**********************************
Monday, April 23, 2007
OB/GYN Grand Rounds
=91Chronic Fatigue Syndrome in Women=92
James F. Jones, MD, CDC
speaking at the Univ. of Arizona Health Sciences
[ [?] indicates difficulty transcribing]
http://streaming.biocom.arizona.edu/people/?id=3D11525
[Introductory Speaker]: Well good afternoon everyone and a special
welcome to our remote sites, I would ask you to please turn off your
microphones during the presentation, and then I will invite you to
reactivate those after the presentation, and that way the background
music, haha, the background discussions won=92t interfere with the
presentation.
We=92re extremely fortunate today to have as our guest speaker Dr. James
Jones. And as I was thinking about the presentation that he is doing
today, two things came to my mind. For those of you that have been in
the field of obstetrics and gynecology for any length of time, we have
all seen those scenarios where a disease entity, or a problem entity
comes into our specialty and we never know quite what to do with it,
because if there isn=92t an excess or deficiency of something, we can=92t
really categorize it or buttonhole it in a comfortable way, and it
takes years for this to really materialize, and I can even recall back
in my career where we really thought that pre-menstrual syndrome
wasn=92t a real entity, it was just something that certain patients had
manufactured. And whether the speaker will agree with me or not, I
think that the Chronic Fatigue Syndrome kind of falls into that area
where we=92re learning more and more about it and trying to be more
effective as practitioners in dealing with it.
Then the second is just the background of our speaker, and although as
I see we=92ve never had an opportunity to interface, Dr. Jones has been
primarily in the area of pediatrics where I=92ve been in OB/GYN, we have
a lot of things in common in that we were both at the University of
Colorado for a period of time, I would guess that some of the
colleagues and faculty that I knew at the medical school who were on
the faculty at National Jewish Hospital would be familiar names to
you(Dr. Jones), and as well as some of the professors that trained me
when I was at pediatrics.
Dr. Jones received his Bachelor of Arts from Duke University, and his
M.D. from the University of Texas Medical Branch. His career has
focused more on the research area than the clinical area, and as you
read through his curriculum vitae, besides the plethora of articles
that he has published you see the presence of Dr. Jones in many NIH
study groups, and as a reviewer for many of the journals. And his
interests, I believe, have been chronic conditions and chronic areas
of illness. And so recently as I see this he has developed a
significant expertise in chronic fatigue.
I was telling Terry that often we receive these invitations to have a
visiting professor, and then we respond and they just go away, we
never hear from them again, so we were delighted to be able to attract
Dr. Jones to talk to us today.
So with that I hope not too long introduction, please welcome Dr.
James Jones, who is going to talk to us on Chronic Fatigue Syndrome in
women and the work that=92s going on with the Chronic Fatigue Syndrom
Research Group. Please welcome him with a nice round of applause.
[Dr. James Jones]: So good day. Actually Chronic Fatigue Syndrome is a
evolving entity and my involvement in it actually began quite a while
ago but with a recent four and a half year- or four year move to the
Centers for Disease Control from Denver.
We started looking at this illness back in the early 80's when I was
actually in Tucson on the faculty, as a chronic infection, or a
chronic illness associated with the consequences of infection, and it
evolved eventually into what the current state is. And so let=92s get
started with definition.
(5:00)
As it stands it=92s related to fatigue but it also has two other
components. And the fatigue is present it has to be there for at least
six months, it=92s not alleviated by rest and it=92s a substantial
reduction in activities. The second component is there has to be no
underlying or explanatory medical or psychiatric cause, and thirdly
you have to have four of these eight symptoms for that six month
period or more.
And you can look at this right away and see that it=92s probably not a
disease, but it=92s a true syndrome, and that the orange in the middle
there(referring to slide), the no explanatory medical or psychiatric
causes, one thing I want to bring up from the start is that if one
excludes people who fulfill this definition because they have one of
those things, you=92re still stuck with someone who has the fatigue and
has the symptoms.
In other words, are- should we be excluding anyone, or should this be
a syndrome similar to fibromyalgia when you can have other illnesses
and still fulfill the syndrome? In essence we don=92t know when we
exclude someone whether they=92re- what they=92re perceiving as illness is
associated with this problem or whether it=92s associated with their
primary illness. The assumption is that it=92s the primary illness, but
we really don=92t know that.
So CFS in the US. The little dots on the map really are associated
with sites where we=92ve- where people have done clinical studies. In
Seattle, Dr. Dedra Buchwald, and we=92ve done studies in San Francisco,
there was another clinical epis- in different parts of California,
Lake Tahoe Nevada, we=92ve done studies in Wichita Kansas, the study in
Georgia, years ago and then in obviously various sites in the country.
So the illness is not limited to one particular place.
At latest count there are probably four hundred- I mean four million
people in the U.S. with this- the full blown syndrome, and another six
plus million with a syndrome that is CFS-like but is- but is minus one
of the components or you have three symptoms and not four symptoms or
you=92re are- are so on and so forth.
