Stanford's Dr. Jose Montoya on Chronic Fatigue Syndrome

Chronic Fatigue Syndrome (CFS)
A disorder that causes extreme fatigue that is unchanged with rest and which interferes with one's ability to attend to daily activities. Discussion about CFS and current research regarding diagnosis and treatment and the possible CFS-infection connection.
Speaker: Jose G. Montoya, MD, Associate Professor of Medicine, Division of Infectious Diseases

Good evening.

thank you no doubt for

Thank you Nora, for making possible this's evening's

hopefully dialogue. Chronic fatigue syndrome

is arguably one of the most

controverted, misunderstood, misperceived

fields in medicine today. Although

it is clear that the health of millions of people

has been compromised significantly by this disease,

still, in medicine, we face situations

where an extreme, even in our own medical community--

the diseased is not believed, that it is real.

Which is a shame. So the one thing, if there is one thing

of anyone in this audience here today, that I would like to

have us a point to take home, of your family members, your friends, or yourself,

is to not kid yourself--this is a real disease.

And what I would like to do tonight is share with you

the evolving understanding

that here at Stanford we have put together. What we tell you today

may not be true tomorrow, but what we tell you today

hopefully is better than what we had as a model or as an understanding

yesterday. And it is evolving. It's changing.

But we have a simple goal, is--one day,

one day, have CFS,

a history of the past, so we do one day be able

to conquer the disease, and be able to bring relief finally to the many patients

who are suffering.

I do not have the time frame for this, but trust me,

we are working hard in making that time frame

the shortest possible. Allow me to start the

presentation with a real case. This is a patient--

I don't know if she's in the audience or not--but it's a 53-year-old woman

who came to see us in 2008

because she had had disabling fatigue

Twenty-three years. She had a wonderful life;

she has a supporting and loving husband--

still he's with her--who works for a high-tech company,

two super children, enjoy her full-time jobs as a sales manager

and as a housemaker. Being a housewife or a housemaker, as you know, is

a full-time job on its own.

She had two full-time jobs. And she was the source of constant joy

for her family and friends. She had probably achieved what many will call the

"American Dream."

In 1985, that dream came to a stop.

At the age of 30, and after giving birth to her first child,

she developed fatigue--fatigue that became worse over the

next 23 years, becoming disabling

in 2003. She can only do 30

percent of what she was capable of doing before she fell ill.

Even running small errands, like going to grocery

shopping, has become a major ordeal. Here we have

a life that has come to a standstill:

Thirty percent of what she's capable of doing for 23 years.

So I want you to carefully weigh everything that is being presented to you; this is

a real case.

So how is it possible to live with a disease

that makes you be thirty percent of who you are, and still

be able to live with that for 23 years?

In addition to that primary, persistant

fatigue, she develops other worrisome symptoms:

Brain fog. It's not uncommon for patients to tell you

they have brain fog. And it's expressed by significant cognitive impairment--

all the way to 30 percent. So 70 percent of her brain function

was taken, or has been taken, by her illness.

mental tasks leave her fatigued; compiling information became extremely difficult;

she feels jumbled and confused. She in addition has had headaches,

cough, sore throats, unrefreshing sleep.

She wakes up in the morning as if she would have not slept--

she had not slept the night before--with the same level

of tiredness as when she bed. Post-exertional malaise.

Not many diseases--and I see respectable physicians here in the audience--

not many diseases will give you what the patients with chronic fatigue syndrome

experience

when they overdo it. And overdoing it can be just running a small errand.

Overdoing can be walking a mile. But after that

level of exercise, or that level

of, of putting the body through that stress--and it could be mental,

could be emotional, cognitive

or physical--they go into a crash

period. It's not the physical

sort of strain that you experience when you go and run

a whole mountain, around miles when you are healthy, your feel tired afterwards

but you have the

endorphin kick that makes you feel good because you did a lot of

exercise or physical activity. It is not that.

It's a crash where the patient feels sick, many times with the feeling

of having a flu. In addition to

post-exertional malaise, she feels muscle pain,

joint pain. Her primary care provider

is arguably one of the best internists in the Bay Area.

And she has been fortunate to have him, because he has been there for her

for all this period, being sure she doesn't have a cancer,

low thyroid, a rheumatological disease--

he has been so careful in being sure that we don't treat her as (having) chronic fatigue syndrome

when in fact she could have had something else that can be put in a box,

and it can be treated from, you know, day one to day X.

And, most importantly, he believes that her

illness is real. I cannot tell you that--

--whatever we are doing at Stanford that may have worked, and we are

pleased with those results, may have worked for some patients--

it could be still (up) for debate. We still have to do a lot of more work

to understand

what are we doing to the patients, that some of them have

gotten better. But the one thing: a hundred percent of--and not all of the

patients get better, unfortunately--

--but the one thing that I can tell you, that a hundred percent of the patients

are grateful,

is when we tell them, "You have a real disease."

And they break down there. Because for the first time they find somebody in the

medical community

telling them, "You are not lying, you are not faking, you are not malingering;

you have a disease you have no control on."

And then, then they feel at least validated. So it's very important for--

hopefully, one day, my dream is that our medical community

will produce a formal apology to the patients

for not having believed them all these years, that they were facing

a real illness. It's true that currently we don't have a single way

to determine that somebody has CFS in an objective way.

It's true that we don't have a single treatment, but

the patients do have a real disease.

The fact that the patients give you so much

history of suffering, and that is incapacitating,

that when you try to look for objective signs that

that, that correlates with what they are telling you--that dichotomy between

they telling you, "I am so sick, I cannot

even leave the house." But then when you do testing,

when you examine them, you do not find anything that is

palpable or tangile, that is not new.

Even back in the 1900s, when physicians

who had this special skill

for having, for finding diseases in the physical exam, like William Osler

famously said, "In all forms there is a striking lack of accordance

between the symptoms of which the patients complain and the objective

changes discoverable by the physician." So it has been more than two hundred years that

that discordance is known, but what is sad is that it has been equated

to the patient has something that is in their head, something that they have

control, just with their minds. So CFS

is a real disease. It's experienced by

one to four million Americans, perhaps 17 or more million people (it's worldwide);

there are no diagnostic tests that can identify with certainty

the patient. Pneumonia: pneumonia, for example,

is an infection. And when a patient has cough,

and fever, and tired, and sore throat,

we do a chest X-ray and we see something. We see

a shadow in that chest X-ray, and we say the patient has pneumonia.

