Dr. Darryl See, the CFS researcher in Irvine CA, gave a lecture entitled "New Concepts in Cause and Treatment of CFIDS" on January 17, 1997.  Here is the transcription thanks to the work of Sue Bailey and Rebecca Bailey.  Dr. See kindly gave permission to disseminate this information.  In addition, you can view a compilation of Dr. See's statements about drugs and supplements.

        "I transcribed the following lecture by Dr. Darryl See from a tape sent to me. Question marks both before and after a word indicate my uncertainty about the word. Throughout, comments within brackets are mine. At the lecture, Dr. See distributed an outline which he followed during his lecture. I have incorporated his outline--using all capital letters--into the following transcript; I have modified his numbering system slightly. Also see a summary of drugs and supplements from this lecture."

                                --Sue Bailey, September 2, 1997

New Concepts in Cause and Treatment of CFIDS

A lecture given by Darryl See, M.D., January 17, 1997, Los Angeles, CA

Dr. See distributed the following outline at the lecture. (Note: question marks appeared on his outline.)

  1. Pathogenesis

    1. Genetic predisposition + environmental "trigger"--?virus, ?toxin
    2. Limbic system dysfunction
    3. Endocrine disorder (hypothalamic-pituitary-adrenal axis dysfunction)
  2. Viral connection

    1. Reactivation
    2. Recurrent/persistent infections de novo from immune suppression
    3. Allergic response to persistent virus
    4. Interpolation into host genome, inhibiting transcription/translation and/or causing immune activation
    5. Types of viruses:
      1. Enteroviruses
        1. Clinical syndromes. ?cardiomyopathy ?diabetes ?ALS
        2. Elevated titers: Scotland epidemic, other patients
        3. Serum VP1 antigen
          1. Yousef 1988: 51% vs. 7%
          2. Halpin 1989: 30% vs. 2%
        4. Virus in stool: 22% vs. 2%
        5. Viral RNA in PBMCs: 75% vs. 2%
        6. Viral RNA in muscle: 25% vs. 0%
      2. Human Herpes virus 6 (HHV-6)
        1. Mononuclear cell tropism
        2. Roseola
        3. Elevated titers, especially early antigen (77% vs. 7%)
        4. Increased viral load in PBMCs by quantitative PCR
      3. Retroviruses.
        1. Oncoviruses - HTLV I and II
        2. Lentiviruses - HIV 1 and 2
        3. Spumaviruses - HSRV
        4. (+) HTLV-2 Genomic RNA and mRNA, but )(-) titers (discredited)
        5. (+) HERV antigens compared to controls
  3. Immune system function

    - 4 findings
    1. Decreased NK activity
    2. Decreased lymphoproliferative activity, dysregulated expression of cytokine receptors
    3. T-cell activation
    4. Decreased IgG subclasses
  4. Intracellular Metabolic Dysfunction

    1. Defective mitochondrial morphology and function
    2. Defective ATP production (Kreb's cycle, Fatty Acid metabolism, electron transport chain)
    3. Cells are ENERGY STARVED
    4. Possible etiology: defective translation of host proteins from interference by interpolated viruses at the transcription level
  5. Therapy

    1. Adrenal insufficiency
      1. Potential cause: subacute/chronic stress from debilitating viral illness modifying axis (Moutschen, Acta Clinica Belgica, 1994; 49:274)
      2. Treatment: replacement
        1. DHEA, 10-200 mg daily
        2. Testosterone - Androderm patches 2.5 - 7.5 mg daily
        3. Florinef - 0.1 mg tiw to qd for orthostasis
        4. Prednisone - only for blunted response to ACTH
    2. Natural Killer Cell functional deficiency
      1. Potential causes:
        1. Depression (Straus, 1994)
        2. HHV-6 infection (Lusso, 1993)
        3. Limbic system dysfunction (Goldstein)
        4. Defect in interferon/RNAase L pathway (Suhadolnik, 1996)
        5. Intracellular metabolic defects (personal observations)
      2. Treatment:
        1. Antioxidants
        2. Intracellular metabolic resuscitation
        3. High protein diet/amino acids
        4. Interferon
        5. Ampligen
        6. Echinacea
        7. Ginseng
    3. Immune System hyperactivity
      1. Responsible for many CFIDS-related symptoms
      2. Potential causes: modified HPA-axis (Demitrack 1991); persistent viral infection (personal observations); intracellular metabolic defects
      3. Treatment
        1. Antioxidants/metabolic resuscitation/amino acids
        2. Intermittent Prednisone
        3. Judicious use of benzodiazapines
        4. Immunoglobulin
    4. Reactivation of latent viruses
      1. Cause: immune dysfunction including IgG subclass deficiency (especially IgG3)
      2. Treatment:
        1. Treat immune dysfunction as above
        2. Immunoglobulin
    5. Cognitive dysfunction
      1. Potential causes
        1. Limbic system dysfunction
        2. Up-regulation of NMDA receptors (Cheney, 1994)
        3. Immune dysfunction
        4. Intracellular metabolic defects [See "a"below.]
        5. Persistent viral infection [See "a" below.]
      2. Treatment
        1. GABA agonists (Neurontin)
        2. Vasocon opthalmic drops
        3. Guarana
        4. Gingko
        5. ?Hydergine
        6. Antioxidants/metabolic resuscitation/amino acids
    6. Fatigue
      1. Treat other conditions
      2. In addition, trial of SQ Vit B12 (Cheney, 1989)
      3. Low dose Armour thyroid
    7. Posterior pituitary dysfunction
      1. Treatment: intranasal oxytocin
    8. Mycoplasma incognitus infection
      1. Treatment: Doxycycline or Azithromycin for 3+ months


INTRODUCTION [tape started late] back to outline

.... infectious diseases; I'm also very involved in immunology; I've been doing CFIDS research about the last five years. I see a lot of familiar faces. I spoke here last year. But since that time I have been fortunate to be part of a multi-national research team. We studied CFIDS in France. There were investigators from around the world, including France, Australia, Japan and other parts of the United States. So what I'm going to do today is pretty much focus on those research findings that I and the other investigators worked on back in France, particularly regarding causes of CFIDS and pathogenesis and, I think what is more interesting for all of you, implications for new treatments.

I heard someone from Immuno Sciences talk about mycoplasma incognitus and I'll talk a lot about that as well. It should make Immuno Sciences Lab rich. We send a lot of samples to Orange County as well. But it's a good test.

Question [Q.] Can you also at some point tell us about the [inaudible]

Absolutely. Let me start off with that then, before we plunge in. Previously I've been handling CFIDS patients pretty much myself at UCI, and pretty much doing the research myself, but I'm fortunate enough to have teamed up with Dr. Bryan Andrews, who's rheumatology by training, but has a lot of experience in molecular biology and immunology and infectious diseases and is particularly an expert in fibromyalgia. He handles a lot of the fibromyalgia cases, but he also, by my tutelage in part and his knowledge in part, has become an expert in chronic fatigue syndrome as well. So we've started a new CFIDS clinic at U.C. Irvine. And Dr. Bryan Andrews and myself see the patients. And although we call it a CFIDS clinic or center, the patients are not seen by students or residents or fellows or anything like that. Dr. Andrews and I handle everything. Any questions about the CFIDS Clinic?

Q. ....Dr. Kirk Sanders.... ?

We use him as a sort of referral. He doesn't see patients, but he sends us questionnaires sometimes and helps with psychiatric studies. We refer him patients for psychiatric studies, psychometric testing, etc., but he doesn't see patients primarily.

Q. How do we contact the clinic?

Let me give you some numbers. My research office is 714-456-7612. I can be reached through that number. The direct line into the center is 714-456-7100. So all you have to do is just...it's kind of a long drive for people up in this area, but hopefully... So the direct line there is 456-7100, and you'll probably talk to...George or Ellie. They set up the appointments, right now, until they lose all hope and somebody else comes in.