Now the clinic populations where most of the studies were done until
recently show that they were primarily women. The general population
studies that we=92ve done, there=92s one been done in Chicago, we did one
in Wichita, and we have one that=92s hopefully going to be in press soon
from the Georgia population. And we still find that people with this
illness are primarily women.
In the original clinic studies they were upper-middle class
professionals, and in the general population they are as many in the
lower socio-economic groups. In the original studies they were
primarily white and now they=92re everybody. And most reported a sudden
onset originally, and when you go into the population however to
identify people, they=92re- they are gradual onset of chronic illness.
The average duration in each instance is over five years, and many
physician visits per year in the clinic populations, but only sixteen
percent in the patient- in the population studies have- were
identified in their population and received treatment. So it=92s- it=92s
a- there are a group of people out there who fulfill the syndromic
definition who are not receiving care.
The economic impact is significant, the annual productivity loss in
our study in Wichita was nine billion dollars, men and women both but
predominantly women. And the annual loss to each family was at least
twenty thousand dollars.
So there are some limitations to this definition, still. And it was
originally developed by consensus, it was not empirically derived.
It=92s based on clinical experience not population based, it was defined
by symptoms and the consequences of those symptoms. It focuses on
fatigue, and the sensitivity specificity is not defined. In other
words the specific patho-physiological processes have not been
identified. And like I said before it requires exclusion of other
illnesses.
(09:50)
There are some correlations however that have evolved over the years,
in terms of impairment, with the- with both fatigue and symptoms of
classification. In utilizing the medical outcome survey short form 36,
there are eight different domains, and you can see that the scores in
the chronic fatigue people in each of the domains is- is much less
than in people who don=92t quite fulfill the definition, the so- ISF, or
insufficient fatigue, and then individuals who were not fatigued at
all. The higher the number the better the score with the medical
outcome survey.
And like-wise, the multi-dimensional fatigue inventory, another
questionnaire scale, patients have higher scores than do the other
groups, and a higher score in this instance is more symptomatic. And
then the CDC symptom inventory scores are much higher as well. So that
one can apply these questionnaires and empirically identify patients
with the syndrome. And that=92s based on a- or it=92s been reported in BMC
Medicine December 2005, and use up- utilizing these four scales of the
SF-36- physical function, social function, role physical and role
emotional, if the scores are less than these numbers in any one of
them, and they are greater than thirteen and greater than ten in these
two, and you have symptom scores greater than twenty-four, then you
fulfill the definition.
So that instead of the process of us- of trying to sort out whether
they have been fatigued, for how long, whether they don=92t- their
fatigue isn=92t interfered with by rest, etc., you can use these
questionnaires to try and identify patients.
So we=92ve been doing this now in Georgia, and the reason I bring up
Georgia is it exemplifies the method that we used to identify people
in the- in populations.
We were interested in whether or not there are differences between, or
among, metropolitan, urban, and rural areas. And so, we actually
contacted several tens of thousands of people. Five thousand people
were interviewed on the telephone, and you can see the numbers there,
and in this study we used the concept of unwellness rather than
fatigue to identify patients. And unwellness meant that they had one
of the four major symptom areas, they had- besides fatigue, they had
fatigue, they have cognitive problems, they have chronic pain, they
had muscle aches and/or joint aches.
So in identifying those individuals, we eventually got seven hundred
to clinic; and in our studies we have to bring them to clinic to
exclude other primary illnesses. And so the individuals who are
CFS-like, fulfill the definition but they haven=92t been to clinic;
whereas those that as you can see here, these individuals who are
CFS-like, there were another two hundred sixty eight that were
chronically unwell, who didn=92t fulfill the definition, and then there
were one hundred and sixty three well and again, some people who were
unwell for a long period of time who didn=92t fulfill the definition
with or without fatigue.
So this demonstrates more critically the screening interview of
nineteen thousand, ten thousand were well, eight thousand were unwell,
not fatigued, and then another three thousand were well. And these
individuals had a detailed telephone interview, after random
selection, random selection of the non-fatigued showed two thousand
people and then these fatigued individuals.
So anyway, the- if you can see that, I don=92t know whether that can be
seen very readily(referring to slide), the detailed telephone
interview determined demographic data, it determined fatigue in the
last month, duration, severity, whether rest improved, limitations,
onset, and then whether they had the eight- any of the eight symptoms,
duration, frequency, severity; they were screened for exclusionary
conditions, they did a short-form twelve, which estimated their
disability, and then they had other questionnaires looking at lifetime
experiences, health services utilization, occupation, and impact.
(14:40)
Then the ones that were identified were brought to two different
clinics, one in Atlanta and one in Macon, where they had a very
thorough evaluation, and I- you all hopefully can read that better
than the last time(slide)- and so we got medication history, they had
an exam, they had screening lab tests done for our study, they had
cytokines and some genotyping studies done, cortisol was measured
because the HPA-axis is considered to be a problem, and then they had
all of these other questionnaires done.