We don't have the equivalent to that shadow in CFS.

We desperately need that, and this is one of the goals that we have set

our group at Stanford, is to one day be able to tell our patients,

"Yes, you have a shadow in your chest X-ray, CFS disease,

and yes, that validates you. There are no

definitive treatments, and I'll tell you the

small progress that we have made at Stanford with some groups of patients in

this regard,

and it's true that some patients spontaneously improve,

but after a certain period of time, their rate of improvement really is small.

It could be as high as seventy, eighty percent

in the first year of disease, but it becomes really much lower

as the years come (pass).

So what makes CFS such a difficult challenge?

We have, of course, compassionate colleagues and

people who are extremely smart in our schools and

in offices, but what makes it so hard

not to see it many times as a real disease, for one side,

is the fact that there are so many symptoms coming from so many angles.

We physicians have this thinking that if you give us a symptom,

we try to look for what organ it's coming from.

So the cough could be coming from the lungs,

from the heart, from a medication, occasionally from some area of the brain,

so we start to see where the organ that is involved.

And many times the symptoms sort of like,

are [related] to a single system, to an organ, but when the patient

gives you, with validity, the symptoms coming from so many organs:

muscle pain, joint pain, brain fog,

fatigue, et cetera, then it's hard for a physician to take,

"What do I do with this?" So it's the constellation,

it's the complexity, it's the fact that they are so hetereogeneous

that has made this disease difficult to deal with.

And things will only get worse when we have

health care systems that only allow physicians for the first visit

45 minutes or 60 minutes, and for follow-up, 15 minutes or 20 minutes.

That's going to get

only worse. The disease is disabling,

the combination of symptoms--not only is the fatigue the central core

of the symptom, but what I refer to you as brain fog.

Unfortunately, the name "chronic fatigue syndrome"

has not served well the disease or the patients.

There are other symptoms. It's not just the fatigue.

And the most and the recognized symptom in patients with chronic fatigue

syndrome is the cognitive impairment.

It is real. It is there. It incapacitates patients.

Patients say that they have difficulty concentrating,

finding words; they cannot produce the same level

of executive function that they used to exercise,

and they cannot sustain those activities for much.

They also have sleep problems and pains in the joints and muscles.

They usually have the disease for six months or longer.

So we are trying to differentiate those situations where you get the fatigue

and fortunately it goes away

within a short period of time. So it has generally been agreed upon

that if you have the fatigue for more than six months is when you have to worry

about the possibility that initial illness

could have been the beginning of the nightmare

that will ensue months or years later.

Many patients--many patients will tell you

that their nightmare began with a

viral-like illness. They will tell you that. They are--

you know, the way I see this disease is that,

it is speaking to us. It is telling us the clue--it's giving us the clues,

we just have not had the patience

and the time

to really listen to the clues that the disease is giving us there.

But they tell us, "I was totally fine."

And they give you the month. Sometimes they give you the date,

the day of the month, and the year, when their whole

life crumbled, like the patient that I illustrated to you.

It is important, however, every time that somebody says that they have

chronic fatigue syndrome,

that we rule out other potential explanations

that are more circumscribed to a single

ideology or cause that can be fixed relatively quick.

This is this study that validates what the patients have been telling us

all along. This is a study that was done in Australia,

where they have the capacity and resources, that as soon as somebody gets

diagnosed with acute

infectious mononucleosis, or Epstein-Barr virus infection,

or another infection that they have common in Australia called

Q fever. Q fever can go into the lungs,

can go into the heart. It's called Q fever, caused by an organism called

Coxiella burnetii.

Or another infection they call Ross River virus.

For the purposes of this conversation, these physicians in Australia have the

capacity

to register and capture patients who have been dianogised

with acute infection of any of those three

kinds: either infectious mononucleosis,

Q fever, or the Ross River virus.

And to their surprise, the people who,

the patients who were followed over time prospectively--

and this is the participants that remain

having fatigue after the acute infection

was diagnosed here--so in the, in the

X axis . . . you can follow

the time after acute infection, six months, twelve months after,

and here in the . . . Y axis,

you can see the patients who have fatigue, and you can see obviously patients

getting better,

and less having fatigue, but look at the proportion of cases

that remain fatigued after 12 months. And they follow those patients later;

Eleven percent of the patients

develop chronic fatigue syndrome after these acute

infections. Our patients were telling us that

all along. And a study had to be done to prove that they were right.

So it looks like at least in some cases of CFS

there is an infectious insult at the beginning

of the illness. Whether it's the infectious agent per se

or the immune response against that agent, what (affects) it that much

is unknown at this time. But hopefully one day we'll be able

to solve that puzzle.

This is another study done in the United States

Similar idea. These are other lessons--these are kids.

They have also been able to capture them at the time they had the acute infection

and they find that about four percent after

24 months--four percent--they have had but they have met the criteria

of chronic fatigue syndrome. So clearly

there is now proof

that a patient can go into this mysterious disease, an illness,

after they have had an acute infection. And

please note that many of those infections

also have what we call an asymptomatic phase. In other words,

people, patients, can get those infections, and not have symptoms.

What they have found is that in general,

the more acute, severely ill the patients are, the more severe the disease is

at the time when they have developed for the first time,

the higher is the likelihood that they will go into chronic fatigue syndrome.

So it is really important, and this is just to make one point--

is that before we declare someone

as having chronic fatigue syndrome, not only that six months have passed,

for now--maybe in the future we will learn to identify

those who will go into chronic fatigue syndrome very early so we can

intervene early--but for now,

the only way we can do it is by waiting. We don't have a way to

distinguish those

except that you can say, the more severe cases perhaps, you will have to pay more

attention to them.