Q. Do you take MediCal?

MediCal? You know what...I'm not involved with the administration of the clinic, but my understanding is that MediCal is fine. The University really runs the center. I understand they're a little bit down on CalOptima.

Q. I couldn't get in...

Well, I can certainly make exceptions. Anyone who comes to my talks, I can make exceptions. Just leave your name and I'll tell them it's o.k. But in general, to be honest, I don't know exactly what they take. I know they don't like Optima very much there..?--? the infectious disease clinic there. I can always override things, a few things, maybe once a month or so, before they start yelling at me.

So, refer to your handouts. The title of my talk today will be New Concepts in Cause and Treatments of CFIDS. Again, much of this is based on the research of the team that I was working with in France. I was fortunate enough to have a bio-medical grant to go over there and study. Not a Federal grant; as you know it's very difficult to get anything from the Federal government to study this, so we had to go over to Europe to do it.

I. PATHOGENESIS. back to outline
The first concept I would like to talk to you about is the cause or pathogenesis of CFIDS. You've heard a lot about this. But we're pretty certain now about the etiology of CFIDS. And it's good news and bad news.

I-A. GENETIC PREDISPOSITION + ENVIRONMENTAL "TRIGGER"--?VIRUS, ?TOXIN. The bad news is this: There is certainly genetic predisposition to the disease. Whether your parents or grandparents had problems--that doesn't really matter. It's a multi-focus genetic problem--probably at least 4 to 10 genes, involving different chromosomes, part of them sex-linked, related to the preponderance of cases of females; but not all the genes are sex-linked. Work on the genetic predisposition is just beginning. There's been a little work out of Portugal, of all places, now. They might have some clues on some of the defective genes. But that work is just starting. And that's going to take a lot of money. We need your support on getting us some Federal funding to do the genetic studies. That's what needs to be done. We feel pretty competent on the virology and a lot of the central nervous system research and a lot of the immunology now. And a lot of the biochemistry. We did a lot of biochemistry over in France, which I'll be talking about. But the genetic part--we're lagging behind, and we need to find out about. Ultimately there won't be any cure until we find out what the genetic basis of the disease is.

Q. inaudible

Absolutely. I'll get to that in the second part. So look at number "A" under "unknown," genetic predisposition. And then there's an environmental trigger. Usually it's virus or toxin but it can be trauma--a motor vehicle accident or divorce or a death in the family or some kind of trauma that triggers the disease. How I like to think of it is, a patient has this genetic predisposition and basically will pretty much cruise through life and not have a lot of problems and then their threshold for developing CFIDS would be just hovering at right about this line here [chart?]. See CFIDS below this and wellness above this? And then some kind of trauma or immunomodulating virus or toxin enters the picture and then you drop below the threshold into full-blown CFIDS.

Q. inaudible

Absolutely. Right. The neurologic part was probably just a manifestation of the genetic, and then the definite trigger. People talk about "when I was a child" and then that really clues me in. That was the genetic part, and then the trigger. The disease can be insidious in many patients. There is a trigger, but it may be hidden. Mycoplasma incognitus may be one of them. You don't know when you get infected by it.

Q. inaudible

Absolutely. I mentioned divorce, a death in the family, a motor vehicle accident. And other significant stressors can absolutely trigger this.

Q. inaudible

Let's do that. Save your questions. Write down your questions and we'll take care of them at the end. O.K., so there's some kind of trigger or environmental agent that sets off the disorder to below the threshold.

I-B. LIMBIC SYSTEM DYSFUNCTION. Other theories include limbic system dysfunction, and with due deference to the proponents of that cause, it seems to be falling into disfavor as a primary cause of chronic fatigue syndrome. As you all know, probably a subgroup of patients, indeed, is perhaps a limbic system dysfunctional group, but most patients are more immunological, virological. Believe me, limbic system dysfunction does not cause the majority of cases of CFIDS, maybe a few cases.

I-C. ENDOCRINE DISORDER. Also there are proponents of an endocrine disorder, hypothalamic-pituitary-adrenal axis dysfunction. But I'll tell you that some of our research findings suggested that this is a secondary phenomenon, not a cause. You know it's a multisystem disorder, and this undoubtedly happens--this HPA dysfunction--but think of it as a secondary phenomenon like depression or something of that nature, but not a cause. It needs to be treated. I'll talk about that later. So I think the number one message to take home is "genetic predisposition."

II. VIRAL CONNECTION. back to outline

II-A. REACTIVATION. Concept number two would be a viral connection. There's definitely a viral connection with this illness. And that could be manifested in one of four different ways. This was sort of my role--my background being in virology--this was sort of my role in the multi-national group. This is what I and my colleagues came up with: Virus reactivation is absolutely a crucial part of the illness. We found in an average chronic fatigue syndrome patient--we studied hundreds--that viral reactivation, or reactivation of mycoplasma incognitus--I kind of throw that in with virus--it was an average of 37.5 reactivated viruses at any one time, in an average CFIDS patient. That's a lot. 37.5. So when you think about it--40 reactivated viruses at any one time in a patient--that's a lot!

Q. In one patient?

That's an average. Some patients had 60 or 70; maybe some had 15 or 20. This is at one time. As you know, many viruses, especially in the enterovirus group and retrovirus group are latent viruses; once they get in the body they stay there. You just can't get rid of them. In patients with normal immune systems it's not a problem. They just stay in a latent state, don't reactivate and don't cause a problem. Maybe you see reactivation once or twice. Shingles is a reactivation of a virus, for instance. It happens, it goes away, it's no problem.

II-B. RECURRENT/PERSISTENT INFECTIONS DE NOVO FROM IMMUNE SUPPRESSION. But in CFIDS, because of the immunologic dysregulation, virus reactivation happens all the time. It's a constant war, in the body. As it turns out--we'll talk more about this later--in a normal human being there's about 10 billion base pairs in DNA, and about 1% of that is not our DNA--our own DNA--most of it retrovirus. That's a normal person, without CFIDS. We found--studies were very difficult, technically difficult--but we found 5% to 10% in a CFIDS patient. Your DNA is not your own DNA. About 5% to 10% of it is virus. We'll talk more about that. We know that there are recurrent and persistent infections from immune suppression. These immunomodulating viruses and viruses ?recurring? drop your immune system and then you're susceptible to things that come in from the environment, and it may not even know you caught it. But internally the war accelerates.

II-C. ALLERGIC RESPONSE TO PERSISTENT VIRUS. There's a group of you--and we'll talk about the immunology later--there's a group of you that just may get the flu all the time and colds all the time. There's other groups that never get the flu, and I'll explain why that happens. And unfortunately, as many of you know, you were well and all of a sudden caught CFIDS and then suddenly became allergic to everything, or a lot of different things. One treats allergies with steroids, for instance. Well, I personally have six patients who are allergic to steroids. What do you do? What do you give them? It's a problem. If you become allergic to vitamins and minerals and herbs and drugs and environmental agents, a whole host... Unfortunately, this happens with viruses as well. So not only are these things reactivating and causing immune system dysregulation, and causing your body to fight them--you're also allergic to them. And the internal allergic response makes you feel bad, by abnormal cytokine production. We'll talk more about that.

