05/21/2013 09:16:00
Cryme Trainer (moved)
Non-HLA-linked Diseases
Hurricane Sandy and Mold-Related
illnesses (like LYMErix and Lyme Disease, and CFIDS/FM).
=======
References for psychotropics-induced brain damage
Older data on the incurability of Relapsing Fever
1986, McSweegan trashes Navy for $$$ for ALDF.com
1988, Dattwyler & about immune-suppressing, seronegative Lyme
1990, CDC: "Diagnose Lyme as if it was Relapsing Fever."
Allen Steere "NeuroLyme won't test positive," 1990.
1992, CDC officer Allen Steere falsifies testing in Europe
1992, CDC patents with SmithKline show 2 kinds of Lyme
Compare the 2 kinds of Lyme in the RICO complaint
1994, CDC's Dearborn Booklet .pdf
CDC's invitation to participate in Dearborn .pdf
Evidence Lyme criminals knew LYMErix produced the same "multisystem disease" as "Chronic Lyme"
LYMErix Damage Coverup
(short)
1998, CIA Oilmen & Israelis plan to overthrow Saddam for the oil.
Bush/Gore Oil/War-(Oct,2000)
Bush's own explainer (Oct
2000) re:
Iraq Oil
TRANSCRIPT: Klempner's Secret Multiple Sclerosis Haplotype found in Lyme Borreliosis patients:
"Um, some people will view this as bad news, some will view it as good news, and some people will say, well, where do we go from here?” I think that really is the question, really is to coalesce and say, ”where do we go from here?
Um, There, these patients obviously, are very, very much interested in that question, as we are, and I just want to highlight a preliminary piece of data of where we think we’re going from here, unpublished*, and not for large, uh, dissemination, but here is the preliminary data. ...
YouTube Movie- Hear Mark Klempner discuss his "unpublished and not for large dissemination" HLA data re the genetic link between Lyme and Multiple Sclerosis (HLA-DQB1*0602) This obviously means not all of us have Steere's haplotype, which has redefined "Lyme Disease." Listen to it "straight from the horse's mouth" -Mark Klempner himself.
And, that is, that when you look for the possibility of an autoimmune disease, the best way to look is to see if there is any genetic clustering in HLA haplotypes. The reason for that is the way antigens get presented in the context of who you are, that is, your HLA haplotype. And we can talk in some detail about that. Those diseases that I think everybody would agree are so called Autoimmune :lupus, rheumatoid arthritis, type 1 diabetes, and perhaps MS, have some clear genetic clustering that leads us to believe that these are indeed autoimmune diseases, although we do not satisfy so-called Koch’s Postulates of autoimmune disease that we’ve written[?-KMD] about. And the odds ratio for your having that particular HLA type, in the case of R.A, a DR4, or a DQB0602 to protect you from type 1 diabetes, are on the order of 3 to 6. One of the ones that is probably highest, of course, is B27, in patients with alkyloiding spondolytis and the like. It turns out that if you look at the first 51 patients with post-treatment chronic Lyme disease, the patient population that participated in our study, there was a very high incidence of DQB0602 with an odds ratio of 770%. So it may well be that exposure to THAT organism with THAT background of HLA haplotype may lead you to develop chronic symptoms. That is a hypothesis that needs to be tested. It would obviously lead to an entirely new form and approach to therapy. "
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I'd like to point out that while Klempner claims he is "stalked" and needs to wear a bullet proof vest, he was actually "stalked" at that very same conference where he made the "stalking" claim, because ActionLyme was there, recording that very speech.
ROTFL
Who is allowed to have this secret HLA data, which Klempner never reported to the New England Journal of Medicine June 12, 2001? The Insider Biotech Profiteers.
http://www.ilads.org/position2.html
Klempner is 100% full of shit and is an outrageous FRAUD and liar and this BASTARD gets to be in charge of a US Bioweapons lab? Like we're going to believe a single thing he says?
Mark Klempner - the REAL findings of his 4.7 million dollar bogus chronic Lyme treatment "study," in July 2001 [below, HLA-DQB1*0602, and only 78 of 1800 patients tested positive to the bogus CDC blood test (4%)]:
(See also the TLR/HLA response data of Justin Radolf in response to OspA on the homepage.)
Here is Mark Klempner pretending to be the victim of crazy Lyme patients at the July 2001 Diseases of Summer Conference in South County Hospital, Rhode Island, caught on audiotape by an ActionLyme investigator:
Questioner2: "Have you had any threats to your life, or harassment, or have any negative [garbled]… similar similar to what you colleague, Allen Steere... [garbled]"
Klempner's Answer: "Um, Not the usual kind of question I get at a scientific, um, symposium. Um, I’ll invite invite you all to look at google. My children, I have three teenage children, I’m very famous to them on google, because there are comments like, 'What caliber of bullet proof vest does Daddy use?' It sounds humorous in this setting, but it’s not at all humorous, and um, the answer to your question, is uh, Yes. '"
Yikes.
As you can see, no one ever made such threats:
Lyme Newsgroup. "Klempner caliber of bullet proof vest" search parameters.
This guy is an outrageous liar.