But it's important that a very good internist, primary care provider,

family medicine physician, does a comprehensive

job looking for alternative explanations--

psychiatric, psychologic, neurological--

Because those can be relatively easily fixed. Be sure that we don't have a

cancer that has not been diagnosed

that is causing the fatigue, that is not a low thyroid,

hormone production. Once that has been done,

then we look at patients who have had the fatigue for more than six months

and who have other symptoms. Unfortunately, there is no other way

to do it. We don't have that shadow in the chest X-ray

that (lets) you see pneumonia--yet. And

We couple the fatigue that has lasted for six months

plus four of any of this impaired concentration of the brain fog,

sore throat, lymph nodes that are enlarged

and painful, muscle pain, joint pain,

new headaches, the unrefreshing sleep, and the post-exertional malaise.

They are often with symptoms of depression.

It's not that the depression causes chronic fatigue syndrome.

It's that they are depressed because their lives have been been ruined,

their life has been taken away, and they want that life back

and they cannot have it. So it is unfortunate that

we tend to see the periphery and not see how

it evolved. Clinically,

those patients, their fatigue is not

alleviated by resting,

and it's not the result of, because they are doing something

something and they are not stopping. And in many cases,

they lose their previous levels of occupational,

educational, social, or personal activities.

It's very important to note that many of them

give you neurological symptoms

that are hard to put in any category.

At a meeting we were participating last night

in, in the Washington area, we were sitting with

neurologists and other physicians, and it became very clear

that everybody's seeing the same thing.

Not only the fatigue, not only the brain fog,

but these funny tremors, twitches, that we call

myoclonus fasciculations, things that normally will trigger the possibility of a

neurlogical disease--

these patients are having something in that area.

so again, it seems like the disease is speaking to us

in soft tones, and we're just not able to listen to it

in a careful way. So it is a real disease,

but it's an infectious, it is immunological,

it's endocrine, neurological, cardiac, psychiatric,

and so everybody seems to be looking at it from the wrong angle

depending on what their area is. And

hopefully one day will be able to see it three hundred and sixty

to be able to comprehend better what is really is, what it's doing--

the disease to these patients. And part of the problem

is that, as I said, it's a constellation of systems, so it's a systemic

challenge; it lasts! It can go on for decades.

Is it possible that the CFS that one patient has is different than the other?

Of course it could be possible.

Like in pneumonia, you have this same shadow in two patients

but it's caused by a different organism.

So when you study CFS patients in the air, in general,

it could be that you are studying different subgroups, and as you try to

make it a one,

your findings could be diluted for that reason.

Also is very likely that the disease evolves.

It changes. The patient who has illness for less than a year

possibly will have a different kind of test, positive or negative,

than someone who has had the disease for ten or twenty years.

I have to bring up this study. Because in

our infectious diseases community--so I told you that many patients tell you

that there is an

infection at the beginning of the illness--this is this study that has been

cited as a study that shows that an anti-microbial intervention

does not work for patients with chronic fatigue syndrome. It was a study that was

published in the late 80s,

where they took 27 patients. They had high titers against Epstein-Barr virus

virus; they had been ill for at least seven years;

and they gave those patients acyclovir for thirty

days. So they got IV for seven days,

and oral for thirty days. So no more

of treatment. And what they found, if they gave

the drug or placebo--so they would randomize to drug

for month-and-a-half, or placebo for month-and-a-half,

what they found is that there was no difference. But just

put that in the in the back of your brain. The fact

that that patient, those patients, got a month-and-a-half

of antiviral treatment, or acyclovir.

So the one thing that we changed at Stanford about

seven years ago, was that we

brought a new model. And we

thought if the patients have been here for a long period of time,

and if it's possible that an infectious agent is behind the symptoms

at a chronic level, will it be possible that

if we intervene with the appropriate agent--and finding that appropriate agent

may be a really

daunting task--is it possible that then long-term,

with appropriate anti-microbial interventions, can improve the symptoms

in subsets of patients, not to repeat the mistakes of the past,

of treating all the patients as the same homogeneous group.

And to our surprise, when we took patients and--

it's beyond the scope of tonight's conversation on how we

ran into this surgroup--we found that if patients had high levels

of antibodies against Epstein-Barr virus, the same virus that has been

clearly tied to the onset of CFS, and another virus

called Human Herpesvirus-6, if they have high levels against

those two viruses, it looks like when we gave them

another drug called Valganciclovir

for six months in this abscissa. You have

a year's, so goes all the way to six months, half a year here,

and in the same abscissa, but for when the patients were starting before therapy,

you have all the way up to twenty years. So the patient may have been sick for

eighteen years,

one year, five years--no matter how long they were sick

when we gave this drug for six months,

total surprise to us. They had this remarkable

improvement in their physical and cognitive

function. And to our surprise as well,

the initial reaction to

them was, they got worse. And then they improved.

The worsening was a complete surprise to us. And we made a mistake initially

because we let people believe that for patients to get

better with this intervention who had these markers in the blood,

they had to get worse. And that later on

turns out to be not correct. There are patients who can get better

without significant worsening, but still we see patients who get worse

with the initial treatment. Now, we cannot

be certain that this would have not been done because we perhaps

validated the patients; we

listened to them, so that we were doing a placebo effect.

It's hard to argue that this is placebo when somebody has been sick for

twenty years,

or eighty years, they get an intervention for six months, and they suddenly get better.

But granted, we have to go to what is called a

randomized, placebo-controlled double-blind

pilot study, to see if we could give the drug

to patients when they didn't know they were getting the drug,

or the sugar pill, and we the physicians

will not know the same thing. So: double-blind.

And we were fortunate to have the sponsorship.

The answer for many of the questions we face

with chronic fatigue syndrome is doing clinical trials, but those are

very expensive things to do, enterprises to do,

and we were lucky that we had the sponsorship from the manufacturer

of the drug in this case. Like any

intervention, we do need a team.

Nothing can happen these days in research without having

an outstanding team. And what we did is

randomized the patients to two areas: to either placebo,

sugar pill, or valacyclovir for six months,

and then for three months we stayed blind still.

At nine months, we took the data, put it in

three CVs, shipped it to three different,

three different places, so that nobody could touch the data

after the blind code was broken,

and then we broke the code and see how the patients did

on the drug versus the sugar pill.

This is a graph that shows what happened

to the patients who are either on the

placebo in red, or who are on the treatment

in green. And in this scale,

going down means you are getting better.