II-D. INTERPOLATION INTO HOST GENOME, INHIBITING TRANSCRIPTION/TRANSLATION AND/OR CAUSING IMMUNE ACTIVATION. Very, very recent data, and this is just hot off the press--I'm trying to write this up now, is the following. This fourth category--it's something you never [?or might have?] heard of before. We found that, in patients with CFIDS, because of a genetic predisposition in ?promotor? site function, that these immunomodulated viruses get into the cells and they actually interpolate themselves into the host DNA, and actually inhibit normal transcription, normal ?post? proteins. Transcription, just briefly: You have your DNA and you make messenger RNA off that DNA, which is later translated to proteins. So DNA to messenger RNA--that's called transcription. Messenger RNA to proteins is called translation. This process is very dysfunctional in patients with CFIDS. You do not produce normal intracellular proteins. And proteins are the building blocks of the cell. You have to have normal proteins for your cell to function properly. So this was a very important finding. We found that the presence of these viruses stuck into the host genome were causing abnormal messenger RNA and ultimately abnormal proteins were being produced. But we have some ways that we can intervene in that. And also this abnormal process causes immune activation and abnormal cytokine production.

II-E. SPECIFIC VIRUSES. So, let's go over some specific viruses. My training, my history, is enterovirology, and I've had an interest in a variety of enteroviruses over the years.


II-E-1-a. CLINICAL SYNDROMES. ?CARDIOMYOPATHY. ?DIABETES. ?ALS. I was one of the first discoverers to find that coxsackie B viruses are a leading cause of idiopathic dilated cardiomyopathy, which is the most common indication for heart transplantation in the United States, so some of you know me as a heart transplanter, you've heard about that, so...it's probably a virus, coxsackie B, that caused that initially, and an immune reaction to that. Also, coxsackie B viruses are responsible for many cases of Type I diabetes. And while I was in France--the Europeans were hiding this from us for the last year--I got involved when I was over there, and actually sequenced the virus that causes Lou Gehrig's disease, or ALS. That is a viral disease, a coxsackie B variant. This is one paper I'm working on right now, just to let you guys know that you're the first to hear of this. The ?--? aren't out yet. But the next step of course is to work up therapies for the coxsackie Bs. And we know that coxsackie Bs and other enteroviruses are very important in chronic fatigue syndrome as well. There's no doubt about that.

II-E-1-b. ELEVATED TITERS: SCOTLAND EPIDEMIC, OTHER PATIENTS. Evidence: Among other things, there was an epidemic in Scotland in the early 1980s, and this was one epidemic of CFIDS where we actually found the viral causation, or at least the viral relationship. Patients with CFIDS had very high antibody titers to coxsackie B viruses compared to normal controls, and...

Q. Can you please slow down a little?

Sure. I mentioned the epidemic in Scotland in relation to the coxsackie B virus, and I actually first became interested in the illness when I had patients referred to me who had obvious acute coxsackie B virus infections, and didn't get well. They were sick months later, and that interested me. That had never been heard of before at that time. Enteroviruses six years ago were not considered to be chronic viruses. But now we know that they are, and so we know that they are real important here.

II-E-1-c. SERUM VP1 ANTIGEN. Other studies, just real briefly: They have been shown to clearly indicate that viruses play a role in chronic fatigue syndrome. VP1 antigen is a protein that is found on enterovirus cells. There were two studies in 1988 and 1989 that looked at this antigen in the serum of patients with CFIDS versus normal controls. And let's just look at the...

II-E-1-c-1. YOUSEF STUDY in 1988. 51% of the patients with CFIDS had VP1 antigen vs. 7% of the controls and the...

II-E-1-c-2. HALPIN study in 1989 showed the same thing: 30% in CFIDS vs. 2% in controls.

II-E-1-d. VIRUS IN STOOL: 22% in CFIDS vs. 7% in controls. But these are fairly insensitive studies for enteroviruses.

II-E-1-e. VIRAL RNA IN PBMCs. A study we were involved in was looking at viral RNA by PCR [polymerase chain reaction] in peripheral blood mononuclear cells, and we found that 75% of CFIDS patients had enteroviral RNA in their mononuclear cells vs. just 2% of controls.

II-E-1-f. VIRAL RNA IN MUSCLE. And some investigators in England found enteroviral RNA in muscle cells, probably accounting a lot for muscle weakness and muscle aches and probably part of the etiology of fibromyalgia as well.

Q. inaudible

I want to hold questions for afterwards, unless you want me to speak up, or... Please just write down your questions. And 0% in normal controls. So, that virus gets in there and it gets into the muscles. To sum up the role of enteroviruses in chronic fatigue syndrome: It probably initiates or acts as a trigger in a small percentage of cases--maybe 5 or 10%. It reactivates ?---? in most patients. We found 75%. It causes all these problems with immune activation, and causing that internal war. You won't know when you have an enterovirus reactivation, but your immune system does.

II-E-2. HUMAN HERPES VIRUS 6 (HHV-6). The next virus would be human herpes virus 6. You've heard a lot about this organism. There were very good studies at the NIH, prior to our work, suggesting this is a very important organism in chronic fatigue syndrome. There's no doubt that this virus reactivates, and I personally use HHV-6 titers as a marker of virus reactivation. You can't run all the viruses but HHV- 6 is a very simple test to run, and I consider a value of 1 to 160 to be pretty good evidence that HHV-6 reactivation is recurring, so I use this as a normal part of my CFIDS workup panel.


II-E-2-b. ROSEOLA. HHV-6 actually causes roseola in children. You all probably caught it--all of us caught it--when we were little. It just stays in your body, doesn't cause a problem until your immune system becomes dysfunctional and then it reactivates, causes a lot of problems.

II-E-2-c. ELEVATED TITERS, ESPECIALLY EARLY ANTIGEN. And there have been really good studies from the NIH showing elevated titers, especially the early antigen, which is clear evidence of an active infection--77% in CFIDS patients vs. 7% of controls.

II-E-2-d. INCREASED VIRAL LOAD IN PBMCs BY QUANTITATIVE PCR. A study that I did was to look at HIV viral load. We can do the same thing for HHV-6 by quantitative PCR and we found the amount of viral load in CFIDS patients was thousands of times greater than in normal controls. We do find a little bit in normal controls because it's such a sensitive test, but it's thousandsfold greater, or ?lawns? greater, as we say, in patients with CFIDS. So HHV-6, the role in CFIDS, perhaps it acts as a trigger in a few cases, certainly it's a very important reactivator.

II-E-3. RETROVIRUSES. Next, we'll get to the real interesting category of retroviruses. There are three families of retroviruses: the oncoviruses, which have been associated with a number of tumors, particularly leukemias; the lentiviruses, which are the AIDS group; and the third family, the spumaviruses, or human spuma retrovirus.

II-E-3-a. ONCOVIRUSES - HTLV 1 and 2. (+) HTLV-2 GENOMIC RNA AND mRNA, BUT (-) TITERS (DISCREDITED). And there was great excitement about four years ago that maybe HTLV-2 was an important player--maybe a cause. A group in Florida found high levels of genomic and messenger RNA from HTLV-2 in patients with CFIDS compared to controls, and several other laboratories looked at this and did not find the same thing. So it has been pretty much discredited as well.


II-E-3-c. SPUMAVIRUSES - HSRV. ?(+) CULTURE FOR HSRV, BUT (-) TITERS (DISCREDITED). There was a lot of excitement about five years ago that maybe spumavirus was an important player in CFIDS but about six very good laboratories in the United States looked at this, and a laboratory in Germany as well, and it just did not hold up. Spumavirus is not important in CFIDS. There's really good data.

II-E-3-d. (+) HTLV-2 GENOMIC RNA AND mRNA, BUT (-) TITERS (DISCREDITED). And there was great excitement about four years ago that maybe HTLV-2 was an important player--maybe a cause. A group in Florida found high levels of genomic and messenger RNA from HTLV-2 in patients with CFIDS compared to controls, and several other laboratories looked at this and did not find the same thing. So it has been pretty much discredited as well.