================
See the rest below
================
THE KLEMPNER TAPE (BELOW)
KLEMPNER_DISCUSSING_HIS_UNPUBLISHED_FINDINGS_IN_JAN_2001
-- Found Bb to survive in fibroblasts up to 14 days exposure to ceftriaxone in vitro. Then sampled synovial fluid and spinal fluid for 700 samples from 128 patients and reported this to mean there is ZERO borrelia. Steere and several others also have reported that spinal fluid is usually culture-potential zero, because these are not blood borne relapsing borrelia, they are tissue-borne relapsing borrelia. They can be selected out by borreliacial antibodies to specific Osps, and then what remains can be seronegative. Or, later re-emerge from sequestered sites and become seropositive.
-- Demonstrably defends the CDC's standard as "THESE, are the criteria" for Lyme disease (Steere's 5 of 10 IgG bands from the Strain Tricks deal at the Farcical Dearborn Conference.)
-- Stores inadequately urine samples, and then clearly does funny sampling things from incorrectly stored vessels, and reports this as validation that Urine Antigen Testing is no good, when one of the best spirochetologists in the country reported that this was a good method, many years ago, Johnson.
-- Another Klempnerizer:
ILADS' rebuttal to July 12, 2001, NEJM Klempner article: http://www.ilads.org
=========
'Ready to die laughing?
"Cognitive function in post-treatment Lyme disease Do additional antibiotics help?"
Kaplan RF, Trevino RP, Johnson GM, Levy L, Dornbush R, Hu LT, Evans J, Weinstein A, Schmid CH, Klempner MS.University of Connecticut School of Medicine, Farmington (Dr. Kaplan).
(Kaplan is a UCONN Psychologist-- No medical background)
"CONCLUSION: : Patients with post-treatment chronic Lyme disease who have symptoms but show no evidence of persisting Borrelia infection do not show objective evidence of cognitive impairment."
Neurology. 2003 Jun 24;60(12):1916-22.
==========
Klempner and Matrix-metalloproteinases (degrading/restructuring enzymes):
THE KLEMPNER TAPE:
Intro: Excerpts,
NOT REVEALED TO THE PUBLIC:
"Um, some people will view this as bad news, some will view it as good news, and some people will say, well, where do we go from here?” I think that really is the question, really is to coalesce and say, ”where do we go from here?
Um, There, these patients obviously, are very, very much interested in that question, as we are, and I just want to highlight a preliminary piece of data of where we think we’re going from here, unpublished*, and not for large, uh, dissemination, but here is the preliminary data.
And, that is, that when you look for the possibility of an autoimmune disease, the best way to look is to see if there is any genetic clustering in HLA haplotypes. The reason for that is the way antigens get presented in the context of who you are, that is, your HLA haplotype. And we can talk in some detail about that. Those diseases that I think everybody would agree are so called Autoimmune :lupus, rheumatoid arthritis, type 1 diabetes, and perhaps MS, have some clear genetic clustering that leads us to believe that these are indeed autoimmune diseases, although we do not satisfy so-called Koch’s Postulates of autoimmune disease that we’ve written[?-KMD] about. And the odds ratio for your having that particular HLA type, in the case of R.A, a DR4, or a DQB0602 to protect you from type 1 diabetes, are on the order of 3 to 6. One of the ones that is probably highest, of course, is B27, in patients with alkyloiding spondolytis and the like. It turns out that if you look at the first 51 patients with post-treatment chronic Lyme disease, the patient population that participated in our study, there was a very high incidence of DQB0602 with an odds ratio of 770%. So it may well be that exposure to THAT organism with THAT background of HLA haplotype may lead you to develop chronic symptoms. That is a hypothesis that needs to be tested. It would obviously lead to an entirely new form and approach to therapy. "
'JUST ANOTHER RELAPSING BORRELIOSIS:
Klempner: "This is a very, very important question. What, It strikes at the heart of What is the Placebo Effect. You know there’s an awful lot of controversy now that’s been raised that there is no such thing as a placebo effect. I view, and I wrote in the paper, that I belive that the placebo group and identfies and gives us a window into the natural history. And so I think that people, patients have told us for years, that they get better, and they gets worse,at times, tat their symptoms fluctuate. And it may very well be, that the so-called placebo effect really explains the natural history which is a waxing and waning symptom complex."
START:
AUDIO TRANSCRIPT: Mark Klemoner, Tufts University. South County Hospital Diseases of Summer Conference, July 2001, regarding his treatment study of borreliosis, reported July 12, 2001, NEJM.
Uh, so I’m told that, over the last the past 11 of these conferences, there have been at least 5 of them that have dealt with Lyme disease. So it’s obviously a topic, a summer topic that’s of great importance to you all. I hope that I shed a little bit of light. The focus of my talk is really going to be about the study that was recorded in the July 12 issue of the New England Journal, so virtually everything I’m going to say will be, is contained in that … and you can it that if you can’t hear what I have to say. I do believe, however, the most important thing to talk about, when when talks about chronic Lyme disease, is what’s on this slide, which is the very beginning, What are we talking about, what is the patients talking about, because to me one of the great confusions about Lyme is disease is the mixing of different patient populations in different studies.
So I’m going to tell you how I think about LD in terms of categorizing patients and then I am going to focus one particular patient population, which happens to be particularly controversial and then I’m going to talk about the study that we did on that particular group of patients and the results of that study.