So the patient who went on the treatment went down,

meaning they got better, and that

trend of going down was

according to this statistical model, it's statistically significantly

different than those in the placebo, suggesting here

that the benefit that we have shown before, when we were giving this drug to

patients,

is mediated by something that the drug is doing, and not something that they

are doing

themselves through placebo. We also assessed

their cognitive function, meaning we asked the patients

how they felt in terms of their cognitive performance.

And they say, I feel 100 percent, which no one will tell us

when they were sick, or they will say 10 percent or 50 percent and so forth.

That is very hard to correlate, because it also depends on how

good their sleep (is) or what other medications they are taking.

et cetera. So when we looked at

what happened with their cognitive function--self-reported,

but remember, under double-blind conditions, not knowing if they were

getting treatment or placebo--

the trajectory also for those who went into treatment

was better that those who were in the placebo.

Now is one of those things--

the research--never stops either surprising you or fascinating you.

The randomization for this study, meaning we allocated the patients

to either group by pure chance--

the allocation of the patients to the two groups

was done by somebody in Geneva, in Europe. So we will see a patient

and we'll say, "That patient is a candidate for the study."

We didn't allocate them to one group or the other. We will call Geneva, to a

group there,

and they would give us the answer the next day, or whatever time difference it was,

and they would tell us, "This is the group the patient should go, group X."

And they would call pharmacy and they would give us the appeals for that

patient and so forth. Yet, despite that it was

totally by chance and by pure randomization,

if you'll notice, here, the baseline

levels of cognitive function for the treatment group is slightly lower

than the placebo. We were fortunate that that this was not statistically

significant, but the patients in the treatment group started with a slight

disadvantage

over the placebo. And the same thing actually was for the fatigue.

Remember that in this scale, I mentioned to you that the higher the worse,

and again, the patients,

well in this case, you know, the lower is the better, so the treatment is

started at the right place.

And then the other aspect that we did was to see how the cognitive did by

a questioner. So the previous light was how they did

with self-reported cognitive function; this is how they do

with a questioner that assesses their mental capacity,

and in this case, going down again is improving

and again the treatment group is slightly worse

than the starting place for the placebo,

yet the trajectory of the treatment group

is statistically significantly better--going down it's better--

than the placebo group. So in this study we

offer perhaps what are the first

evidences that if you intervene with an appropriate drug,

with a specific biomarker in black like titers

elevated against those two viruses, it appears that we can make

a significant difference in these patients' physical

and cognitive status, independent of placebo.

We were not just happy with

just seeing this and not being able to explain it. We wanted to go beyond that.

And we have noticed that in patients who received the drug,

these cells, called neutrophils, increase in a statistical manner,

that is not seen in the patients who get placebo.

So something is associated with neutrophils that

maybe, maybe, (is) one potential explanation of why they get better.

The other cells that change

are the monocytes, in this case they go down in the patients who get the drug,

and not in those who get the placebo. At at the same time,

we took the serum of these patients, and through a

technology that is available here at Stanford, and in collaboration

with our colleagues in the immunology department, we were able to measure

through this technique that is called Luminex technology, where you can

measure a hundred cytokines, a hundred analytes, in a single well

of a single patient at the same time, we were able to measure what we call

cytokines. Cytokines are molecules

that the immune system uses to talk from one cell

to the other. And through this technology we were able to show

that in those patients at baseline that I show you that they were slightly worse

for the treatment group, we show that the certain cytokines were higher

in those who were worse, than in those who were better--initially,

like IL5 and IL17. And more importantly,

over time, the patients on the treatment,

on the Valganciclovir, on the drug, have

elevation in cytokines that were not seen

as much in the patient in the placebo. Cytokines like

IL5, IL17, cytokines that attract neutrophils--the same cell

that I mentioned to you that is elevated. Or cytokines that had to do

with monocyte communication, the same cell that I mentioned to you

that it goes down. And the drug was safe

during the period of administration. And we concluded then

that if the patients have high levels of these antibodies against

HHV-6 and DBV, giving them

Valganciclovir for six months

appears to correlate with an improvement in cognitive and physical

that is independent from placebo and we have

a mechanism, proposed a mechanism

through immunomodulation, meaning that sometime the drugs work;

not necessarily through the fact that they are killing the organism,

but by the fact that they are making the immune system (go) one direction

that is beneficial to the patient. So...

But I want to emphasize two things.

Not all the patients have those blood markers. So not everybody will be

in theory a candidate for that intervention. And unfortunately, not

all the patients with the markers necessarily improve.

so that let us, or has led us,

at Stanford to identify what we call

sub-groups of patients with CFS, those who

meet that profile of the HSV-6, EBV,

we have found other patients that have what we call the herpes simplex one

or two sub-group. Patients who

absolutely tell you that their CFS worsened

when their oral herpes, the famous

fever blisters, the oral blisters, or genital herpes,

that when those exacerbate,

and manifest in the way of painful lesions, those patients

actually, their symptoms get much more worse,

or that their disease began when they have the outbreak, the first outbreak

with one of those two viruses. So that's what we have called a

herpes simplex sub-group. We have had some Brucella

patients, others with Q fever, like the ones that they

found in Australia, mycoplasma, chlamydia,

and we have found patients who have low titers

against HSV-6, but have very high levels

of this HSV-6 virus that

have also clearly been associated with significant fatigue in these patients,

and those patients are the ones that we call chromosomally

integrated human herpes virus six. So this is another

completely different sub-group. And it's a tougher group

to treat. I'm sure you remember the first patient that I

told you. The 50 year-old woman who came in 2008

to see us, with the hope that we could find something,

and we did all these titers, and they were low, or negative,

but she's one of the patients who was found to have very high levels

of the human herpes virus 6 in her blood. She one of the patients

that we call, that the virus has found at clever way

to get into the actual genome, into the genetic material

of her own cells, in a clever way to hide,

and to perhaps to produce the damage. So the patient that I mentioned to you

in 2008, we were studying her--and this is a way to measure

her fatigue and her cognitive abilities.

Being 100 is being in complete misery.

It's really being sick. The CDC has done studies with this questionnaire

for physical and cognitive dysfunction. Most of the CFS patients

are around 60. Being completely well

is around 10. So if you are (a) 60, you are really sick.