II-E-3-e. (+) HERV ANTIGENS COMPARED TO CONTROLS. But, something in the retrovirus family that has held up is the human endogenous retroviruses--HERVs. [Which family do these fit into?] A lot of investigators are doing work with this; we did work with this as well; and everything is holding up, as far as the HERVs. HERVs--those are the viruses that get into your DNA-- they have a DNA phase, and there are a few of them found in any patient, but in patients with CFIDS--there's a lot of human endogenous retrovirus DNA in your DNA. And, but it just doesn't sit there. We did some very sophisticated testing, and we found that these retroviruses not only sat there, but they actually expressed proteins. They transcribed themselves and expressed proteins on the cell surface of patients with CFIDS, and these comprised a very large number of the reactivating viruses--I mentioned the 37 to 40%. A lot of them in people are human endogenous retroviruses. And retroviruses cause a lot of problems when they express the proteins, a lot of immune dysregulation, etc., so they seem to be very important players. Many of them are sensitive to AIDS drugs, interestingly enough. I'm not saying ?--? AIDS drugs now, but it's a thought, it's something we'll be looking into. A very important concept.

III. IMMUNE SYSTEM - 4 FINDINGS. back to outline
So as we looked at the CFIDS story we see that in patients who are set up genetically the illness is triggered, and viruses played a great role; the third part of the puzzle is the immune system. Immune system dysfunction is very important. There are four findings in patients with CFIDS and one can have a variety of these. Finding what immunologic category a patient is, is very important as far as treatment considerations, which I'll talk about later. So it's important to do these studies.

III-A. DECREASED NK ACTIVITY. Decreased natural killer cell activity is found in maybe 50%, 60%, of the patients. Again, this has a lot of implications for treatment.

III-B. DECREASED LYMPHOPROLIFERATIVE ACTIVITY, DYSREGULATED EXPRESSION OF CYTOKINE RECEPTORS. Decreased lymphoproliferative activity and dysregulation of cytokine receptors has an important role. In my slides I have...I can just explain it verbally, some cytokine studies that we did recently, that will be published in the Journal of Clinical Psychiatry in about a month. As it turns out--many of you may have heard some of this before--inflammatory cytokines, they make you feel inflamed, they make you feel fatigued, they may give you joint aches, sore throats. So-called ?full? inflammatory cytokines like tumor necrosis factor alpha and interleukin 6 seem to be big players in this disease. We found extremely high levels of tumor necrosis factor alpha and IL-6 in patients with CFIDS. And these cytokines have been injected into normal controls, to see their effects on the immune system, etc. I actually injected myself with both of these, at different times. On a Friday, so I could have the weekend to recover. I'll tell you, you feel lousy, really lousy. I couldn't think during the weekend, so I started popping the guarana and the gingko. We'll talk about that later. I just wanted to get an idea, a confirmation of what these things do. I just wanted to sleep. It was an interesting experience. These are big players.

Now, on the other side of the coin, it's hard to do much about these. There are some companies working on TNF [tumor necrosis factor] blockers and IL-6 blockers, but you need some, to regulate the immune system. But maybe the more hopeful category is this, and this is the new finding that we just came up with: We also found very, very low levels of interleukin 10. Interleukin 10 is a down regulator of the immune system. And there was no IL-10 in patients, essentially. And IL-10 helps calm down the immune system. When the immune system is activated it calms it down. It decreases the production of ?--? inflammatory cytokines. So maybe IL-10 might be a real interesting therapy. But IL-10 is just in very ordinary trials. So it's going to be a while. But it's an interesting finding.

III-C. T-CELL ACTIVATION. A third category of immune system dysfunction is T-cell activation. It's a real tough problem. In a normal person, your T-cells are in a naive state or resting state most of the time. They're called ?CV45RO? cells, or naive T-cells. They don't produce these ?---?. They just sit there. They wait for a foreign antigen or virus to come in. They kill it--they activate to kill it--and then [explosive sound]; they go back to rest. But unfortunately, in at least a portion of patients with CFIDS, the T-cells activate in response to a virus, but they don't go back to a resting state. This is part of the genetic problem. It's also part of these viruses in the host DNA and it's part of the problem with continually reactivating viruses, always keeping the T-cells activated. Having T-cells activated is a bad thing, because you're always producing these ?-? inflammatory cytokines and they just make you feel bad and they make you feel tired when they're always activated. They should be in their naive state but they're not.

III-D. DECREASED IgG SUBCLASSES. And a real important finding to look for would be decreased IgG in the ?-? subclasses. We found that in IgG subclass 3 and IgG subclass 1 ?-? to a lesser degree are very, very important in anti-viral activity. And this is something that is missed in many, many CFIDS patients, and it's a shame because it's something that's very treatable, if you find it. Decreased IgG 3 levels or IgG 1 levels, and you lose a lot of ?random? anti-viral activity if these are low. But the nice thing is that they can just be replaced by--well, we'll talk about that. This is a very treatable part of CFIDS if this is found. That's the third part of the puzzle. It's genetics, viruses, the immune system.

IV. INTRACELLULAR METABOLIC DYSFUNCTION. And number IV here is just hot off the press. back to outline

IV-A. DEFECTIVE MITOCHONDRIAL MORPHOLOGY AND FUNCTION. It's something that our biochemists found just over the last year. This is intracellular metabolic dysfunction. As it turns out, we had some indication that this might be occurring, by English investigators about three or four years ago who did electron microscopy of muscle cells and found a very abnormal mitochondrial shape. Just looking at mitochondrial shape doesn't mean much but it just gives an indicator there's something wrong inside the cell. Previous research had pretty much focused on looking at: What's the limbic system doing? What's the adrenal gland doing? What are the immune cells doing? But what we decided to do was to crack open the cells, and look at the genes and look at the metabolism of cells. As it turns out--the mitochondria is the powerhouse of the cell; morphology means the shape--it ?--? very defective in ?--? function; it just did not work well at all.

IV-B. DEFECTIVE ATP PRODUCTION. (KREB'S CYCLE, FATTY ACID METABOLISM, ELECTRON TRANSPORT CHAIN) And ultimately, if ?--? ?--? messages, ATP production in the cells... We looked at brain cells, immune cells, gastrointestinal cells and muscle cells. It probably happens in other cells as well. We wanted to look at the adrenal gland, but it was hard to get patients to consent to taking a piece of their adrenal glands. It's right on the kidneys, so it was a little hard, so we haven't looked at that yet. But believe it or not, in Europe it's not that hard to get brain biopsies for research purposes. Here, it's hard, but patients did it. In good hands it's a safe procedure, but obviously that's giving a lot for science. But, in all these cells we found dramatically decreased ATP production--defective Kreb's cycle, fatty acid metabolism and electron transport chain activity. And we found the electron transport chain is essentially a chain of oxygen being carried along, ultimately energizing a ?--?. As it turns out, when this chain is interrupted, as it is in CFIDS--and when we get down to Number D I'll tell you why it's interrupted in CFIDS patients--and when that happens, you've got a bunch of oxygen with one charge sitting there in the cell. They soon have two charges sitting on them. An oxygen with one charge is a very bad thing. It is the ultimate cellular scavenger. It starts combining with everything inside the cell. And so that ?gives? to the concept of antioxidants.

IV-C. CELLS ARE ENERGY STARVED. Antioxidants are crucial in the treatment of CFIDS because of this problem, and now we know why--because of this problem in the electron transport chain. The bottom line is, the point is, cells are energy-starved. When your cells are starved for energy you feel tired. Your muscles feel tired. You just feel tired. As it turns out, the body tries to get ATP produced the best it can, but it's being blocked at several points, so many patients with CFIDS will tell you they gain weight. They gain weight. How can I be starved and yet gain weight? I hardly eat anything. Well, the cells are screaming for energy, but they can't get it because all of these dysfunctional proteins are not producing ATP, and that's the reason the weight gain occurs. To a certain extent. There are also other factors, like inability to exercise, etc. I'll talk about that later.