Mostly what I’m going to tell you is what the patients told us, you’re going to hear a reporting (“for you”? 2 syllables) … of what the patients told us during the course of that study. And I’m going to tell you about what your tax dollars actually bought. Because this was an NIH funded study.
So let me begin by telling what a lot of you already know, and that is that Lyme disease is an infectious disease transmitted by a tick, you have all come to hate and love, and the initial inoculation site, uh, the organism it is inoculating is Borrelia burgdorferi, and there is an acute syndrome, between 3 and 30 days after that tick bite lesions, heralded largely by this Erythema Migrans lesion, but all encompassing in the first few months of that illness are a variety of disseminating possibilities, form that initial skin inoculation site, and they include facial palsy, principally, although other cranial nerves can be involved, heart block, lymphocytic meningitis so called aseptic meningitis, which is not aseptic at all, it’s quite septic, and other similar syndromes. These patients are hopefully easily recognized, are usually recognized, they respond very well to antibiotics. And the vast majority of these people when treated with antibiotics, completely resolve their symptoms. There’s good data to support that contention. The vast majority of patients who are treated for EM, at least, in particular we never see again with any problem.
Because all of the symptoms that I’ve described here self-resolve independent of antibiotic treatment, there are some patients that are not recognized during that acute phase and so that thy don’t get treated with antibiotics but they go on, at least in the US, because we are restricted to only one of the Lyme disease bacteria, typically to develop a septic arthritis. That is, again, mostly in the US, it a knee disease, largely, and it has a variety of names. Long Island Knee, Nantucket knee, etc and we know that if you take fluid out of that joint, and subject it to PCR, which looks for the fingerprint of DNA, of Bb, this group of untreated patients who never got antibiotic treatment, 95% of those patients have septic arthritis, they have Borrelia burgdorferi in their knee.
There’s also a smaller group of patients, so who have chronic so-called neuroborreliosis, among patients who’ve never been treated with antibiotics and had these symptoms self-resolve, and that also clearly is a septic process, we know that the organism can clearly disseminate to the CNS, where again, antibiotic treatment is highly effective for both previously untreated patients with septic arthritis or neuroborreliosis. I want to be absolutely, and that’s this Lyme.
After patient receive abx treatment there are some patient who continue to have symptoms, and those symptoms generally fall into two broad categories. One of them are patients who continue to have bouts of swelling and fluid. You can actually detect synovial fluid, and synovial fluid {..peration?] …you can actually aspirate that fluid and these patients have treatment resistant arthritis. This is a group pf patients who do not respond to antibiotics. There’s very good evidence that the pathophysiology of this illness is non-septic. If you look in that fluid, you do not see PCR positivity, you do not see culture posivity. And we think that these patients genetically cluster with a particular DR haplotope, this is likely to be an autoimmune disease.
There’s another group of patients who after they receive antibiotic treatment at either this stage or acute Lyme disease, or chronic untreated Lyme disease, again, I refer to largely septic arthritis, or neuroborreliosis, come in with quite a different syndrome,. That is, unlike these patients who have objective finding of a swollen knee, where there’s fluid that can be aspirated, these patients walk in the door, complaining of chronic, severe, debilitating pain syndromes, largely musculoskeletal pain, they also complain of neurocognitive problems, “I can’t concentrate”, “I can’t remember”, “I can’t calculate”, “I can’t think as I once did.” They sometimes complain of radiculopathy, or polyneuropathy, and as a background to all of this , many of these patients, as you’ll see complain of profound fatigue. This is the group of patients who we are talking about for our study. Not this group of patients, not patients who had never been treated, not acute patients, but patients who had well documented, acute Lyme disease, who got appropriate antibiotic treatment came back and said, “*I’m* not the same”, “*I* have chronic Musculoskeletal pain”, “I can’t think”, “I can’t concentrate”, etc. This is the focus of the study. So, just to be absolutely clear of what the patient population, that I’m talking about, is.
We know, as I’ve already mentioned, that that acute syndrome, that I mentioned is unequivocally caused by Bb. There’s no other cause for that acute syndrome of erythema migrans. It is one of those pathognomic things. And once you’ve seen it you know what it looks like, although it can be somewhat polymorphic. And in the untreated patients the evidence is overwhelming that that septic arthritis is indeed, a septic arthritis, and that the borrelia persist at that location, at least if they’ve never seen antibiotic treatment.
There have been a number of theories put forward on what it is about these patient who previously received antibiotic, but continue to have those constitutional symptoms, that, that I’ve mentioned. And they include persistent infection with Bb, coinfection with one of the other tick-borne microorganisms. I’ll comment on if it’ll be easier Erhlichia, TBE virus, maybe some others that we haven’t identified, and autoimmune possibility has been raised, as well as structural damage that is irreversible.
That, uh, set of proposals and hypotheses for the cause of those symptoms led to this study. And it actually, as you’ll see reported in the New England Journal, is reported as two studies, I’m going to combine largely them for you, but tell you a little bit about the difference in the populations. And the study was entitled, “A randomized, double blind,” we didn’t know, patients didn’t know, “placebo-controlled, multi centered trial of the safety and efficacy of treatment ceftriaxone and doxycycline in patients who were either seropositive”, and I’ll define that in a moment, “or seronegative”, and this syndrome of constitutional symptoms as their manifestation of Chronic Lyme disease.
