majority of M.E. patients.

Now let's turn to other objective laboratory studies. This is a

paper published three months ago, in which we basically summarised

10 years of laboratory studies, conducted on over 700 patients with

M.E. from two different geographic areas in the States, who over 10

years have had 18,000 lab tests. These patients were compared with

healthy people of the same age and sex. All blood samples were

tested by technicians who did not know if a sample came from a

healthy or an M.E. person.

We found very striking increased frequencies of abnormalities:

Immune complexes were found nearly 27 times more often in M.E.

patients than in healthy controls. Elevated levels of immunolglobin

G were found nearly nine times more often in the M.E. patients.

Unusually shaped white blood cells were found 11 times more often.

Several other abnormalities were also found. So these tests are

saying there is, in the M.E. patient, an activation of the immune

system. The unusual white cells are typically taken to mean evidence

of a virus infection. There is more evidence in the literature that

the immune system in M.E. is chronically turned on. I think the body

of evidence overwhelmingly says there is a chronic state of immune

activation in these patients - as if they're fighting against

something - what are they fighting?

Now what is the evidence of abnormalities in the brain? This (slide)

is the top part of the brain of a 55 year old man who became

suddenly ill in 1985 and has never returned to full health. Here are

black areas of what we call 'white matter', and here you see

circular white spots that shouldn't be there. Another patient

(slide), and here in the deeper part of the white matter, you see

larger white spots. And that patient had no clinical evidence of

multiple sclerosis. This (slide) third patient had terrible problems

with balance and gait early in her illness. This part of the brain,

the cerebellum, is important for balance, and there in the

cerebellum are those white spots. In a large study of 150 patients

we found nearly 80% had these spots, compared to only 20% of healthy

age- and sex-matched people. Many of us have some inflammatory

illness of our brain at some time that leaves a little spot. So

these spots don't always indicate a current abnormality. What's

striking was the much higher frequency of these abnormalities in the

patients. Three other research groups have reported similar results.

Another way of taking a picture of the brain is called SPECT scan. A

chemical is injected and travels through various parts of the body

including the brain. That chemical emits a signal of radioactivity

that is picked up by a special camera. It creates a picture (slide) -

this is a healthy scan and here you see the outer part of the

brain, called the cortex. In a healthy individual there would be no

holes in the evenness of this picture.

Look at the outer part of the brain in this M.E. patient (slide).

You can see holes where it should all be smooth. We started SPECT

scanning in 1982 on a patient I'd been following for five years. He

said " I've got to see you, this has been the worst week since I got

sick. All week I've been bedridden, but I also have trouble thinking

and particularly expressing myself - my family says I'm not making

sense, I'm saying words that are not really words. And the entire

right side of my body feels numb, with tingling. "

Now that combination of symptoms suggests there's something wrong

with the left side of the brain, which is critical in speech and for

sensation on the right side of the body. I saw him and did a very

careful examination. I wasn't sure I could find any objective

evidence, so we got a SPECT scan. And there (slide) was the left

side of the brain - there should be a yellow margin around it, and

there's none. Three months later much of that abnormality had gone

away. Now it was the left side of the brain that doesn't look so

good, and that week, although he felt much better, the one problem

he was having - he's a computer graphic artist - was getting the

objects straightened out on his computer screen. The part of the

brain that looks at space and understands spatial geometry is there

on the left (slide).

So is there an objective abnormality in M.E. patients with symptoms

that suggest the brain is involved? We subsequently did SPECT scans

of a large number of M.E. patients, patients with AIDS

encephalopathy, major depression, and healthy individuals. The

computer counted how much signal was coming from the brain. Here

(slide) is the signal in healthy people, and in major depression

which is essentially the same. But here was the signal in patients

with AIDS involving the brain, and here in M.E. involving the brain.

Both statistically significantly lower. So there's something

impairing the blood flow to the brain in these two groups (AIDS

encephalopathy and CFS) compared with these two groups (depression

and healthy controls). Is there objective difference?

In studies we have underway now, not yet submitted for publication,

we have measured brain waves (EEG) - activity generated by the

brain. We also did this with the computer which is scoring a

brainwave as normal or abnormal. Two kinds of abnormal brainwaves,

called sharp waves or spikewaves, are seen more often in patients

with M.E. than in patients with major depression or healthy people.

Yet another objective measure that says 'there's something wrong in

the brain.'