They were also looked at in terms of psychiatric diseases, residence
history, health services utilization, family history, anything and
everything you wanted to know, and then very importantly they had
life-experience looked at, and I=92ll tell you why in a moment, and then
ways of coping. So this addresses the entirety of illness. This is
just not people feeling tired. These people are ill, and these
questions really try and get at the bottom of why they might be ill.
One of the things that we did identify were exclusionary illnesses.
And even in the people who said they were well, three percent had
psychiatric diseases, and twenty six percent had underlying medical
diseases. Those that weren=92t- didn=92t quite fit the definition were
slightly higher, and then in the chronic fatigue themselves, there
were significant numbers of individuals with underlying diseases.
Therefore, they were excluded from the CFS evaluation. They haven=92t
been thrown out though, because I=92m in the process now of looking at
these people to see if they are- if they differ in any other way from
the syndromic definition. And thus far they don=92t, as a matter of fact
they=92re probably sicker.
The exclusionary diagnoses that these people had were as listed
here(referring to slide), many of these people had been undiagnosed.
They didn=92t know they had a thyroid condition or they didn=92t know that
their thyroid control was not adequate. A number with anemia,
likewise, and diabetes. So although you- we think that patients are
being identified properly in the population, this suggests that some
of them aren=92t. The most meaningful one was a woman with diabetes,
whose doctor kept fussing at her because her diabetes was always out
of control, and it turned out she had Cushing=92s Syndrome. Totally
unknown to her providers. And likewise the psychiatric diagnoses also
were not uncommon.
Now in Georgia, and this gets into the distribution of illness. In the
metropolitan area, you can see that Chronic Fatigue Syndrome occurred
four point four times more frequently in females than it did in males.
And this number is high, this number- two point two percent, is ten
times higher than had been seen in our Wichita study. Those that have
insufficient fatigue, they didn=92t quite fit the definition, and those
that were unwell, fatigued, are very very high, but they=92re equal in
the population. The unwell fatigued, there=92s no difference between
males and females. You see it in those who almost approach the
syndrome, and in those who definitely have the syndrome. This suggests
that it=92s not more common in rural areas, but is still more of a
problem in urban and metropolitan areas. Let me define urban and
metropolitan, metropolitan is the Atlanta area, two counties, several
million people, urban is the city of Macon, which is a small city of
several hundred thousand, and then the rural are the counties
surrounding Macon. So the distribution does appear to differ amongst
the different geographic areas, but that the total numbers are very
much the same. It=92s just that there seems to be more of them in urban-
more women in the urban and metropolitan areas.
So this leads us to the rather obvious statement that CFS is a complex
illness. There are environmental stressors that impact illness, there
are major life events, there are emotional stressors, all of these are
involved in perceived stress. There are behavioral responses that
impact illness, there are host factors that impact illness, and then
all of these also impact physiologic responses.
(19:45)
One of the things that we=92ve been looking into recently is the process
of interoception. I don=92t know- is Bud Craig still associated with the
hospitals here? Did he move on? Anyway, he and others have decided
this process- or described this process of interoception, which is how
your brain monitors what is going on, and how you feel in response,
how you register those. So your monitoring is- you sit there, your
brain is monitoring everything- you=92ve just eaten, it=92s monitoring
glucose levels, it=92s monitoring gastrointestinal function, etc. And so
if there is a problem there then interoception leads to adaptive
responses, you adapt both at the physiological level and the
psychological level, and that one of the things that is monitored in
this respect is a concept called allo-static load, which is supposedly
your lifetime stress. So that when you can- if you can imagine in all
these factors are involved in this illness, and you started up here
and you looked at each and every one of these(referring to slide),
finding out what might be going on, as I=92ll show you, might be more a
problem than you think. Whereas if you look at this line, as we=92re
starting to do now, you might be able to sort things out a little bit
readily- more readily. And so, to an OB- and originally this was an
OB/GYN talk, but it certainly impacts the interns here.
And so the question is, since there are so many women in this, this is
an obvious question, do sex and/or gender play a role, we don=92t know
which. Obviously yes, but how, is it the cop out that certain of us
are from Mars and others of us are from Venus, or is it sex vs.
gender? Gender is become a modern term for sex but it really isn=92t. It
was originally intended to emphasise social and cultural as rather
than the biological. And these definitions comes from the online
version of the Oxford English Dictionary, which is a great source.
Sex however is distinction between male and female in general, but it
has to do with structure and function of reproductive organs on the
ground which humans are distinguished as male and female. And the
reason I bring this up is that everybody seems to think that one of
these two things might be involved in this syndrome to explain the
increased prevalence in women, but we also have to think about genes,
and is it gene- at the expression level, is it at the SNP level, are
there epigenetic factors involved, which is methylation, are there
protein products or proteomics involved in this, is it all
X-chromosome or are the other chromosomes involved- or products of the
genes in those involved? So we=92re looking at this but the majority of
these studies are still pending.