The study was led by me, at NEMC, initially, I’m now at Boston University as some of you have been told, and I had some key co-authors, co-participants. Lindon Ku (phonetic) who saw all the RI patients for our study, Arthur Weinstein, who was at New York Medical College, who also saw some patients down in Maryland and Washington DC, and Janine Evans. who saw patients in New Haven and all of the screening clinics that we did in CT. We did, to recruit these patients, about 200 of these screening clinics in various locations.
So here were the aims of the study, as it as originally proposed, and I’m going to try an answer each of these questions for you.
First question, that I think was the principal one of most interest to many practicing physicians and their patients, was does an intensive course, that means 90 days of antibiotics, improve these patients symptoms, as they reported to us.
Second, is there evidence of persisting Borrelia burgdorferi infection in these patients, using the most sophisticated techniques that are currently available.
Third, was there evidence of other tick-borne infectious disease, because that has been one of the hypotheses because put forward for a cause of their symptoms.
Fourth, could we find an abnormal laboratory profile that would identify these patients and/or predict those patients, this is number 5, who responded to treatment. Those were the goals of the study.
I think it’s very important top focus on the patient population, again, exactly who we are talking about. We’re talking about a patient population that was required to have a history of acute Lyme disease, had to be acquired in the United States, because we did not want to include patients who had the other two strains of Borrelia burgdorferi that cause Lyme disease , especially in Europe. In the United States, it’s *only* the Borrelia burgdorferi sensu stricto . And they had to have a history of Erythema Migrans, or multiple erythema migrans, or neurologic disease, or cardiac illness or arthritis And that after they had been treated with antibiotics, as I’ll show you, they continued to have symptoms that occurred within 6 months of that initial infection and lasting between 6 months and 12 years. There was cut off of 12 years for the duration of symptoms, largely because as we did the demographics of our population, it turned out there were relatively few patients who has symptoms of longer duration. And there needed to have some cutoff to make this whole thing make some sense.
The symptoms that we were looking for are exactly the symptoms that I told you about, are these constitutional symptoms, that include widespread musculoskeletal pain, fatigue, memory, concentration, calculation impairment, and some of the patients also, as I said, complain of symptoms that have been interpreted as meaning axonal form of neuropathy, and/or what this really meant is dysesthesia or shooting pains largely in the extremities for most people.
This to me is very important, and that is, the other key inclusion criteria were the following: patients were required, so that there would be absolutely no question that the patients had previously had acute Lyme disease , to have one of two things, in the seropositive group, they were required to have an IgG positive Western Blot, so this is 5 or more bands on a typical MarDx, which is the one that we use, an which has been highly validated of the Western Blot. So, this is an either/or. So, if you fell into the seropositive group, we’re defining seropositivity here, as positive Western Blot, IgG Western Blot, not IgM Western Blot, which should not be used on these chronic patients.
And also the patients must have had prior documented treatment, uh, let me return for a minute here, If you were seronegative you must have had a physician-documented
“I saw it, I wrote in the chart you that had an EM lesion. I saw the EM lesion, I thought it was Lyme disease, I treated you for it.” These were key findings, because it distinguishes this patient population and makes it a lot more rigorous than many other studies that you’ll see, where patients are mixed together. These patients either had a positive Western Blot or a physician documented erythema migrans lesion, from an experienced physician.
Everybody had to have had prior treatment and that prior treatment had to at least met with guidelines for acute Lyme disease treatment and the reason for this is that, as a double blind placebo controlled trial, we didn’t want to be giving people placebo who’ve never previously been treated, since I’ve told you that we believe, like I think most everyone believes, that that is likely a septic process.
And finally we required the patients to have no comorbidity that could interfere with the evaluation of the treatment efficacy, so, for example, if someone said, “I have terrible..uh, I have stroke”. Or, “I have uh, severe rheumatoid arthritis,” or “I’m taking narcotics.”
It would have hard for them to respond and for us to determine whether their symptoms did or did not get better in response to the treatment. There were too many interfering variables in that circumstance, so they were excluded.
The treatment regimen was as follows: and it included 30 days of intravenous, 2 grams a day, ceftriaxone, followed by 60 days of 200 mgs a day of doxycycline. Obviously all coded, nobody knew what they were getting, we didn’t know what they were getting, the doctors didn’t know, doctors didn’t know, the patients didn’t know. And the IV placebo, which was a dextrose solution that had a little bit of coloring in it, so it looked just like ceftriaxone, because that’s a little bit yellow for those of you who have seen it hanging, and they got matched dextrose placebos for the doxycycline pills.
I want to emphasize the rigor of that treatment, and the reason I say that is because I salute this group of 129 patients, who said that I’m going to have an indwelling catheter put in my arm for 30 days, with the possibility that I’m going to get sugar water in that arm, or I’m going to get IV antibiotics. This was an incredibly brave group of patients, and I’ll show you that we were hopefully attentive enough to all of their safety concerns, because when I think that when you put a catheter in, the numbers sorta go,uh, 9 septic days for every thousand patient days that you have an indwelling catheter, this is the high end of the statistic, the low end is about 3, and we, in 129 patients you can multiple that by 30 days and not a single episode of line sepsis, which we’re quite proud of and I think we owe that all to the nurses.