She was around (an) 80. This is the same woman,

patient, wife, mother, that I talked to you at the beginning.

We started with the antiviral, and you can see how

by different antivirual interventions of certain kinds,

finally she has some relief here. Where

her level of function going from 80

to almost 25 is significantly improved.

She went from not been able to run errands,

to now go out, and travel, and enjoy the graduation of her

daughter, et cetera, et cetera. However, those drugs,

for us to be able to achieve this resolution

we had to give them at very high doses, and you can only go

with this drug so long. So we have to move her to other medications that are not

so effective.

And unfortunately she has relapsed recently.

For her, we're going to try hopefully a clever way

to measure what is in her blood that changes that makes her feel

so much better, going from 80 which is

near hell, to around 20 which is near

health. So hopefully we'll be able to

achieve that, but I just want to show you this as an example

that there is something there that we can improve.

All we have to do is devote resources and more people

to be able to unveil this mystery.

So that has been, so far, our experience.

I would like to mention two things quickly because I'm sure you have

questions about it.

It is what recently has been reported as the famous

XMRV virus. The XMRV virus

was--that, and the Lancet study about degraded

exercise. So I'm going to comment on those two things, because they are very

timely. So the XMRV is a virus that was found

in prostatic tumors, and it was thought that it could be associated with

prostatic cancer. But then the surprise came in 2009

when it was reported by a group from Nevada that patients with

the disease had 70 percent--it's 67 percent, but you can't remember a 70 percent--

the CFS patient had the virus. Well yes, only four percent

of healthy controls had it. So that caused a major splash

and hope of the possibility that this agent

could be behind, also, in addition to the other ones that I showed you,

and in addition to the ones that we are going after at Stanford.

The problem has been, that following that study,

there have been two others supporting those findings

and about six others that show that the association

is not there. So there is one, this is one study from the U.S., the 70 percent

versus the four percent that I mentioned to you

that have the 70 percent in the patients versus four percent in the controls.

The other study that was positive is a study from Boston

when it was not 70 percent, it was almost 87 percent,

and in controls it was about 7 percent.

All the other studies, all the studies in Europe have been negative;

the other studies, other than those two in the United States, have been negative,

except one small one that has not been fully reported that was also positive from New York City.

so it is a mystery, it's a challenge, it's a controversy,

and we just have to step up to the challenge and solve it

for the patients and not shy away and not take a position

he has been really disappointing to me to see how

colleagues who do not find the same thing that others do

step up to the podium and said, "The other findings are wrong;

we find the truth," et cetera. We are not going to be able able to solve this disease

through taking dogmatic positions like this. So it is controversial

but no group has produced proof

that the association is there; nor any group has produced proof

that it's not there. The retroviruses--this is a retrovirus--

they have a great capacity to hide and to do

bad things, either in a long period of range

or very short. It's the same group with the HIV virus

but it's not HIV. A kind of

unique life cycle where they can get very cleverly

inside the cell and they can integrate into the human

genetic material, hence their ability to hide

and to cause, in a very sneaky way,

disease (in) us. There are several kinds;

this XMRV virus came from mice--no question about it--

and some of those viruses have mutated to the point that they are only

able to stay in humans;

there are others that can be in mice and humans,

and there are others that cannot be in humans. So there are different kinds,

but the reality is that the question is out there

and it needs to be solved. And we as America

and the scientific community need to step up and

solve the mystery. There are different ways to measure the virus, so that's

possibly part of the problem. There are ways to measure the actual virus;

with measuring the nuclear acid to look at the proteins,

to look at the cultural dividers, to look at

how the antibody responds in humans to the virus, as a way to detect the virus--

So there are different methods that make it a little bit more difficult, but not

impossible, to understand what is happening. Also,

people, or different laboratories, using different

reagents; they use different

positive or negative controls; the virus appears to be in very small amounts,

so that makes it hard for people to find it.

And also, the studies come from different geographical areas.

Infectious diseases is characterized by this.

There are infections that present only in the United States and ever seen in Europe.

There are infections that are only seen in Latin America, never seen outside

the Americas. So this is not news--

that an infectious agent could be restricted to certain geographical

locales, and it could be the case in this situation as well.

So what is the bottom line? What is the bottom line with this

XMRV virus? It can be present

in people who have no disease. And it could be, according to the study so far

up to seven percent. It can be present in patients with prostate cancer:

up to 27 percent. It can can be present in patients with CFS:

up to 87 percent. All the European studies have been negative so far.

In the study from Boston, there were patients who were positive

in blood samples that had been taken fifty years

ago--they went to those patients again, they got blood again, and they were

positive again.

so we know that the virus can be there

for long periods of time. And obviously

we need to have the right studies

in a smart way and we are fortunate, the Stanford group is fortunate,

to be associated now with a group at Columbia

with directions, and the directions of the NIH, to hopefully be able

to provide the right kind of data that will help

to support one way or the other. And another possibility

is to do a specific intervention, because the drugs that work against a virus

are very specific. In the next few minutes,

I would like to share with you how at Stanford we have tried to put this together

as a model of pathogenesis of this disease.

So as I told you before, it is known that some patients start with infection

and that the more severe the infection at the beginning,

the higher is the chance that they go into chronic fatigue syndrome.

Most of the infections that have associated with

chronic fatigue syndrome are intracellular: they hide

inside the cell. They like to go to the brain;

they like to go to the lymph nodes. So I think that they are telling us something

there from a mechanistic point of view. Several

infections can do the same thing; they can

trigger CFS. I think that this is telling us

that what is most likely responsible for

the problem it's not the organism itself attacking the patient, but it's the

immune response to them.

Several of them can do it; the severe ones seem to be

doing it more successfully, so it's likely that is the immune response against them

what is doing it. It's possible

that it is doing it because they all share something in common

that triggers the same immune response that is damaging

or that they00:02:18,150 --> 00:02:21,330
for 23 years.

similar mechanisms of damaging, or immunopathology,

as also is known. The fact that the disease can be pressing for so many years

is telling us something. It's whispering to us something.

The fact that somebody could have a disease and not die of it

for so long is giving us clues of the mechanism.