So when you try and think about differences between men and women in
terms of illness or disease expression, there are a lot of components.
Now I will mention a couple of studies that have attempted to address
this. And the on- the reason I=92m add- going to mention a couple of
studies, is that=92s all there are. I mean we=92ve known about this
prevalence difference for years, but there are only two real
publications. And this happened to be based on the nineteen eighty
eight definition, the one I gave you was the ninety four, and the
eighty eight definition was more complex, you could have eleven
problems, you had to have physical findings, and it was abandoned
after a study in the early nineties showing that it was- it identified
too many people with somatization disorder, and that it was impossible
to determine, or to use in it a fifty percent reduction in activity,
and so on and so forth. So, that=92s why the ninety four definition came
into being.
So this study used individuals with the eighty eight definition, they
found a hundred and fifty people from a research center in Boston, and
a hundred and forty nine non-gynecological pat-peoples in the medicine
waiting room as control subjects. So it=92s not really a population
study but it=92s a highly biased clinical study.
The summary in this was that the individual with CFS had increased
gynecological problems, and decreased pre-menstrual symptoms, which
one finds interesting if you think that this is a female hormone
problem. This slide is simply shown to show the factors that they were
addressing, whether they used contraceptives, their menstrual periods,
bleeding, hormonal imbalance, endometriosis, thyroids, etc. as you can
all read here.
(24:52)
The critical part of this is that the differences between cases and
controls suggested that hormonal imbalance may be an important
phenomenon, since the odds ratio there was 4.1/. Endometriosis was
more common, uterine fibroids, polycystic ovaries, were likewise had a
high risk factor, the highest risk factor was galactorrhea, but
clinically speaking in twenty years of seeing these people this was a
relatively uncommon phenomenon.
So there was no significant association between birth control pills,
irregular cycles, amenorrhea, bleeding between periods, etc. So just
as Dr. Maddox was saying the pre-menstrual syndrome, it probably may
not be related to overt findings in this arena. I remember being on a
program once with David Rubinow, who is now chair of OB/GYN and I
can=92t remember exactly where, but he left the NIH and he was studying
pre-menstrual syndrome, and the message of his talk was that when you
looked at hormone levels between the two different groups there are
absolutely no differences whatsoever. So hormones may not be the area
of interest that we need to look at.
Now in terms of pre-menstrual symptoms, it=92s interesting that the- and
again, I=92m not going to go through all these, but there were two areas
here where the pre-menstrual symptoms were- I mean most of the
controls had more pre-menstrual symptoms than did the cases, and these
were individuals before the onset of the syndrome. And I found that to
be rather intriguing, that the- except for weight gain and one other
thing down here somewhere, the inability to concentrate, these were
more prevalent- these symptoms were more prevalent in controls than
they were in the patients who eventually went to CFS definition.
And these are the odds ratios of the selective pre-menstrual symptoms
following the onset of symptoms, and you can see that the major- the
two major really have to do with the syndrome and not necessarily the
pre-menstrual syndrome. And that=92s fatigue and the inability to
concentrate. So these are probably related to the development of the
syndrome, how vision problems rolls into this we obviously have no
idea. But I think the issue again is that if you want to blame this
illness on menstruation and menstrual problems, the data are not
necessarily there to support it at this juncture.
Pregnancy. The second study is a pregnancy study. And this question
raised a lot of hoopla back in the early days of the syndrome when
there were actually lay publications that suggested that women who had
this syndrome who became pregnant should terminate their pregnancy
because of the syndrome. And I had the unfortunate experience of
visiting with one woman who did that and she was absolutely
devastated. And it turns out that there was no reason to foment that
belief even at the time. Pregnancy in this study did not worsen CFS,
maternal and infant outcomes were not worse. Of those who had
pregnancies before and after the CFS, the majority had pregnancies
after the onset of CFS, and spontaneous abortions and developmental
delays were associated with maternal age and parenting and had nothing
to do with the syndrome. In fact I had one lady who had six of seven
children because she felt so good when she was pregnant. Her CFS went
away. So you have now heard the world=92s literature on the relationship
between CFS and pregnancy and the female hormonal system, and we don=92t
know very much.
Now this might be more important. We did a study similar to the
Georgia one that I talked to you in Wichita, previously. And the thing
that came out of this one was CFS was associated with early life
stress, and that 86% of the individuals who we studied were women. And
this had to do with sexual abuse and emotional neglect. So that- and
that CFS is greater in individuals with allostatic load, which has
become an interesting phenomena. And in terms of the chromosomes,
chromosomal studies, CFS is associated with MAOA receptor
polymorphisms in women. And again that=92s a preliminary finding and
needs to be looked at further. So that both the probably the gender
and perhaps the sex issues may be impacting illness. CFS is not
associated however with serotonin receptor polymorphisms in women or
men.
