![[title]](https://montereybayholistic.files.wordpress.com/2012/11/naturalsuppressant.jpg "[title]")
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 for 23 years. 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 than a month-and-a-half of treatment: a month-and-a-half 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 they trigger in independent pathways 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]