If it's an infection that is doing it, it will mean

that the infectious agent is capable of coming out of the hiding place

at a low level. And the immune system attacks the infection,

successfully puts that pathogen back in the hiding place,

but it's the same immune response perhaps that is making the patients sick.

Ad it just perpetuates the cycle. The patients tell us,

they had been telling us for years,

"I get this fluctuating level(s) of disease."

And I think the immune system is acting as a double-edged sword;

it's putting that organism back in (its) hiding place, but it's making the patient

possibly sick.

So the other observation is that most of the patients are women;

most of them get better during pregnancy

and most of them get worse after birth.

Remember that patient that I mentioned to you: that she got the disease

after the birth of her son. So that suggests

an autoimmune disease, or an HLA association. Many diseases

that have been found to be autoimmune had that exact

same behavior. Lastly,

I wanna comment to you, comment with you,

the highly publicized study

that came out of London where they

did what is called adaptive pacing therapy,

cognitive behavior therapy, or graded exercise therapy,

or simply, a specialized medical care

for patients with chronic fatigue syndrome. Adaptive pacing therapy

is to tell the patient, "Do what you feel, but do not

overdo it. Cognitive behavioral therapy

is they work with a counselor, with a psychologist,

to be sure that they overcome the fear of doing things, because they would crash,

but they also get the same message: avoid the crashes.

But this time they do it under cognitive

behavioral intervention. Graded exercise therapy

is they work with physical therapy individuals

with the same goal--not to crash--but they do have some kind of

schedule, graded exercise activity.

in all the groups, either adaptive pacing therapy,

cognitive behavior, graded exercise therapy, the main goal was to

avoid the patient crashing, however the idea

was to achieve that through these different means that I described to you.

And a fourth group, a specialist medicare care--

those patients simply got a good physician who new chronic fatigue syndrome

but did nothing other than just provide general medical care.

And this is what was found.

So. The patients who got the adaptive pacing therapy

just don't don't crash, trust your instincts--

basically did not, so, in this score--

in this score, going down is getting better.

and really, these patients are really

Sick. And in this case...

In this case, it was clearly that the patients did not improve

by simply telling them, "Trust your instincts."

The patients who had the cognitive behavioral therapy,

they actually improved their performance

but they did not get cured from CFS.

It is so sad that this study is being cited

as "cognitive behavorial therapy is curing CFS."

It's not true. The patients simply got better, and it's good that the patients got better,

it was statistically significant, but they were far from going back to

their normal levels.

The same thing with the graded exercise therapy--they got better

in a statistically significant manner, but they were far from being completely well.

And the same thing, the same findings were for the physical

function in that regard. So that the

same authors of the papers said, "Our finding that

(the) study treatments, like those, were only moderately

effective," they are not saying that they are curing CFS,

also suggests that researching to more effective treatments are needed

and that the fact that behavioral intervention means that patients get better

by no means means that this is psychological in nature.

And I have to say that, because I had a very sad conversation with a family

member of a patient who

was doubting that our patient had the disease,

and cited this study to say that now

there was proof that "CFS was psychological"

and that with psychological intervention, the patients "could get cured." This is far

from truth,

from the actual findings of the study. So I think we have

lots of work to do; we need

all the best minds at Stanford, and we are gathering the best minds at Stanford

around the team. We need to find an objective,

a form of saying, "yes,the patient has CFS";

we need to find black levels--

biomarkers that can identify the situation; we need to find ways to

identify the subgroup, which is the pathogen behind--

it's possible that there are patient with CFS that are not infectious as well.

We need to find those agents and to the right trials.

The attitude that was have taken at Stanford

reminds me of what we want to do, is similar to what's found in this

late 70s movie (The Wild Child) from Francois Truffaut:

they have found this child in the forest of France.

it was wild. Did not know how to speak, perhaps couldn't even hear.

Basically it was a wild child with an entity of behavior

that was not understood at all. However,

when he was brought to a room where a physician who wanted to really

help him and understand him, was trying to describe

the length of his hair, teeth, numbers of scars in his skin,

et cetera; made, uh,

(an) observation. The kid

did not react when a heavy noise

was produced in the room. And he said, "Did you notice?"

He didn't react to that loud noise. He's deaf.

Then, another man who has seen the kid in the wild,

from the village, says, "How can he be deaf

when in the large I've seen him turn around

when a nut was cracked behind him?"

So the physician who is trying to make the observation says, "Write this:

Indifferent to loud noises... whereas he turns around

when a nut is cracked behind him." So

it's really having a candid attitude towards this disease:

observing what is there, what the disease is telling us, what I think that one day,

hopefully, we'll be able to (use to) make a difference. And that would not be possible with a team.

So we're very grateful to the Brennan and Taskey families for their support;

Lindsey Merrihew, who is right here in the room--none of these things

trust me, would have been possible without Lindsey. She's really the head

and the mover and the doer in the team. And all the people

below her: Jane Norris, Amber Ruiz, Dr. Marzie Zinn, who is also here,

Dr. Marcie Zinn has given the challenge of

helping us to understand the brain fog and how to measure.

So none of those things would have happened without the intervention

of this great team. Thank you.

[Question asked] Now the doctor has asked the question that,

you know, obviously, this,

uh, we have a problem.

And it's the waiting time. Lindsey, what is

the waiting time now?

Two to three years. So we are trying to desperately try to,

um, to to cope with the high demand.

There is a physician in the area, in El Camino Hospital,

[Dr. Andreas Kogelnik]. So [K-

0-G-E-L-N-I-K.]

And Lindsey and I can give you his contact information,

who is seeing now patients with chronic fatigue syndrome, with an approach

similar to ours. So that has helped us, to

have patients being seen by him.

Thank you, yeah, you are correct, it's right here, his name:

Kogelnik, actually. K-O-G. Kogelnik.

Um, so, but... you know, our hope,

our goal, in addition to one day

be able to understand the disease and erradicate it,

in addition to that dream, is that we need to desperately bring

education our colleagues, medical students,

fellows residents, so they can perpetuate that

model. [Question asked] So the question was made that,

what was the dose that was used in the study that we cited in the late 80s,

where patients with chronic fatigue syndrome were treated with acyclovir,

and the answer is that they used the standard dose

for that time, that were not high doses.