(30:35)
So the gender issue goes back- this goes back to the stress study by
Christine Heim based on our Wichita data, and it demonstrates that
both sexual abuse and emotional neglect are really critical in
childhood in developing later on the Chronic Fatigue Syndrome. So
gender probably is terribly important.
Allostatic load, I don=92t know how much you all are doing with, or how
much anyone is making sense out of allostatic load, but it=92s a way to
try and quantify the cumulative life stress in people.
And these are the variables that go into determining the risk, and
they=92re cardiovascular factors, C-reactive protein, I must remind
people, is not just a cardiovascular factor but it=92s associated with
inflammation response to infection, changes in menstruation, all kinds
of things. And then standard heart rate, diastolic blood pressure,
albumin is a factor involved in maintaining vascular volume, which
obviously has to do with vascular function. And then you have the
metabolic factors associated with lipids, glucose metabolism, insulin,
body mass index and so forth.
So coming up with values above this when we looked at our patients in
our population study, it turned out that the odds ratio for CFS was
quite different between females and males, particularly with high
allostatic load variables. The odds ratio was 5 =BD if the allostatic
index was greater than 6 in females, it was 2.3 in males, but- in
other words when we do our population studies and we look for illness
and Chronic Fatigue Syndrome, are we really measuring a syndrome or
are we simply measuring- studying individuals who have had marked
accumulated life stress and are developing the illnesses that one
develops when you=92re 50 years of age or more?
So the associations we found, that the unwell people- those who didn=92t
have necessarily Chronic Fatigue Syndrome, had a very high allostatic
load- remember these are the people who were up to 17% of the
population. So that there- it appears that there are a lot of
unhealthy people in Georgia. And the Chronic Fatigue Syndrome are
distinguished from the unwell by their marked increase in a very high
allostatic load. Association with allostatic load in unwellness are
detected among females and what could it- this is the big question,
what could account for these observations? And I don=92t think I have an
answer but one approach is the metabolic syndrome. Another evolving
area in medicine and probably in OB/GYN, in that people with metabolic
syndrome have impaired glucose metabolism, insulin resistance, they=92re
at risk for diabetes, myocardial infarction, stroke, etc. And in the
NHANE study, which was a national health survey conducted by the CDC,
it=92s also associated with [angina?] heart attack and coronary heart
disease.
(34:28)
And these are the factors that allow identification of metabolic
syndrome. And one is abdominal obesity, high triglycerides, lipids,
blood pressure and fasting glucose. And applying those criteria, the
odds ratio of metabolic syndrome [?] with CFS was 7. Whereas in males
it was much lower. So the issue is in this population of individuals
identified with Chronic Fatigue Syndrome, are they ill because of the
metabolic syndrome or is this simply a coincidence?
So let=92s talk about diagnosing the syndrome and what one may need to
do that. It relies on history and physical. Fatigue- when you see a
patient who complains of fatigue, you have to know what the fatigue
means. The idea is finding out what the matter with the patient is and
not- and not simply identifying the syndrome.
So one example is that they- if they say they=92re sleepy when they=92re
lethargic. If they say their fatigue is like having the flu, which is
lack of energy and other symptoms, then you have to be concerned about
infection or inflammatory disease. If you say they have leaden limbs,
and it=92s similar to a post-exercise state, you have to worry about
cardiovascular phenomena and obviously if they=92re sad and down you
worry about depression.
So this lists a variety of exclusionary conditions, and if you have a
chronic active infection and you feel sick well then you have a very
good reason for your fatigue. If you have cancer or you=92re on a
chemotherapy you have a very good reason for your fatigue. And so
these are the illnesses that are virtually automatic excluded when a
person comes in complaining for fatigue or is referred for evaluation
of their fatigue. I mean they have fatigue, and one of the conundrums
is that particularly in inflammatory diseases and in the thyroid
diseases that you hear the rheumatologist say =91well their primary
disease or lupus or RA is under control, their labs are normal, they
don=92t have any active joint problems=92 but yet they complain of all
these different symptoms. So the query is why do they feel bad, do
they feel bad because of the rheumatologic disease or do they feel bad
because of this constellation of symptoms that has been labelled
Chronic Fatigue Syndrome?
And again the exclusionary psychiatric illnesses are listed here, and
there are a variety of co-morbid conditions that are not excluded.
Fibromyalgia is not exclusionary and as this list goes on. And one can
also wonder whether these illnesses also have to do with alterations-
cumulative alterations in monitoring bodily processes and that this is
really an illness of interoception, or an alteration in your
self-perception.