IV-D. POSSIBLE ETIOLOGY: DEFECTIVE TRANSLATION OF HOST PROTEINS FROM INTERFERENCE BY INTERPOLATED VIRUSES AT THE TRANSCRIPTION LEVEL. We think the possible, or probable, etiology is defective translation of most proteins by interference of these viruses that are in your DNA. Some of them may be just sitting in the nucleus or cytoplasm. They interfere with the processing of normal proteins, so you don't produce normal proteins. You don't produce normal enzymes. But there are things you can do about that. I'll talk about that next. That kind of concludes the most up-to-date thoughts on the pathogenesis of CFIDS. We think of it in four ways.

IV-D-1. Number one--there's the genetics; we have a long way to go on that.

IV-D-2. Number two--there's the role of viruses, which I talked about.

IV-D-3. Number three--there's that role of immune system dysfunction.

IV-D-4. And number four--there's that role of intracellular metabolic dysfunction.

V. THERAPY. Coming right out of the laboratory were some thoughts on treatment. Let's go over these one at a time. back to outline


V-A-1. POTENTIAL CAUSE: SUBACUTE/CHRONIC STRESS FROM DEBILITATING VIRAL ILLNESS MODIFYING AXIS (Moutschen, Acta Clinica Belgica, 1994;49:274) I mentioned that there's dysfunction at the level of the hypothalamic-pituitary-adrenal gland axis. And potential causes are probably from--the probable cause is subacute ?chronic? stress from a debilitating viral illness and immune dysfunction that modified the axis. It's probably not a primary problem. I just mention a reference there. But you have to look for this, and the nice thing is you can treat it.


V-A-2-a. DHEA, 10-200 MG DAILY. You treat the hormones that are not being produced. DHEA is deficient in many, many patients, and you just replace the DHEA. It makes patients feel better--if you're defective. If you have normal levels, it's not going to help you, probably.

V-A-2-b. TESTOSTERONE, ANDRODERM PATCHES 2.5-7.5 mg daily. Testosterone is defective, and that includes women, as well. I've seen many women now who have zero testosterone in their bodies, and that's not normal. Women need testosterone as well, for normal immune functioning, normal bodily functions. So I replace testosterone in women as well, and it helps. There are ways of doing it safely. You have to be careful there, obviously. You don't want growing beards and that type of thing. There are ways of doing it safely, and you must do it if there's a deficiency there.

V-A-2-c. FLORINEF, 0.1 MG TIW TO QD FOR ORTHOSTASIS. You're all familiar with the Johns Hopkins studies showing the neurally mediated hypotension, and there are defects in mineralocorticoid production from the adrenal glands. Florinef helps patients that have that. That turned out to be a low percentage of patients, and the Johns Hopkins people were wrong, as it turns out, on the etiology of that syndrome in CFIDS. We'll talk about that later. There's a much more important hormone, which explains the fact that many patients who are treated with salt and florinef don't get better. Some do. Mineralocorticoid defect is important in some patients, but it's not the answer. So if you do have a positive tilt table test it doesn't mean that it's just an adrenal gland problem. I'll tell you what else it may be later. But if it is an adrenal problem then you want to treat it with Florinef.

V-A-2-d. PREDNISONE--ONLY FOR BLUNTED RESPONSE TO ACTH. And we do screen ?cortisol? levels to look for decreased steroid levels. They're found in a number of patients, and if this is found one must do an ACTH stimulation test, to confirm that it actually is a steroid deficiency, because you don't want to be treated with steroids if you're not deficient. It's too dangerous. So if it is confirmed, then one can treat with Prednisone, particularly in intermittent dosing. What I'll do is...five days every two months is pretty safe. You can do that. What I'll do with patients that are particularly T-cell activated--cortisone, Prednisone really can down-regulate that T-cell activation. It really works very well for that. And [?I'm interested in?] one other thing that really works well for that. But you can't take Prednisone all the time. And you only take Prednisone if you're in that T-cell activation group. If you have natural killer cell dysfunction, and you give a lot of Prednisone, your natural killer cell activity will go down, and all of a sudden you'll start reactivating viruses. It's dangerous. So you have to be in the right category and you have to be careful. But if you do, it works very well.

V-B. NATURAL KILLER CELL FUNCTIONAL DEFICIENCY. O.K., we'll move down to natural killer cell functional deficiency.

V-B-1. POTENTIAL CAUSES. Potential causes are many:

V-B-1-a. DEPRESSION (Straus, 1994);

V-B-1-b. HHV-6 INFECTION (Lusso, 1993); There's a very interesting article in 1993 that showed that HHV-6 actually infects natural killer cells and kills them.

V-B-1-c. LIMBIC SYSTEM DYSFUNCTION (Goldstein); in most patients who have that, it will cause a decreased natural killer cell function.

V-B-1-d. DEFECT IN INTERFERON/RNAase L PATHWAY (Suhadolnik, 1996); real important--Dr. Suhadolnik at Temple has found--you may have heard about the CFIDS marker protein? There are several candidates. One candidate is a ?68? ?--? protein kinase in the interferon pathway ?--? the natural killer cells and other cells. That's an abnormal protein, so your cells do not respond adequately to interferon. If you don't respond adequately to interferon, if there's a defect in this pathway, you're not going to kill intracellular viruses well. And there is a defect here in many patients, and because of this defective protein, kinase, and it's found in a fairly high percentage of patients we see, greater than 95%, and it's pretty easy to assay, so it may be a good marker of disease.

V-B-1-e. INTRACELLULAR METABOLIC DEFECTS (PERSONAL OBSERVATIONS). And again--I'm going to hit this point many times--these metabolic intracellular metabolic defects occur in the natural killer cells, too--the mitochondrial problems, etc. ?- -?



V-B-2-b. INTRACELLULAR METABOLIC RESUSCITATION. There's a ?--? that I call intracellular metabolic resuscitation. Together with a biochemist we identified a very large number of the enzymes that were defective in CFIDS. We also--I say we, it was the biochemist, really, who did it--actually came up with a form of ATP that could actually be ingested orally, and get into your cells. And, along with that, is anti-oxidants. And also, we can partially overcome the problems in your proteins by giving lots of amino acids. The problem is, the gut of patients with CFIDS are inflamed because of the viruses, but we've come up with an enzyme that helps absorb those amino acids.

Because I can't keep my office stocked with a bunch of herbs and vitamins, etc., I left the card of an herbalist I trained down in Orange County, who knows all of this very well, and she also helps me with my HIV patients. We're finding many of these findings in HIV as well. That's, again, it's a retrovirus that gets in your host DNA and causes...it doesn't just kill cells, etc., it causes these intracellular metabolic defects. And the biochemist continues to work on this and they continue to e-mail me with new findings. There will be new ones that we've found, and I'll continue to pass it on to my patients, and we'll work those into the formulations.

I'm sure many of you use supplements and vitamins, etc., spend hundreds and hundreds of dollars on them, thousands of dollars. What we're trying to do now is find the ones that really work. I spent the last three years--I've published a couple of papers on herbs, antioxidants, vitamins, etc.,--and we think we're now getting close to identifying the ones that really work. Actually, if you take the wrong herbs, it's going to get worse. Let's say that you have a bad problem with T-cell activation. If you take an herb that activates your T-cells, the herbs must be doing good things, and it boosts your immune system. But it activates your T-cells ?worse? and you feel worse. The only problem we've run into in this process, and again, we're just taking this right from the laboratory and we've had experience of about two months with this, but it's looking very good. Patients have done very well with this. The only problem is, some patients do react to some of the herbs and even some of the vitamins, etc. We just try to work around that--slowly and one at a time, giving the ones that are least immunogenic or allogenic and then working the way up.