Let me give you an idea of the study procedures and the rigor of this study. I can tell you, as I presented it to the patients, most recently, there are close to a million data bits on this patient population there’s about 30,000 blood, urine, cerebrospinal fluid, uh serum specimens that have been garnered from this study. So, I know that this is a complex slide, but it really can be divided pretty simply.
The patients were screened initially to make sure that they fell into one of the two groups, that is, that they ere either seropositive and met the entry criteria or that had a positive, and documented by a physician and met the entry criteria. and didn’t have any of the exclusion criteria which I haven’t gone over here, some of which I did mentioned which is that they weren’t allergic to medications, that they were 18 and could give us informed consent, etc. And most important that they didn’t have any interfering complicating illnesses.
The patients were then were seen, at a so-called baseline visit, where they underwent history and physical exam, detailed, uh, there’s more to this that I’ll show you in the next couple of pages, and at that baseline visit, we also inserted the catheter, and gave them their first infusion and then they had a home visit every other day, for the next 30 days by a nurse, who checked on the line, and made sure that the doses were counted , made sure they took the doses, etc. And then on certain days, days 3, 5, 13, 21, 30, 45, 75, 90, 180, and 260 we took blood samples on these patients as well, so we could document what some of the longitudinal findings were. They had physical exams, they had encounters with us, and prescreened, baseline, when they had the line placed, 30 days, 90, days, 180, and 360, and I’ll highlight those points in a moment.
In addition, the patients had a large number of laboratory studies done. Most of these were for safety purposes, so that we were making sure we weren’t giving drugs and making people anemic or raising their liver function tests, etc. You can see how frequently they were done, every few days during the IV phase and twice during the oral phase at day 45 and day 75. Remember the IV therapy went to day 30, and then patients at 15 days later who were taking doxycycline and placebo had another safety set. And they did again at day 75.
In addition we looked for some possible associating illnesses, like autoimmune diseases, where we looked for ANAs, we looked for hypothyroidism, uh, we looked for these other coinfections, which I will come back to in a minute, and serologies for these other etiologies. We also did some intensive investigation in their spinal fluid. Every patient, 129 patients, who did get into this study, underwent a lumbar puncture, mostly done my me and Dr. Hu. And so there’s a lot of spinal fluid data on these patients, I should tell you that we had no major complications there either. As you know you can do these without a lot of difficulty.
And I’ll talk to you a little about the data there as well, in terms of the PCR on that spinal fluid, level of abnormalities, albumen, cell counts, etc. cultures. And maybe I’ll comment a little bit, every spinal fluid was cultured, as well as, can I move back here, um, yeah. One of the ideas that some of the patients helped us with, initially in the Lyme Advisory Panel, was the question of whether if during treatment if there was a sequestered organism and you were killing that sequestered organism, would it be possible that you might liberate some of the DNA of that organism and therefore go from PCR negative to PCR positive.
And so you’ll see in here that during the course of intravenous treatment would have been potentially the most likely time to do that as you do sometimes with other organisms, we not only got a baseline PCR in blood, but we also repeated on days 3, 5, 21, and 30 where we re-looked at blood PCR to determine of there was any liberation of DNA. As you know, the thought is that the Herxheimer reaction is exactly that in previously untreated patients, where you liberate a large amount of endotoxin during that first initial infusion.
Okay.
The primary outcome was really very simple, although it feels complicated because it’s administered in a very structured way. And that is, we basically asked patients, “Do you feel better, do you feel the same, do you feel worse.” And we asked it using the SF-36, which is a highly validated test followed patients recording of the symptoms, it’s been administered to over four million people in the US. We know how reliable it is, it can be done over the phone, although we didn’t do it here over the phone and there’s a definition of what the SF-36. It’s basically these 8 different scales that are then combined with a particular algorithm into summary scales, the physical summary, or PCS, the Physical Composite Score, the Mental Composite Score, and that’s all summarized in the overall SF-36. This is a study by the way, that you may know originates in the Medical Outcome Study, which is a summary of patient self-reporting of symptoms. In addition to that we used the FIQ that’s also been used in patients with Lyme disease in the past, and there are many other outcomes as well, but this is the principal one.
And there were two major, while we collected data at day 30, at baseline obviously, and day 30, at 90, and 180, the major outcome number that we were focused on was the durability of a response at 180 days, although you’ll see data at the end of the intravenous phase, and the oral phase, would mean at the end of the antibiotics, as well as three months after that. Or 180 days. If that’s not clear I’ll come back to that when I present that data.
For each patient, what we did, is we said, “Where are you starting”, so we had a baseline score and, “Where are you at each one of these time points”, well defined, 30, 90, 180, 260,
and saying what’s the change score? And we knew what a significant change score meant and then we categorized people into Better, Same, or Worse.