So what do you do with these people? You identify the primary symptoms
interfering with their function. If they say it=92s their sleep you go
into a detailed sleep history as we=92ll do in a minute, you treat the
co-morbid conditions, medication- over medication is a real problem in
these people because they go see their docs, the doc wants to make
them feel better so they give them 5 or 6 pills and if they don=92t work
they increase them and they give them more, and very frequently the
medications are actually contributing to the program.
The two most common effective, documented therapies are graded
exercise and some type of cognitive behavioral therapy- CBT. Graded
exercise means that if you=92re not doing anything, you start doing
something in a very low level. You don=92t automatically go to the PT
and get put into an hour program. You start walking for 5 minutes, and
when you can walk for 5 minutes every day for a week and not feel
tired, you go to 7 minutes. So it=92s really an extraordinarily slow
program. But in essence you=92re training the individual and they=92re
training themself that being physically active is ok and that lying on
the couch is not ok. And likewise the formal Cognitive Behavioral
Therapy teaches them about the illness, teaches them how they need to
alter their behavior, and it has been shown to be very helpful. A
common sense approach using the same or devising the same coping
skills also is very helpful, and then obviously social support. So
management takes work and this is part of the problem with seeing
these people is you just can=92t tell them to go do this or go do that,
take a pill and they=92ll get better, it takes effort. And I think here
are some management resources that will be made available regarding
the Cognitive Behavioral Therapy, this was a meta-analysis in JAMA in
2001 which was very good, and then the efficacy of graded exercise.
(40:00)
Now if we have time we=92ll go through a few examples. So this lady is a
clothing store franchisee who comes in with fatigue, trouble
concentrating, aches in her legs, has occasional headaches, and her
symptoms are worse following exertion. She had been to another
physician who on the first visit diagnosed her with CFS. Unfortunately
that=92s a problem because one thing you don=92t do is diagnose people
with this after the first visit. You want to know why they might be
there and what might be going on. She was treated with a serotonin
re-uptake inhibitor and pain medication and rest. And she had no
improvement over 18 months despite multiple medication changes. A more
thorough history revealed that her fatigue was similar to pre-morbid
episodes of unrefreshing sleep. Her sleep history was- sheets were
very disturbed, husband moved to a different bed to avoid being kicked
at night, the symptoms increased with medication, particularly the
serotonin re-uptake inhibitors, and she had some additional laboratory
tests including serum iron, total iron binding capacity and ferratin.
All of those were abnormal. And it turns out her restless leg syndrome
was associated with deficient iron stores and appropriate iron
replacement therapy allowed this lady to get well. So, you know, the
key obviously here is taking a good history and trying to understand
the illness rather than just assigning a syndromic diagnosis.
Now this is another lady who was post-menopausal who had three
children and her husband was a post office employment, ten months
prior to that he was a manager at a fast-food job and he lost his job.
The complaints were fatigue, headache, unrefreshing sleep, muscle
aches, more malaise- malaise means both fatigue and feeling sick after
physical and mental activity, and the complaints had been present for
8 months and had interfered with her activity. So she=92d be an ideal
candidate. The history [?] identify any potential underlying medical
illnesses. Her BMI was 29, which was high, her glucose was 135, blood
pressure was high and a psychiatric screener did not identify any
primary psychiatric diagnosis.
And so one could work with her and make a working diagnosis of Chronic
Fatigue Syndrome versus a situational reaction which would be very [?]
understood. And the query is whether she might be developing diabetes
or have diabetes type II. A counseling program for the family was
initiated along with sleep hygiene recommended to the patient, a
graded exercise program and a diet was started and the patient
gradually improved.
Another way of looking at this same lady was that she was told it was
all in her head and she was depressed. She was given medication for
sleep and anxiety, she was not on hormone replacement therapies so
that was a consideration, and that sleep problems became worse and her
other symptoms did not improve, the medications were changed and
increased in number. The last course was that she was told she had
Chronic Fatigue Syndrome and she was to go to bed. Her children were
left to their own devices, her husband took a second job, her oldest
daughter who was 16 began with similar symptoms and then she comes to
see you. So you are the proud recipient of all the mishandling of this
lady that has taken place in the prior months.
(44:01)
And lastly- this is one of my favorite slides, came out when we were
considering this illness back in the 80's as a chronic mononucleosis
illness, and so Joan says that she=92s pregnant.
=93You mean what?=94
=93That=92s right, pregnant, so what do you think?=94
=93It=92s incredible. Maybe you better sit down.=94
=93Ok =93
And then on a chair.
=93Maybe it=92s mono, did he check for mono? Or God forbid it=92s CFS.=94
So anyway the spectrum of illness that=92s involved with this problem is
large, we don=92t know why it=92s associated more readily in women than it
is in men, but I think that fatigue is a major complaint in people
coming to OB/GYN and medicine clinics, and that it=92s worthy of looking
at because of the morbidity involved with it, and I think that, oh,
you go to the CDC website if you need any more information or look at
the nice material that Terry[sp?] has provided from the CFIDS
Associated[sic].