Recently a group from s Hopkins medical school looked at the

autonomic nervous system, part of the brain that controls blood

pressure, heart rate, breathing, and other basic processes. And they

used tests of the autonomic nervous system including 'tilt-table

testing', and found this test was abnormal by very stringent

criteria, in 70% of M.E. patients and none of the healthy control

people. We have also been doing similar studies for the past four

years. We published a paper a few months ago on balance, or

disequilibrium, in patients with M.E. On objective tests of the

balance centres of the brain and the inner ear, we found very

abnormal results in a substantial fraction of the patients.

So the answer comes back 'there is something wrong with the brain'.

I don't believe, fortunately, that M.E. produces permanent damage.

What is plain, from the research that's been done is that there are

cyclical or periodic dysfunctions of various kinds in the brain. "

The following is the second part of an address given on 18th

November 1995 in London by Professor Komaroff, Professor of

Medicine at Harvard Medical School, Boston, USA.

Q. (Dr Shepherd) A lot of us do not like the term Chronic

Fatigue Syndrome, which seems to have become a dustbin diagnosis for

everyone who is tired and unwell. I think research is moving towards

this disease being some form of encephalopathy. Do you have views on

what we might call it in a few years' time?

A. (Prof Komaroff) I share your views on CFS, which has not only

become a waste-basket, but because fatigue is a universal

experience, and it trivialises the illness. I think CFS is a

terrible name, and I'm partly responsible for it. I would have said

five years ago M.E. was a bad name because there was no evidence at

that time of any inflammatory process of the brain or spinal cord. I

actually think M.E. is getting to be a better name, but I'm

reluctant to keep changing the name of this darn illness, before we

understand it better. Even though M.E. may be a name no-one

understands, and CFS trivialises it, now that most of the public

knows what these are, we would confuse people. I think that bad as

the names are, we should stick with them until we are in a position

to find a much better name.

A. Well the question was about ataxia, which is a kind of balance

disorder when a person's gait is very broad. In my experience, that

kind of broad gait is not permanent - it can be transient for days

or weeks. Dysequilibrium, being a little bit unbalanced or bumping

into walls, that's much more common.

Q. What do the little white spots on the MRI images mean?

A. Without a brain biopsy of those little spots, and then looking at

them under the microscope, there's no way of answering that

question. But based on studies in animals, they could mean a small

patch of inflammation, that could now be an old scar, or could be

currently active. And that inflammation could be caused by a virus

infection, or just by a non-infectious immune system attack on parts

of the brain.

Multiple Sclerosis for many years has been believed to result from

an immune system attack on the cells that make what's

called 'myelin', that wraps itself around the brain cells. That

doesn't imply there's an infection going on, it could be what's

called an auto-immune disease. It is also possible that the spots

indicate an impairment of blood flow in very small blood vessels

that led to a period when those vessels blocked off and scarred the

part of the brain they would normally feed.

A. Infection can change the body chemistry in ways that could be

pertinent to M.E. At the Brussels meeting there were some studies

where changes in the energy chemistry, in the mitochondria, were

examined in patients with M.E., and there were indications that

there were abnormalities there.

Q. How close are we to a good diagnostic test for M.E.?

A. I don't see a single test or even a small battery of tests that

would be good enough to qualify as a diagnostic test. But that could

change tomorrow. There were some papers at the Brussels meeting that

looked pretty promising, but I've been down this road many times

before. It's common in science that some initially encouraging

reports on diagnostic tests later prove not so useful.

Q. A question about the age of M.E. patients .

A. This illness typically affects young adults, but can affect

children down to the age of five, and can affect people for the

first time in their lives in their 50s and 60s. So it's not an

illness restricted to young adults. A couple of other stereotypes

are demonstrably wrong - it is not restricted to upper or middle

class, and it is not restricted to people who are Caucasian (white),

it appears to affect people from all walks of life, in the developed

nations of the world where it has been studied.

Q. Were there any new treatments discussed at the Brussels

conference?

A. There were papers on the metabolism of carnitine, but there was

no paper on treatment results with carnitine, as there was not

enough information to present a statement. There was only one paper

on treatment, that was from a Dutch group that showed Prozac was of

no benefit.

Q. What do we mean by fatigue? Is fatigue distinguishable from

fatiguability?

A. Fatigue means different things to different people. For a muscle

physiologist it means that when a muscle is challenged repeatedly,

it loses strength more rapidly than it should. For some people with

CFS, fatigue means a listlessness, an inability to get up the energy

to do anything, physical or mental. I don't think I would make the

distinction between fatigue and fatiguability, as much as this post

physical exertion malaise, that is a very important part of the

syndrome; it's very commonly present, and my guess is it is surely

telling us something about what the immune system abnormalities in

this illness broadly are.

Q. Can HHV-6 virus be responsible for glandular fever (infectious

mono) in some patients, and when M.E. has started as glandular

fever, could HHV-6 be the culprit?