There were also many outcomes that were done in the laboratory. I won’t focus that much on them. They are still a focus of great interest for us. And that is these serial plasma samples for PCR, at the dates that I mentioned here to try to determine if we could pick up sequestered infectious organisms. Urine samples on multiple days for antigen testing and I’ll comment on perhaps at the end of there’s time, about the Lyme Urine Antigen Test- what we found in that regard. Um, a new test that we’re still working on, looking in the spinal fluid for a particular matrix-metalloproteinase, a CSF gelatinase, which I won’t have time to comment on. We published on this before, we’re still looking at it, and it may be an interesting marker in these patients.
No patients actually underwent a skin biopsy, because we felt that the location of the initial EM lesion was so remote that it was unlikely that we would continue to find organisms at that location. Remember that these patients have all been treated, and data had come out in the interim that said that after a single dose of antibiotics the EM lesion is generally not culturable, at least not for these organisms. There were also serologies, as I said, and PCR for these coinfections.
Okay, So let me move down. I apologize for the lightness of this, but I will go through it in some detail, and that is, “Who are these patients?” Do they look like the patients that you see with what we’ve termed post-treatment Chronic Lyme disease. Post treatment to distinguish it from patients who’ve never been treated and believed to have a septic illness.
And that is on one side are patients who were in the seropositive group, and the seronegative group, and the doxycycline and ceftriaxone group, and the placebos. This all adds up to the 129 patients. What I can tell you at the outset that there are absolutely no differences between the patient groups, so the seropositive and seronegative groups look identical for all these demographic characteristics other than there … [glitch in tape] … look the same as you look at the rest of their characteristics. In terms of age, a population in their mid-fifties with a range of 18 to 81. It was equally distributed between men and women, and this will be important to recall as you talk about patients in the Fibromyalgia talk that I think follows me. It is suspected that there will be different numbers between men and women there, this was pretty equal.
Most of the patients are white. There are very, those that are not, are largely American Indians that we saw from the islands.
Everyone one of our patients at least told us that they had a tick bite. As you know, in the seronegative group, you must have had a physician documented EM, so that they all did, 100%. Roughly 60% of patients who were seropositive group, also told us that they had an erythema migrans lesion. And these are their other symptoms of their acute illness.
Their current symptoms as you’ll see here, were largely that, and driven by pain. And that is musculoskeletal pain, was the major symptom in over 90% of patients, but in addition, patients complained about neurocognitive problems, to the tune of about three quarters of the patients. And we can mix and match those if anybody’s interested. Fatigue is also very common. About 90% of the patients. About half them said that they had sleep disturbances. And a smaller percentage complained of intermittent headaches.
I think it’s important to note whether these patients looked like yours in terms of their prior antibiotic therapy. Everybody was required to at least have had one prior course of antibiotics. These patients on average had about three prior courses of antibiotics and their mean duration of treatment of treatment was about two months of prior antibiotic treatment, most of it oral. And we had patients that ranged in prior antibiotic treatment from the initial course to 650 days, or a few years, a couple years, of prior treatment.
Um, this is that same thing just combining it all, I think I’ve already gone over that.
How about their baseline laboratory studies. What does their spinal fluid look like?.
By and large their spinal fluid was completely normal. The only abnormality is that of a slightly elevated protein in some patients, as you can see here. The number of patients that had a CSF protein greater than 45 was somewhere around 25%. Most of these numbers were between 45 and 74. The highest one was 74. Many of these patients were older. I believe the CSF protein of 45 is not normal, is not abnormal in the 50s actually, in that patient population. But we used the standards.
Um, the cultures for spinal fluid were done in both hypertonic and normal media, the so-called BSK medium, were uniformly negative, and there were PCRs done for B. burgdorferi at baseline and in those subsequent bloods and they were all negative.
We also did cultures of blood, CSF, and sequential specimens, all to add up to, in cultures and PCRs, 740 specimens that were cultured or done PCR, in which we were unable to find a single positive in any of the patents at either baseline or the subsequent studies.
Um, again, I think that this is, uh, just combines the groups of patients, and again there’s no difference between the two groups of patients.
Um this is really, the, um, a very important finding, and that is, one of the really key things that we needed to do, was determine the level of compromise or disability that the patient had at the outset. And of course that would have a strong effect on whether we would have had any chance of seeing improvement, because if you start normal, it’s very hard to get super normal on any test. And one of the things that was quite impressive to us was the level of compromise, and uh, for lack of a better word, disability, that patients complain of. This SF-36 physical composite score and mental composite score, um, with numbers in the 35 to 40 range represent two standard deviations, represent a major compromise in patients ability to function as a result of these symptoms.
To give you a sense of what those numbers mean, the normal would have been 52-53
in these patients because if they had no problems. Um every ten points is a standard deviation, so you can see that’s about a two standard deviation difference.. And what’s important to note about that is, if you take a group of patients with congestive heart failure, or osteoarthritis, and ask them the exact same questions, same tests, you get numbers in the 40s, typically. So these patients are at least as compromised as your patients who walk in the door and say, “I can’t walk up the block”, ”I can’t do my grocery shopping”, “I’m in pain”, etc, etc, etc. We were very impressed with the level of symptoms and compromise in all of the patients.
In addition, the Fibromyalgia Impact Questionaire. The normal was below 16, uh, this is a set of questions that look a lot like the SF-36 and really asked a series of questions that asked, “How compromised are you in doing most of your daily activities by virtue of pain?”
And this ism, uh, really the end of a story that took five years. Can be summarized in one slide.