And what is striking is they used only five weeks,

yet they went out and made that as the Bible,

that antiviral intervention does not work for CFS.

[Question asked] The question is, if valgancyclovir is available.

Yes. It is available; it's approved by the FDA;

when we did the trial, we went to the FDA,

got the permission at the FDA to use it for this other indication.

It needs medical supervision--

there is a safety issue with the blood cells, but

if you have proper supervision, that usually is not an issue.

There is a question mark on the long-term use about,

in animals, it can cause cancer, we do not know if that happens in humans, but it

has to always be

discussed with your provider in that regard.

[Question asked] So the question is, like--could people, knowing

that some of these infections can do that devastation, can you do something

in a prophylactic manner, to prevent that [you're] going to that

unhealthy cascade. Not that we know of.

If we were to write something in a magazine, in a journal, we

would have to say "nothing is known." If we were having a

coffee table conversation, then you could say some things like,

"Please don't--you know, there are many patients who, when they are sick, they try

to go to the extreme, they try to to back to work naturally.

I would suggest that common-sense measures of rest when they have the

acute illness

be exaggerated, in fact--that they take more time to rest.

The other thing that we have found, but this is totally anecdotal, is some of the

kids of our colleagues at Stanford who have come down with the acute

infections, and we have measured the [levels] and they had been positive;

we had given the antibiotic right there

and it seems like--but it's very anecdotal--that they

recover. But, anecdotal. [Question asked] The question is about

the levels of HSV-1, or HSV-2,

and even with HSV-6--do they travel travel together?

Preliminarily, it seems like the EBV and HSV-6,

they travel together in a surgroup of patients. We thought that that surgroup was gonna be

large, the one that we allegedly found,

but he seems like it's a small surgroup.

It's rare to have a patient with HSV-1 and HSV-6.

We don't know why yet. Or HSV-2 and HSV-6.

It's not not uncommon to have HSV-1 and HSV-2.

And the levels of antibodies seems to be high.

We have had a surgroup of patients with

HSV-2, genital, HSV-1,

oral blisters, and we have intervened them with acyclovir, which is a much

simpler drug to give.

And after a year, year-and-a-half intervention,

It seems that we see these recoveries that are truly dramatic.

In a surgroup of patients. Ideally we should do

a randomized trial; I'm trying to see how we can come up with the funds

to do the right study, similar to the other, to prove that that's the case.

[Questions asked] Two questions: one is, if the drugs that I show you, the one that we have used,

if they're anti-retroviral, meaning anti-HIV drugs,

what I have shown you--emphasize that--what I have shown you

they are not anti-retrovirals; they are not anti-HIV.

And the second question: if there,

if there is like a stem cell base for the disease,

because the virus can get into, some other viruses can get into the genetic

code, and the answer is, "not as far as we know."

It seems like it has to do more with the germ line cells.

The very early cells, but not stem cell

based. And as far as we know it's not stem-cell based.

But there is very litle known about that part.

[Question asked] So the question is about: if long-term,

careful, safe, thoughtful,

antiviral or anti-microbial intervention can result in the improvement of

chronic diseases like this. So that's the model that we are operating. So the--

if you see what we're doing behind, it suggests that

infection at low levels can do a lot of stuff. That's

the model that we are using. And then that's--

So pressing that for long periods of time should improve. So

the question suggests the possibility that what about if we did that,

for the long term effects of varicella-zoster virus, or shingles virus

in terms of pain, this is well known, that it can do this problem.

Preliminary--but again, just two small patients, but

highly gratifying. We have patients who had come to us for five years of

pain, that is clearly what we call the

"herpes without rash."

and this woman, after like a year and a half of acyclovir, is

back to like,

smile, bubbly personality, normal--

those are anecdotal. The point is,

I think it calls for that. It calls for patients who have the shingles

to be randomized to long term antiviral suppression

versus not to show whether it has an impact on the post-herpetic pain

or neuralgia. Very good point. [Question asked] What about

families who share the same environment, who could have the same markers. And,

the right study has not been done, though we do have,

I think it's--correct me if I'm wrong, Lindsey, but we have four families now,

four families, in whom they share the markers,

and not all of them express the disease. So it looks like

something else is needed. So we have four families who had that behavior.

So it seems that you need more than the infection to express disease.

[Question asked] The question is, are we testing patients for XMRV.

So we asked the Microbiology Department at Stanford

and they are stepping up to the plate. They are

setting up the test. We need to find a few more resources, but they are,

they are doing it. And some of our patients are doing it

through the other--it is a commercial laboratory that now,

that's it. Good question. [Question asked] The question is are there any

clinical trials? There are clinical trials of (a) different nature and kind.

There is, for example, a clinical trial with interferon.

Interferon is an antiviral, and it's given to patients with the hope that they

will recover. And that's (they are) the Nevada group.

There are others in Europe that obviously our patients will not have access to.

Our idea, our dream, is to have

a whole group at Stanford that would just do

clinical trials for these kinds of patients. But that is an

infrastructure that is relatively large. And unfortunatel, the NIH

does not give much money for clinical trials, and that's

unfortunate. [Question asked] So the question is about the role of alternative treatments.

What (I've) shown you, the role of cognitive-behavioral intervention,

the, sort of like, physical therapy intervention,

clearly points to the fact that there are

things that patients can do that could be thoughtful,

not expensive, that could work for the patient.

So there are things that the patients can do, and they can

be helped. The answer is yes. And they are in the alternative

[Question asked] The relationship--is there any any relationship between fatigue,

that is temporal, versus chronic fatigue,

because as it's pointed (out), some interventions

from a good cup of coffee, or provigil,

or ritaline, make patients with short-term fatigue

better. There is a subset of patients with chronic fatigue

syndrome that experience that temporal improvement with those same

interventions,

but they are not lasting. All of them tell us,

when they use those interventions, they basically lead them to

overdo it and crash. And it's very

short-term--the effect is very short-term.

We don't know if the same thing that causes fatigue

are the same mechanisms that cause chronic fatigue. Our suspicion is that there are

two different things doing it. Because the patient who had the chronic fatigue,

more than the fatigue, they have all these other other symptoms.

Many of them describe--it's like having a bad flu

going on for years, or for decades. [Question asked] So the question is, are we

seeing family members of patients with chronic fatigue syndrome

higher incidents of autoimmune problems?