And I'll tell you about some of the more important ones for us. Among the antioxidants we've pretty much ranked the most potent antioxidants yet found. The most potent antioxidant by far is extract of rosemary. It's excellent. What we did in France was this. We took...we asked all herbal companies around the world who wanted to send us herbs and vitamins and minerals, etc., and we tested them. It was a very laborious process, but we tested them in parallel, in the same cells, to find out which ones work, which were the purest and which worked the best. We took the same extract of rosemary from several different companies, same ginseng, etc., and believe me, they're not all the same. I highly recommend not to go into herbal stores and just pick out things from herbal stores. I'm trying to train other herbalists--I only have one now--but I'm trying to train other herbalists about CFIDS and to train them about the disease and about allergic reactions to herbs and to vitamins and minerals and amino acids, etc., what to do about that, what's necessary, what's needed, which antioxidants are potent, which companies make good forms of this.

I don't want to get into this a lot. I've left the card of the herbalist back there and she doesn't, I've made an agreement with her, she doesn't charge any consultation fee, and keeps things down to distributor prices, so it keeps the cost down, and I hopefully will be setting up some conferences with other herbalists, and teaching them the same process. But in health food stores it's hit or miss. You can find things that will help you, but it's kind of a random process at this point, but again, we found those that seemed to work the best and had the best quality control, etc., but I'm not going to go into that, because I don't want to get involved with that. You can talk to the herbalist about that.

Extract of rosemary is the most potent antioxidant by about a hundredfold. The second most potent antioxidant is schizandra berry extract. And we're really starting to push that. Extract of rosemary is [END OF SIDE ONE. THIRD ANTIOXIDANT IS MISSING, but I think he said that pycnogenol] is a very good antioxidant. These three in combination are synergistic. In other words, they potentiate their effect, and they're excellent. They're great for anti-aging, and I take them, just because they're great for what's called ?tialamare?, disintegration of cells. That is ultimately responsible for your cells not ?reproducing?, aging of the skin, etc., and they help stop that. Antioxidants do that.

Everybody should take antioxidants, but particularly patients with CFIDS because of the problem with the electron transport chain that I mentioned. And then the activity goes way down from there, into the vitamin C, E. A and E are about the same, and chromium picolinate has some activity as well. There are some other minor players too, but those are the major players.

V-B-2-c. HIGH PROTEIN DIET/AMINO ACIDS. Amino acid resuscitation is crucially important. You should take amino acids. There's a new... There's also been discovered an enzyme called aminogen that allows transport of amino acids across the gastrointestinal tract and into cells. That is really important, because even if your blood shows you have enough amino acids, or your urine test shows you have enough, you don't in your cells, because they're not pulled into the cells right. This enzyme is very nice. It gets them across the gastrointestinal tract and gets them into the cells. So you supplement with amino acids and take this enzyme, and it works very well.

V-B-2-d. INTERFERON. Also therapies...we've worked a lot with interferon. I mentioned that defect in the protein kinase in the interferon pathway--you can overwhelm that, by giving enough interferon, as it turns out. It's miserable the first month on it. But if you fall into the natural killer cell defect category and you're pretty clean--your T-cells are pretty clean--and there are patients like that, treatment with interferon works very well. We've done two clinical studies now, showing that. I've had patients who have gone back to work and a professional singer I know, who was bedridden for three years and is on interferon now, is back singing again professionally, and there are a lot of success stories with that.

V-B-2-e. AMPLIGEN. Ampligen--also a lot of success stories. Ampligen has anti-viral activity, and it has interferon properties. The nice thing about Ampligen over interferon is it doesn't have the side effects. So it's going to be very nice. We're fighting the big war for Ampligen with the F.D.A. right now, trying to get it available, but it's not.

V-B-2-f. ECHINACEA. Echinacea is great for stimulating NK (natural killer cell) function. I'm just in the process of publishing a paper on that. So is ginseng.

V-B-2-g. GINSENG. Echinacea and ginseng are--I screened about 250 different herbs and these were the best. Echinacea loses activity over time, so you just take it intermittently. What I recommend--if you feel like you're reactivating the virus or catching a cold, you take echinacea for a few days, then stop. And ginseng, you can probably take all the time. But again, the problem with echinacea and ginseng is they do activate T-cells. And so if you have a bad T-cell activation problem you're going to get a positive and negative effect. Which outweighs which? It's variable. So you have to be careful. You have to do those immune system tests to know where you're at.

V-C. IMMUNE SYSTEM HYPERACTIVITY. Let's move on to the most difficult problem in therapy--that's immune system hyperactivity, ?those? activated T-cells.

V-C-1. RESPONSIBLE FOR MANY CFIDS-RELATED SYMPTOMS. And this is responsible for many CFIDS-related syndromes--headaches, sore throat, muscle aches, etc., via ?mediation? of these pro-inflammatory cytokines.

V-C-2. POTENTIAL CAUSES: MODIFIED HPA--AXIS (DEMITRACK 1991)/ PERSISTENT VIRAL INFECTION (PERSONAL OBSERVATIONS); INTRACELLULAR METABOLIC DEFECTS. And also diminished hypothalamic-pituitary-adrenal gland function will also cause T-cell activation. And I get back to the other point. As it turns out, if your T-cells, if the T-cells are ?fighting? themselves, with this intracellular metabolic defect, they'll activate. They'll activate as well.


V-C-3-a. ANTIOXIDANTS/METABOLIC RESUSCITATION/AMINO ACIDS. So all these things about amino acids, and antioxidants, etc.--they help ?--? your T-cells as well, and may be the best hope for T-cell activation.

V-C-3-b. INTERMITTENT PREDNISONE. Intermittent prednisone is very useful, to give to patients during the holidays, that type of thing--to get them through the holidays, or bad allergy times, etc. Like I said, intermittent ?--s? are safe.

V-C-3-c. JUDICIOUS USE OF BENZODIAZAPINES. ...and very judicious use of Benzodiazepines. Klonopin works very well. Xanax, Valium, Adavan--they block cytokines, and ?reactivated? T-cells. The problem is, of course, they're addictive. So you have to weigh the benefits versus the risks with Benzodiazepines. I tend to give them, but I try to use Adavan or Klonopin, which are the least addictive by far. Klonopin does one other good thing, too, which I'll talk about later, so I like that.

V-C-3-d. IMMUNOGLOBULIN. We're considering the use of high-dose immunoglobulin in T-cell activation disorders, because high doses of immunoglobulin actually blocks IL-6 and tumor necrosis factor alpha production. And it's being used now in a lot of autoimmune disorders, which are involved with these same cytokines. You have to be real careful with it, because immunoglobulin is an immune stimulant, and it can activate the T-cells, ?unless? given in the right dose and to the right patient. We're working on that. We don't know which T-cell activated patients to give immunoglobulin now.

V-D. REACTIVATION OF LATENT VIRUSES. Next is reactivation of latent viruses, and the causes of immune dysfunction, including IgG subclass deficiency, especially IgG3.

V-D-1. CAUSE: IMMUNE DYSFUNCTION, INCLUDING IgG SUBCLASS DEFICIENCY (ESPECIALLY IgG3). Look for this. If you haven't had it tested, you need to.



V-D-2-b. IMMUNOGLOBULIN. [You need to be tested for immune dysfunction] because it can be very easily treated with immunoglobulin--either shots or intravenous. Intravenous works much better. And it treats other immune dysfunction as well, the reactivated viruses. Probably our best therapy--our best one-two punch for CFIDS right now is as follows: Killing reactivated viruses, clearing the bloodstream of viruses is very important. The only thing that I know that does that well is immunoglobulin. It will clear these reactivated viruses, and we've shown this in the laboratory. And there have been some clinical studies that suggest this is true. So we kill these reactivated viruses so they don't...if they're not floating around in the bloodstream they won't get in your cells, and they won't interpolate themselves and cause these ?transport? problems. Then on the other side, we treat cells that are already virally infected with this intracellular metabolic resuscitation. Rid the cells--help them to kill the viruses that are already inside them with this process. Kill the ones that are out in the bloodstream. It works very well.