And the way that the data is presented here, is as follows, on each one of these bars, um, the total represents all of the patients in that group. So these are the antibiotic-treated patients at 30 days, at 90 days, and at 180 days. This represents at the end of IV treatment, at the end of total treatment, so at the 90 days of treatment, and at the end of, or three months after that, or a hundred or six months. And on the left hand side is patients who were treated with antibiotic, that the shaded one, and the unshaded one is the patients who were treated with placebo. The top portion are patients who improved, the middle are patients who stayed the same, the bottom are patients who said that they were worse.
The principal outcome really is over here. And that say, that at the end of this treatment regimen, waiting three months after that, there are no differences between the two groups, and while the numbers are not quite 33, 33, 33, they’re close enough to talk in thirds. That is to say, that a third of the patients said they were better when they took antibiotics, and a third of the patients said that they were better when they took placebo. A third of the patients said that they were unchanged when they took antibiotics, and a third of the patients said that they were unchanged when they took placebo. And a third of the patients said that they were worse when they took antibiotics and a third of the patients said that they were worse.
That translates into 66% or so of patients saying that I am unchanged or worse when I take antibiotics. I am unchanged or worse when I take placebo. And there were no differences between these groups, stratified any way that we could. The same holds for the Fibromyalgia Impact Questionaire data, and again this was completely blinded, we didn’t know, the patients didn’t know, and I’m am reporting to you what they told us, after they took 90 days of placebo or treatment.
So, in part, this validates exactly what patients have been saying right along. And that is, “Some of us get better when we take antibiotics.” It’s absolutely true. Uh, it’s also true the same number of patients get better when they take placebo.
Um, this is the physical composite score. No differences again. The mental composite score. Uh, again, no differences. This is the Better group, Same, Worse. They really were not distinguishable, about what you talked, uh, in which group you were in. And I also would tell you that there were no differences between the seropositive patients and the seronegative patients. I presented then as one study, but they’ve been analyzed as separate studies. This is that paper that just appeared last week in the New England Journal and many other places.
So, I think I uh, I just want to highlight a couple of other points and that is the adverse. Full, almost*25%*, a quarter of patients, had some adverse events that could be attributed to participation in the study. There were some patients that had adverse events that it was hard to attribute to the study. A patient had an MI during the course of the study, during, while he was taking doxycycline. Um, Etc. So these are, this just tabulates adverse events that could be attributed to treatment with either placebo or antibiotics. I do want to tell you that there were difference between the rash, diarrhea, vaginal …[garbled ?puritis?]… phlebitis, headache, was much more common in the patients who took antibiotics. And what’s really most important, was the two, life threatening , serious, adverse events. We had two patients who almost died during the course of this treatment. One of them from a GI bleed while they were taking intravenous antibiotics, probably from antibiotic induced colitis. Um, and a second patient who developed a large pulmonary embolism, actually. Probably originating from the catheter, although we never could find that catheter, uh, find the source of the embolism…[‘lege…’grams..] were negative. So I presume it came from that catheter. Uh, the two life-threatening ones were in the antibiotic treated groups.
It is not without consequence to give patients a treatment that doesn’t benefit them any more or less than placebo.
Um, some people will view this as bad news, some will view it as good news, and some people will say, well, where do we go from here?” I think that really is the question, really is to coalesce and say, ”where do we go from here?
Um, There, these patients obviously, are very, very much interested in that question, as we are, and I just want to highlight a preliminary piece of data of where we think we’re going from here, unpublished*, and not for large, uh, dissemination, but here is the preliminary data.
And, that is, that when you look for the possibility of an autoimmune disease, the best way to look is to see if there is any genetic clustering in HLA haplotypes. The reason for that is the way antigens get presented in the context of who you are, that is, your HLA haplotype. And we can talk in some detail about that. Those diseases that I think everybody would agree are so called Autoimmune :lupus, rheumatoid arthritis, type 1 diabetes, and perhaps MS, have some clear genetic clustering that leads us to believe that these are indeed autoimmune diseases, although we do not satisfy so-called Koch’s Postulates of autoimmune disease that we’ve written[?-KMD] about. And the odds ratio for your having that particular HLA type, in the case of R.A, a DR4, or a DQB0602 to protect you from type 1 diabetes, are on the order of 3 to 6. One of the ones that is probably highest, of course, is B27, in patients with alkyloiding spondolytis and the like. It turns out that if you look at the first 51 patients with post-treatment chronic Lyme disease, the patient population that participated in our study, there was a very high incidence of DQB0602 with an odds ratio of 770%. So it may well be that exposure to THAT organism with THAT background of HLA haplotype may lead you to develop chronic symptoms. That is a hypothesis that needs to be tested. It would obviously lead to an entirely new form and approach to therapy.
Um, I’m not sure if I have time for this other thing. If people want to hear about the Lyme Urine Antigen, I’ll be happy to comment on it, I know it is something you get presented with it, Um, There’s a paper that we published about a year ago, I’m not even sure, maybe about 6 months ago, looking at the reliability of the Lyme Urine Antigen test. And I just want to let you hear from the horses mouth, what we did, so that you understand exactly how unreliable this test is and why it should not be used. And this is a terrible slide and I apologize if you can just really, it’s really.. What we did is something incredibly simple. And that is, we took ten people, myself included. And we asked these people, excuse my expression, to pee in a cup.