A. The answer is Yes. There are studies both from Germany and from

the US showing that HHV-6 can be a cause of glandular fever - not as

commonly as Epstein-Barr virus, but often enough.

Q. What makes people recover?

A. Patients have recovered from M.E. and we have gone through our

groups to see if there is something in the data we've collected that

predicts that they will recover, and therefore gives a clue as to

what made them sick in the first place. And we've been unable to

come up with anything that's useful, to my disappointment. I have

studied about 500 patients with the illness, and I was sure we could

find recoverers who would teach us something about the illness, but

try as we might, we have not found what predicts who will recover.

Q. Where do you think the next research should go in this illness?

A. There are so many areas that appear to be fruitful, studies of

brain chemistry, studies of various infectious agents. We need to do

studies of the immune system to explain the post-exertional malaise

and possibly other symptoms. Then studies of what some might regard

as the softer sort - what's the effect of this illness on the

patient's family, for example. I think it's terribly important to

understand the burden this illness places on the family and friends

who are sharing the work of dealing with it.

I believe that you throw the door wide open, and then you read a lot

of people's ideas and decide which seem the most promising. You may

get hundreds of ideas for research, you may think 10 of them are

good, and some of those are things you would never have though of in

a million years.

Q. A question about young people, and I take it you mean children as

well as teenagers.

A. Whether the incidence in young people and the general population

is rising, is a very hard question to answer. There's such great

public awareness now, and greater awareness among doctors, that what

appears to be a rising frequency may be nothing more than a rising

understanding of the illness. There is no good scientific evidence

to say that the frequency is rising over the last decade. The

literature suggests its been with us for a long time. As for whether

children recover more rapidly, we only have anecdotal evidence at

present.

Q. Are there parallels between neurasthenia, which was a diagnosis

made in the 19th Century, and M.E.?

A. From reading the literature of a hundred years ago I would say

that neurasthenia sounds a lot like M.E. There's no evidence that

neurasthenia as an illness died out, it died out as a diagnosis,

because without the capacity to understand what was causing it, and

with no treatments for it, doctors lost interest in using that

diagnosis, that's how I read history. None of the tests we are doing

now in M.E. cold have been done in the late 19th Century with

neurasthenia patients.

Q. What causes the muscle pain that is part of the illness, and how

do you treat it?

A. There's reason to believe that poor quality sleep - inadequate

amounts of time in delta-wave stage 4 restorative sleep, may be an

important part in what causes myalgia; I'm a believer in the use of

low doses of tricyclic drugs which improve the quality of sleep, and

analgesics, but they are not fully helpful in many patients. I wish

I really knew what causes it - there is growing evidence that there

is something wrong with muscle, and with mitochondrial function

particularly. That's preliminary evidence, but if it becomes firmer,

it may explain some of the underlying pathology in myalgia.

As for disbelievers among physicians, when I think of what it was

like a decade ago, then none of my colleagues knew or cared to know

anything about this illness. The situation now is the difference

between night and day. As one example of the interest in the medical

profession, since the new case definition for CFS was published last

December (1994) in the ls of Internal Medicine, there has been

the greatest outpouring of requests for that publication to my

knowledge of any scientific article - over 100,000 requests for

reprints. So I think there's a growing interest and understanding of

the illness.

Q. A question about balancing activity and rest, for recovery.

A. I believe, without any scientific basis for it, that regular

limbering exercises and light aerobics are useful, and at the same

time, that if people push too hard they can cause a relapse of the

illness. I believe in rigid hours of work, rest, and sleep, of

trying to avoid sleeping during the day, and in getting a long and

good night's sleep at night, I think this is good for all of us.

Q. A question about chest pain and sudden episodes of rapid

heartbeat.

A. Most patients experience episodes of palpitations, for no

apparent reason, not related to physical exertion or other

stressors; and a much smaller number, in my experience, getting

chest pain. I think the chest pain is mostly not of the heart, but

of the wall of the chest, and involves muscles holding the ribs

together, that get strained and hurt in the same way as muscles in

the rest of the body. The rapid heartbeat is most likely a

reflection of this autonomic nervous system abnormality - not an

effect of the heart itself, but of the way the nerves regulate the

heat rate and rhythm.

At the moment I would say there's no evidence, and we've looked,

with a number of tests for abnormalities of the heart and muscle per

se, and have not found any such abnormalities. I am aware, however,

of very early research in the UK that shows there may be involvement

of the heart muscle. But this work is much too early to say what

will come of it.

Acknowledgment: reprinted from Perspectives, March 1996, magazine of

the M.E. Association (UK).

Reprinted from Emerge, June 1996.