Ok, I=92m ready to take questions if anybody is so moved. Distant sites
please activate your microphones. We have to have questions from
somebody- Yes sir.
[Question]- =93Dr. Jones, I=92ve been a [?] Over the years I get to see a
fair number of these patients as independent medical exam because of
disability and how much it costs insurance carriers and the [?] in
general. And it=92s interesting in the 80's it was chronic fatigue [?]
epstein-barr virus serologies and it got to the point where they would
come in with their serologies and I finally got mine done so I could
show them mine and we got past that and then in the 90's they=92d come
in with tilt-test studies that would show that they were abnormal and
God knows what else went on. I appreciate- maybe I didn=92t say it clear
enough but is there a single [?] laboratory panel that will tell you
this is Chronic Fatigue? But what=92s more important and you emphasized
that I think very nicely, is that [?] more things that do cause it and
I=92ve seen a couple of adrenal insufficient patients who have chronic
fatigue, I saw a [?] patient who had chronic fatigue, I have a [?]
iron deficient to restless leg syndrome but that is something I=92ll
tuck away. I wondered if anybody ever looked at- took a small section
of these population of the chronic fatiguers and looked at PET
scanning?
[Dr. Jones]- They have. And they=92re all over the map, just as they are
with SPECT scanning. Let me tell you of a study we=92re embarking on,
and that=92s with functional magnetic resonance imaging. And the idea
with this illness is if you take people and look at them at random
times when they come to clinic or office and you do any type of
physiologic measurement on them, you don=92t know where they are in
their illness. So back in the late 90's we did a study looking at
triggering the illness with exercise and measuring a variety of things
and one of the lab studies that we had been noticing over the years
was that of complement activation. And so we=92ve done a study now
looking at gene expression with complement activation but the point of
the diatribe is if you challenge these people with something that is
associated with their illness, then you can perhaps identify
physiologic events. So the fMRI study we=92re going to be doing- one is
associated with cognition and we=92ll be using a variety of learned
memory tests, and the second part which we=92re involved with
particularly is doing a challenge, a mentation challenge that induces
stress. And by doing that we should be able to determine if areas of
the brain, particularly associated with this interoceptive process
that I alluded to, is altered in these patients.
And we know that in individuals who have depression, if you ask them
to remember how they felt when they were depressed, some will activate
certain regions of the brain, some will activate other regions of the
brain. And it so happens that if you activate region A you=92re going to
be very very responsive to medication. If you activate area B, you=92re
going to be very very responsive to Cognitive Behavioral Therapy. So
this is a top-down approach instead of trying to identify every single
physiologic thing you can think of as we have been doing to address
fatigue, but to look in the brain at areas that are going to be
involved. So we=92re going to do something called an N-BACK test which
you have to remember sequences of numbers that you were given, it=92s a
very highly stressful test. The other thing we=92re going to be doing is
having them read symptoms and complaints that are associated with
illness. And we know from studies with diabetes, we know from other
studies that when people do that they activate certain areas of the
brain. So with these two challenge- or three or four challenge
situations, we=92re going to be able to ask the question are different
anatomic areas of the brain physiologically involved with problems in
people with the syndrome rather than simply looking at anatomic areas.
Now the PET is very good to, I=92d like to do PET, but we don=92t have a
PET at Emory, we=92re doing these studies in association with Emory. And
they=92re just getting their PET stuff set up, so eventually that will
be done.
(50:25)
[Question]- [?] inject the thought of [?] in the United States, and
more coming, could chronic fatigue dovetail into Alzheimer=92s, has
anybody looked at that?
[Dr. Jones]- We=92ve looked quite thoroughly at cognitive function, and
that=92s one of the complaints people have, and doing some functional-
cognitive function testing the only thing we=92ve come up with is mental
fatigue. When you do this- use a computerized set of cognitive
function tests, people run into trouble during the test, their
outcomes however are no different than anybody else. So that basic
problems of- related to illnesses like Alzheimer=92s are not present in
the syndrome. Yes sir.
[Question]- As a corollary is there any correlation between IQ and [?]
chronic fatigue.
[Dr. Jones] No.
[background] Could you repeat that question?
[Dr. Jones]- The question was is there a relationship between IQ and
development of Chronic Fatigue Syndrome, and the answer is no. Yes
sir.
[Question]- Is there a severity scale for Chronic Fatigue Syndrome?
[Dr. Jones]- Using this Empirical method that I described that=92s in
the BMC, BioMedicine, you can apply that but we have not done it in
terms of outcome or disability etc. Using the SF-36 though the higher
the scores- well there=92s probably a lot of slides I could have shown
you that I didn=92t, but people with this syndrome are more impaired
than people with coronary heart disease, chronic osteomyelitis and
COPD and so forth. So that the impairment of people with this scale-
using that scale is very marked.