V-E-1-b. UP-REGULATION OF NMDA RECEPTORS (Cheney, 1994) Paul Cheney and others and ourselves have shown an up-regulation of an excitatory neurotransmitter in the brain called NMDA-- ?n-methyl-d-aspartate? This is found in the vast majority of patents with CFIDS. One can think of yourself as having constant mini-seizures. And if you're having constant mini-seizures all around the brain, the part of the brain that should be firing is not, because the NMDA receptors are firing, and some other receptors should be firing. So you always feel foggy and have cognitive dysfunction. And we did studies on that. It's probably easier just to do it verbally than to try to graph it. We did studies looking at pre-action potentials. A very simple test. We hooked our patients up to electrodes and looked at these pre-action potentials.

What they are is this: When your muscle moves, you see a blip on the E.E.G., and that's the muscle doing its activity. But, just prior to that muscle moving--between the signal from the outside--"move that thumb"--to the thumb moving, there has to be pre-action potential. And NMDA is very important in these pre-action potentials. So we measured these pre-action potentials, and do you know what? They don't happen in CFIDS. You don't have this pre-action potential. So there's a huge delay between the time you get the signal to move your thumb and the time you move your thumb. So the signals overlap. So I liken it to this: You're typing the word "the" on the computer. And you get the message, your brain says push in the "t," so a normal person is just going to push in the "t," and the next signal will say push in the "h."

What happens in CFIDS is that while the message for pushing the "t" is coming in, it's slow, so the message for pushing the "h" is coming in behind it. And if you have music going on in the background or flashing lights on the computer or people talking in the background, that's more input that's combining; it's just stacking up, and these pre- action potentials are just not occurring. So signals that should have already been gone are still happening in the brain.





V-E-2-a. GABA AGONISTS (NEURONTIN). So the way we treat this--there is a way of antagonizing the NMDA receptors. The antagonist in NMDA is GABA. GABA is broken down in the gastrointestinal tract, unfortunately. But the biochemists have come up with a form of GABA that gets across to at least a certain extent, maybe 10%. And along with the aminogen, you can get maybe higher than that. And the herbalist can tell you more about that; but there are ways of getting GABA in directly. The use of GABA is to counteract the effects of these up-regulated NMDA receptors, which is causing all these problems in the brain. There're other problems that are caused in the brain, too, not just the receptor problem but it's also that the cells have these intracellular metabolic defects going on and the brain cells are affected by viruses, too. All these things are happening.

We treat the viruses, and the intracellular metabolic defects, as I mentioned--immunoglobulin and the different supplements, etc., and we treat the NMDA problem with GABA agonists. Neurontin is a very good GABA agonist. The problem is, it's a drug. If you don't react negative to it, as far as an allergic reaction, etc., you will do very well. Your cognitive function will improve, if you can tolerate it. A lot of patients can't, unfortunately. Klonopin also is a GABA agonist. Klonopin helps the vast majority of patients, through this mechanism.

V-E-2-b. VASOCON OPHTHALMIC DROPS. And there's a real oddball therapy that works in a lot of patients--it's Vasocon opthalmic drops. What it does is--Vasocon is a simple vasal constrictor of the eye--but it causes a reflex vasodilation in the frontal lobes of the brain and that's where...many of you are familiar with SPEC scan findings showing decreased profusion in that part of the brain? Just giving these drops dilates the blood vessels in that area. It can increase your cognitive function a lot. The half life is short so you have to use the drops a lot. But it does work in at least a portion of the patients. It's very simple and non-toxic.

V-E-2-c. GUARANA. There's an herb called guarana that's excellent for cognitive dysfunction. Again, any of these things I tell you, there's a potential for reacting negatively to them, because of these allergic responses, primarily because of the dysfunctional immune system, the viruses, etc. It can make some patients jittery. The biochemist I work with put together a form that is sort of chelated. The herbalist has that. There may be some in the health food store, too...I don't know. But it decreases the side effects, to have it chelated, guarana. If you can tolerate it, it works very well.

V-E-2-d. GINGKO. So does gingko. Gingko and guarana together are excellent for cognitive dysfunction in many patients. Gingko usually doesn't cause a big [side effects] problem.

V-E-2-e. ?HYDERGINE. Hydergine is a drug that's used in Alzheimer's. We haven't had great results with hydergine, but in some patients it works. Hydergine works, and it may be worth a try.

V-E-2-f. ANTIOXIDANTS/METABOLIC RESUSCITATION/AMINO ACIDS. And then again, I get back to the metabolic resuscitation. That will probably ?--? dysfunction.

V-F. FATIGUE. Next is fatigue.

V-F-1. TREAT OTHER CONDITIONS. Fatigue is multi-factorial, of course. All these other problems I mentioned contribute to fatigue.

V-F-2. IN ADDITION TRIAL OF SQ VIT B12 (CHENEY, 1989). In addition, you might try subcutaneous vitamin B12. There was a trial in 1989 showing that it worked in a large proportion of patients, and it does. I used to kind of pooh-pooh that myself, but as it turns out, some of the gastroenterologists who worked with it looked at the intrinsic factor production in CFIDS patients and it was very low--not low enough to cause pernicious anemia, but low enough to cause decreased absorption of vitamin B12 when given orally.

Unfortunately, usually the sublingual B12 doesn't work either, so you have to get shots. Three times a a week to every day. There's no toxicity problem whatsoever. And your blood levels may show a normal B12 level, so your doctor's going to laugh at you if you ask for B12. He'll check your levels in your blood and he'll say they're normal. But it doesn't get into the cell. The levels are not normal in the cells, and that's been confirmed by the biochemists.

V-F-3. LOW DOSE ARMOUR THYROID. And also, as far as basal body temperature goes, there's kind of a battle that goes on in patients. ?Proinflammatory? cytokines raise the temperature. So if you're in that group that's 99.5 all the time, 99.8, that's because of these proinflammatory cytokines. But, there's another group of patients where endocrine dysfunction predominates. But, even though endocrine tests show up normal, there's still a problem there.

So, have your temperature taken regularly, and if you're down in the 97 range, etc., then thyroid medication helps. And use natural thyroid--Armour thyroid. In some patients. Not everybody. Particularly in those patients with...if your body temperature's normal, or you're high, it's probably not going to work. Even if your temperature's low it may be caused...another reason for low body temperature is decreased ATP production, because that electron transport process generates heat, and if you're not producing ATP your body temperature's going to be low, and thyroid won't do anything for that. It won't do anything if that's the causation. So you don't know. You try it and see what happens.

V-G. POSTERIOR PITUITARY DYSFUNCTION. And a new finding--I was just e-mailed this finding last week, from France--the endocrinologists...there's a guy from...I can't remember where he's from...somewhere in the U.S....who has been tallying oxytocin for the last couple of years. Everybody kind of laughed at him. We're not laughing, we never laugh at anybody, but took it with a grain of salt. Now it's been confirmed that basically 100% of patients with CFIDS have defective posterior pituitary function, including production of oxytocin.

Now, oxytocin is vital in a lot of regulations of the body, as it turns out. So if you don't have enough oxytocin you're going to retain water, and you're going to have low blood pressure and you're going to have a positive tilt table test. All these things that Johns Hopkins said was salt- and Florinef-regulated may not be. They may be oxytocin-related. And oxytocin's also very important for cognitive function as well. And immune system? It doesn't seem to have a great effect, but certainly if your neurally mediated hypotension is taken care of and you're not retaining water and your cognitive function is better, your fatigue's going to get better, etc.