The answer is yes. It seems like they tell us stories

about patients having a higher--the patients tend to have more

thyroid problem(s) of the autoimmune type. Um,

we are starting to pay attention to vitiligo, which is

whitening of the skin when the melanocytes are attacked by

antibodies. So it seems like there is another

clue towardas autoimmunity there.

[Question asked] Are the HSV-6 titers easily done and the answer is

yes. We don't have any commercial tie with

anybody. But there is a lot that we suggest

where the HSV-6 titers can be done, and its

focus, only because we are familiar with their numbers,

we have learned to to know what is low, what is medium, what is high.

But we have no commercial connection with them, but focus laboratory

appears to be reliable in giving us titers that we can

sort of like, act upon. [Question] So it's been said that there are,

there is a support group based in Mountain View,

that there is a sign up sheet outside here,

and it's important to share

these experiences. It's important to

bring this together, and as it was shown in that study in The Lancet,

it sounds like having interventional, behavioral intervention,

cognitive intervention,

it seems like it helps. And it's very important that,

that--do not let people talking to--that study proves

that CFS can be cured, or that that study proves

that it's psychological. In addition to what you said, they excluded patients

who couldn't come to the hospital, so the sickest patients didn't make it into the trial.

Though their scores were really low in terms of performance,

so in addition to the selection issues,

the study does not prove a psychological (connection) and does not prove

that that's the way to cure patients. [Question asked] Is there any

there any neurological or phenotyping difference, phenotype difference, between

those patients who come down with an

illness, with CFS, after they have an acute illness,

particularly an infectious illness, versus those who have their onset

not associated with an infection? Not that we know of,

but we are separating them by when we take the history,

and in the analysis that we are doing, looking for pathogens, or for immune

response abnormalities--

we are taking that into account. So hopefully we'll be able

to answer--no, I think he's asking like, independent of (whether) it's a woman or man,

is there a difference between those who started the illness with an infection,

versus those do do not start the disease with an infection.

It is well-known that 75 percent of the patients with

CFS, 75 percent are women. Now

if we were to take women alone, there are women who started their CFS

without an infection. And so the sample size on the second study was very small.

But women can start their CFS with not an infectious illness.

And the question is, are there differences between those who,

who tell you the precise time where they started,

versus those who who did not. So the question is, when the patients get a

viral illness,

some of them go into CFS and some do not.

The most common factor that has been associated in the study

(that) have looked at this, is severity of the illness.

So the more severe the illness, the more likely they are

to go into having the illness--

as far as it's known. [Question asked] Well thanks to the support of one of our

patients, we started, Lindsey actually,

and Mrs. Kaski are really the people who

we have to thank. We started a website

where, at Stanford, and, Lindsey, the name of the website please?

so http://chronicfatigue.stanford.edu/

...and there we are starting to put up as many resources as

we can, everything that we have learned about,

of the disease for the past few years. [Question asked] We know that some patients

crash. Have we measured the amount of dividers

or cytokines during those crash periods?

so we attempted to do that in the study that I showed you, where we found differences.

But the numbers are so small, and we didn't see any differences.

But I think it's a matter of just doing that.

The tough part of studying that is, how can you justify

to ask a patient, "Take this drug. It's gonna make you sick,

and we'll study you." So ethically it's hard. [Question asked]

These viruses are latent. They are there for the life of the patient.

So we are not suggesting that with these long-term anti-

viral interventions we are eradicating the

virus out of the body, we are trying to, if our theory is correct,

bring them under control. So--and you are absolutely correct--

I think that part of the reason it has eluded

our understanding of the disease, is that they are at very low levels

even when they are causing disease. That is correct.

[Question asked] It's more common in women--have we seen mothers

giving it to their daughters? So we have,

sadly, a few cases where that has been the case.

And mostly related to that situation, where dividers

integrate into the chromosome, the human herpes--so herpes viruses

normally do not integrate into the chromosome

like HIV does, like the XMRV does,

herpes viruses are known for not doing that. But the HSV-6 has found a

clever way to do it, and they--those patients

seem to pass their virus, particularly mothers to daughters,

through their chromosomes. So there are situations,

but that's the exception, luckily. But it's--

these are the tougher (cases) to deal with. [Question asked] So the question is very clever. So the same

way we can prevent--

and that is true--we can prevent HIV-infected mothers from giving HIV to their babies.

Can something like that be done for mothers with CFS?

Unfortunately, the drugs

can damage the baby, theratogenic, so that

makes it very hard to justify doing it with our

proper study setting. So that makes it very hard. But

I was at a meeting last night in

in Washington, with a patient who has

her daughter with it, and she once--her daughter,

through the treatment that we did, went back to complete normality after years of

having the illness. And they are now desperate that she got married,

newly married, and they want to have a baby, et cetera. How do you do it?

At this point there is nothing we can do. Unfortunately.

[Question asked] Two points: one is, do we have ways to

standardize what we are doing, so other physicians can have easy access

to doing those steps, and following the--the answer is yes.

And we talk to other physicians who are--

So many physicians had doing this now, nationwide,

and sometimes the patients, after they have been on the waiting list, they come to us

after they have been treated. And we're just fine-tuning the issues.

so we do have standard formats

that we give out to physicians.

And I think that I can say that, because

it's legal, and medically viable, we can actually put those protocols in

the website as well,

because none of the drugs that we personally,

we at the clinic are using, none of them are experimental.

They are all FDA-approved. And as you know,

any physician has the freedom to use any drug that is approved by the FDA for any

other indication that is reasonable.

so that is not illegal. And we put those protocols

in the website so physicians can download them.

But in the meantime, they can call us, and we give them out, and we talk to the

physicians as well. Regarding the equilibrium--

That is a drug

that comes from China, so we don't prescribe it because we we cannot

guarantee what--how many milligrams and the purity of the drug,

but if the suspicion is that other kinds of viruses called

entero- or echoviruses are behind it, we highly suggest the patient to

consult Dr. Chia in Southern California, because he

really is the one with the expertise, and that's his baby,

and I totally trust that what he has found is valid.

But we don't have the expertise with the administration of the drug.

Thank you. [Applause]