[Question]- I also, this is the first time I=92ve really heard that-
allostatic load, and I can=92t help but think about the obesity epidemic
in the United States and relationship to the fact [?] many of us are
sleep deprived and there=92s interference with our society center and
serving more and we have greater loads, and I=92m wondering- it seems
like I=92m oversimplifying this but just cut down on your calories and
everything will be good.
[Dr. Jones]- Well I think you=92re right, I think that was very eye
opening to us and we still are not sure whether or not the illness
that these folks are experiencing is related to the metabolic or
allostatic load phenomena or whether it=92s related to this syndrome and
that=92s why we have to keep looking at it and that=92s why I=92m
particularly interested in this question of interoception, because as
you know from an infectious disease standpoint when you=92re sick with
an infection your body is telling you to cool it, is to go lay low
somewhere, and that allows you to use your bodily stores of energy to
make new proteins to get over the infection, it prevents you from
becoming the prey if we were still living, you know a millennia ago,
when we had to do that for sure, the irritability and desire to be
alone that you express because it lets you rest because other people
won=92t bother you, and it helps the other people because they won=92t
come near you so you can catch what they=92ve got.
So there are a lot of different reasons for illness behavior, and if
you look at this syndrome it=92s illness behavior, and it was illness
behavior originally identified with a question of chronic infection or
chronic immune stimulation. I mean back in the early 80's when we were
seeing these people, and Steve Straus at the NIH was seeing these
people and we unfortunately wrote those papers in the [?] that
suggested this was a chronic active- mono infection, that=92s why Dr.
McKeller is still seeing people bringing in EBV titres. I do, I get
those phone calls all the time. There are docs out there who still
think that- who don=92t know that it=92s normal to have- The other thing
that=92s new in terms of EBV is, and this was studies done in the UK and
Australia, is that 10% of people with primary mononucleosis, infection
with a virus called Ross-River virus, which is unique to Australia,
and then Q-fever, which is a rickettsial disease, 10% of people with
those illnesses will have a post-infection fatigue syndrome that
cannot be differentiated from Chronic Fatigue Syndrome. And this might
be why the early days of this we=92re seeing people in clinic in terms
of a post-infection illness. And then it gets right back into the
heart of why do you feel sick when you=92re sick? And these people allow
an opportunity to ask that question. Yes sir.
(55:52)
[Question]- [?] the psychiatric, psychological aspects of it and [?]
together with a true Chronic Fatigue Syndrome, but I=92m struck with
some though who I really thought had chronic fatigue, they could tell
me exactly the day it happened.
[Dr. Jones]- Right.
[Question cont.]- And it was like they know exactly when something
changed and it was different in their life.
[Dr. Jones]- That=92s correct.
[Question cont.] And you kind of gave us the feeling that it was a
chronic process, clearly it is, but how often is it abruptly
onsetting?
[Dr. Jones]- Well about- if you go into the physician office/clinic
population, about 75% of people say it=92s acute. If you go into the
population that we do, where you just call up people and ask them,
then it=92s about 25%. So we=92re- we may be looking at apples and oranges
when we compare population studies to clinic studies. And I think that
the thing about wanting to know about it as soon as possible is that
early intervention can likely prevent the- you know, the impact of the
illness and the education of the patient that they=92re ill. And I think
that=92s why we try and do these education sessions, because it doesn=92t
really matter why it started, it matters that it=92s there and then you
can intervene early and try and prevent it from being a lifelong
problem.
Any house officer questions? Student questions? Do you see these
people in your clinics? What do you do with them?
[off microphone discussion, endometriosis mentioned]
[Dr. Jones]- Well that=92s not- abdominal pain is not one of the
components of the syndrome, thank goodness, although we saw a number
of people over the years who did have polycystic ovarian disease who
fit this definition very nicely.
[Question]- Jim I think one of the things you touched on very nicely
was the fact that you have to be optimistic in this disease and you
might not have said it but you inferred it that you can=92t have a
patient who you initially just automatically call them chronic fatigue
because that=92s sort of like giving them a lifelong kind of a bad
disease process and I think if there=92s anything we have to offer these
people it=92s a strong teacher of optimism. And get them into that
graded exercise program that you=92re talking about.
[Dr. Jones]- Well I think you=92re right. And one of the other talks I
have to give this week somewhere else I go into that in great detail,
in that- I mean it- by identifying someone with this, number one
you=92re simply making a working diagnosis. You=92re identifying people
who need certain types of intervention and who need a good thorough
history and evaluation. And if you see someone in clinic for the first
time with this and they=92re allotted a half an hour, you=92re not going
to get anywhere at all. So you need to identify someone who probably
fits into the category, but then they need to be re-evaluated and then
they need to be educated so that they can be treated properly. And
there are several studies- that like I said, to show that Cognitive
Behavioral Therapy is very very helpful in this illness.
[Off microphone speaker]- Thank you very much for a fine presentation.
[Dr. Jones]- Thank you.
[Applause]
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