V-G-1. TREATMENT: INTRANASAL OXYTOCIN. I'm pretty much putting everybody on oxytocin. It's very easy to give. It's available by nasal spray. You just do one squirt a day, and that's it. Pretty simple to do. Not a lot of pharmacists carry it; it's hard to find, but just shop around and you'll find it. It's completely nontoxic.

Q. [inaudible]

Posterior pituitary gland. And again, this is just a study...I put patients on it because it's effective. Whether or not it works I can't tell you, because it's just a week old.

Q. Can we get this over the counter?

No. It has to be by prescription

V-H. MYCOPLASMA INCOGNITUS INFECTION. And a last part of exciting news is mycoplasma incognitus. What's the role of mycoplasma incognitus in CFIDS? I firmly believe that...well, first let me tell you what it does. What we did was take this organism and put it into a broth of immune cells. It gets into the immune cells, it causes these transcriptional/translational problems, kills some cells, and it causes the immune function to just drop, and it activates the T-cells. It does that. It clearly does that. It does that in HIV cells, too. If your immune system is not working well you're likely to be super-infected with it. It's a super-infection.

It doesn't cause CFIDS, mycoplasma incognitus. So you're not going to get cured if you get your body cured of mycoplasma incognitus. So, I don't want you to be disappointed. It's like HTLV2 and it's like spuma virus and it's like Epstein-Barr virus--it doesn't cause CFIDS. But, it does exacerbate the symptoms. So if it's there, you must get rid of it, and it helps to get rid of it. And you can get rid of it, too, by antibiotic use, because it's a bacteria. It's very hard to culture. We can do it in the laboratory, but it's very difficult. The only viable way of making a diagnosis is by PCR test. And as far as I know, Immuno Sciences is the only one that does it. And they're up here, too. We send our samples from San Diego and from Irvine there. The fresher the samples, the better, so you guys are close, so you have the best chance of having an accurate test. In a few patients that I thought--well, they really act like they have mycoplasma incognitus--I sent them to the lab to have a fresh sample, and negative became positive. Is there an Immuno Sciences Lab representative here, by any chance?

I assist in... [inaudible]

Right, right. As it turns out, it's very easy to do the PCR test, and I'm working through the red tape now, but we'll be doing it at U.C.I. too, for the Orange County patients. So hopefully we'll have two ?--?. L.A. patients should, because we need the fresh blood and we have a problem with that--with shipping samples from down south up to L.A., so if you're here you should go to Immuno Sciences, and hopefully we'll... The test is ready. We have it ready. It's really pretty easy to do. We have the primers and... But we're still fighting the dean's office and all that kind of stuff, to actually do the test, so it's not ready yet. You still have to go to Immuno Sciences. If it is there--it's about 20%--then you need to treat it.

V-H-1. TREATMENT: DOXYCYCLINE OR AZITHROMYCIN FOR 3+ MONTHS. The best treatment is doxycycline. It takes about three months at least to eradicate. And azithromycin also works, but the activity is a little less. We're looking at other antibiotics in case you're allergic to both of those, but we haven't found any yet. Penicillin and Keflex and all those things don't do anything. Dioxin may have a little bit of activity. It may explain the reason... I've been hearing for years, patients saying, 'Well, when I take antibiotics I feel better. And when I go off them, I feel worse again.' To a certain extent that's probably... You're treating superinfections in the sinuses, etc., but it may be that you were killing off the mycoplasma incognitus, too. And it just came back because you didn't treat it long enough. And now it's time for questions, because that's all I have, I think. That's it. Thank you. [applause]


We have about 15 minutes for questions. I'm going to start over here.

Q. inaudible

There are a lot of complicated things to remember, so it's no problem.

Q. inaudible

It's too low of an activity for an E.E.G. to pick that up. You have to do what are called ?invoked? potentials to pick it up. Auditory or visual invoked potentials will pick it up. It is possible to do it, but not by a standard E.E.G. No way. A standard E.E.G. will read normal. But it's been confirmed by the invoked potential test that it does happen. To pick up these NMDA ?-? seizures, these mini-seizures. I mean, they are mini-seizures. They are not picked up by standard E.E.G., at least ?-? E.E.G.

Q. inaudible

The question is...any comment on the use of ?patermy?. I haven't...my own philosophy is to use as few drugs as possible. It's a drug, and it supposedly has some activity on the neurally mediated hypotension and cognitive dysfunction. To be honest with you, I don't have a lot of experience with it. I can't tell you...the reports that I've heard at least have been negative. But there's... There may be a few patients it helps. So, sorry, I can't help you with that one, because I haven't used it very much.

Q. inaudible

Well, one thing I should have mentioned... Some of the slides I forgot to put on the handout. Candida, candida overgrowth. It occurs in the gut very frequently, so you should have a candida test done and treat the candida if that's, if it's negative... Actually viruses get into the gastrointestinal cells, and they cause the same problems they do with the immune system and the brain and the muscle, and that's why the inflammation occurs--because of the viruses. And that's very unfortunate, because it makes it hard to take things orally.

But there are things you can take. My advice, in that case, is to reverse things slowly. Start off with things that are hypoallergenic, like extract of rosemary and schizandra berries and GABA and amino acids and aminogen, and get those cells somewhat better and then you can start moving up to the other things--some of the herbs. It works well. A treatment through antioxidants and things that you don't react to so much. Stay away from drugs. And then build your way up slowly.

Q. inaudible

Yes. [phrase inaudible] ...before you entertain it. But I think any herbalist should be trained before you...

Q. mostly inaudible...A lot of us have taken gamma globulin over the years and found it very, very helpful, and then the effect tapers off, and I myself have found that two years later it worked again.

And it worked again. What happens is, you kill off all the viruses that have high-level protection in the gamma globulin. There are some very rare viruses that... CFIDS patients have a lot of these human endogenous retroviruses. You don't find antibodies for those in gamma globulin. So what you do is you kill off all these other viruses, and these HERVs come in and replace them. And the gamma globulin has no effect against those. And then when you stop a balance is achieved again. It's a bad balance, ?--?, but then these gamma-sensitive viruses proliferate. They've struck a balance with the HERVs. Then you treat again with another course of gamma globulin, and then you kill those again. The HERVs come back up, and that's how it works. But one way we might be able to get around that is by treating with AIDS drugs and gamma at the same time. But, again, it's up to you and your doctor. I haven't started doing that.

Q. inaudible

It certainly can happen. Absolutely. It can go up and down, because when you're virus-reactivated then your temperature can go up because you're producing the cytokines. When viruses aren't completely activated, and you have some kind of adrenal or glandular problem and the low ATP part predominates, then your temperature's going to go down. That's one reason for it to go up. If it does that, I still wouldn't try thyroid, because it won't hurt you if you're 99.5 occasionally. It won't cause virus reactivation. That's the reason--because there's a balance between ?--? cytokines, low ATP, and gland dysfunction.

Q. I have fallen at work [inaudible] my doctor wants to give me a ?test? to eliminate my tiredness; if I had a thyroid problem that would eliminate the chronic fatigue and fibromyalgia or adrenal inaudible and so forth. From what I was hearing you say, if it was triggered by this, that in turn may have started the syndrome, so that they're trying to eliminate it, so...do you have a one-liner to respond to that?

All I can say is, if all your tests are normal--thyroid, etc.--do CFIDS testing and see what your immune system looks like and...

Q. I think they may be low.

What may be low? Thyroid?

Q. Adrenals, thyroid, pituitary and...which are lower now than they were before, and they're trying to say, well, if these were low, that's your makeup, and that's why you're tired, as opposed to the act of being a catalyst.

It's hard to say. I would say in that case you should treat those things and see what happens. You need to treat those things anyway. If they are low you should treat them as I mentioned, and then see how things go from there. If you don't get better, then you should look at the immune system and the viruses, etc. And SPECT scans if necessary, to confirm the diagnosis that it's actually CFIDS and not the hormonal problems.

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