We then took that urine specimen and we divided it up into 5 specimens, in 5 tubes, we sent all 5 tubes, and instead of saying, you know, Mark Klempner, 1 , 2, 3, 4 5, it said, Mark Klempner, John Doe, Jane, you know, we gave them numbers, that were different people, but they were all from one single urine specimen. We did that with 10 people so we had 50 specimens. And we sent them off to the laboratory that was doing the Lyme Urine Antigen test for us. The exact same specimen. And what we got back was completely different results, in almost every specimen.
So, um, here’s, here’s a range. This is a test that is advertised to be able to distinguish 9 nanograms per mL. That’s [garble ? “be able to assign”}…9 micrograms per mL, which is the difference between negative and positive, overall. And you can see the exact same specimen went from 29-40, from zero to 371, from zero to 92, from zero to 292. So it would have come back as negative, positive, highly positive, highly positive, highly positive, on these patients, and you have to understand that these are me, and my lab personnel, who have never had Lyme disease. Um, so and I think that it’s pretty graphic here, that “processing” which is something that people have talked about, should have no bearing, this is not inter -sample variability, this is* intra* sample variability. So this is a test that is worse than a coin flip. Much worse than a coin flip. You should not use this test, to examine your patients for the possibility of Lyme disease. And I hope it’s not a distraction from the major point of my talk, which is, that patients with this particular syndrome of so-called post-treatment chronic Lyme disease, have a tremendous amount of disability, whether they’re seropositive or seronegative. Some of them get better when they take antibiotics, but an equal number get better when they take placebo.
There’s no evidence that these patients have ongoing borrelial infection, with the best tools that we have, 750 specimens, roughly. And what I didn’t get to show you is that the incidence of
babesia and ehrlichia and tick-borne encephalitis virus, I’ll give you the numbers. Tick-borne encephalitis virus was zero. So nobody had that. And to be honest, we’ve never had a case reported in this area. But we did it anyways because one tick was identified several years ago that had the virus in its gut. Um, for uh, babesia, we had an 8.4% seropositivity rate. If I were to go in this room, it would be a little higher than that. Um, there can be completely asymptomatic people. And our incidence of ehrlichiosis was 2.9%, across the board, so it can in no way explain any chronicity of symptoms in these people. They’re, if anything, slightly less commonly infected, or coinfected with those organisms.
So, uh, I’m pretty close to being on time here, I’ll be happy to answer questions, couple questions. And I know that there’s a talk to follow. Thanks you very much for your attention.
[Applause]
Questioner1: [Inaudible]
Answer: Patients who started out PCR, we felt, should not get placebo. And the reason was, is, it is the best surrogate that we have for potential culturable organisms. Which is why we use the same test. So the point of it was, is that if you’re going to give people placebo, we would want to exclude patients who could at the outset document were septic. The other problem is that the validation. the validity of the PCR test, in blood, of very questionable. And the reason I say that is, is that there are so many interfering substances in blood/PCR, that it would be difficult to justify. The flipside is I believe that the PCR is spinal fluid is excellent, because there are very few interfering substances there, and we requires the patient to, we didn’t want anyone who had the DNA of the organism in their spinal fluid to get placebo.
Questioner2: Have you had any threats to your life, or harassment, or have any negative [garbled]… similar similar to what you colleague, Allen Steere... [garbled]
Answer: Um, Not the usual kind of question I get at a scientific, um, symposium. Um, I’ll invite
invite you all to look at google. My children, I have three teenage children, I’m very famous to them on google, because there are comments like, “What caliber of bullet proof vest does Daddy uses? It sounds humorous in this setting, but it’s not at all humorous, and um, the answer to your question, is uh, Yes. But we’re out here doing the best we can. We’re out here telling people data. Mostly in telling people what the patients told us. This is a study, where, if you dispute this, you’re disputing what the patients is what patients told us. We’re reporters, here. This isn’t a new technology. This is really saying, “Are you better?” in a structured way.
Questioner2 or 3: are there people who look like these people who’ve never had Lyme disease…fact that they’ve ever had Lyme disease… and if so….the fact that they’ve had Lyme disease…is relevant to…
Answer: Well I think the next two lectures will address that exact same question.
There are people who say they have chronic musculoskeletal pain, I have neurocognitive symptoms, I can’t think, calculate, etc. What distinguishes those patients this group of patients
is that their doctors saw within 6 months of the onset of those symptoms, an erythema migrans lesion, or documented, an IgG Western Blot. So, yes there’s a lot of people who complain of similar symptoms. But the proximity to the onset of the symptoms for the change to a well documented case of acute Lyme disease is what distinguishes this group of patients.[can’t hear, garbled]
[Moderator 10-12 minute break]
Klempner: …Um, well, quite honestly, we actually asked the editor, what he thought, and the editor was [“ten-tam”?] and the reason we asked him was because we thought this was of substantial interest to practicing physicians. When one finds a piece of information, when the first time that there is controlled information available, that if there are patients who are being put at risk, one should intercede and it was our feeling that patients are being put at risk. Um, so that was the reason that it was done. Plus the fact, I think of, the timeliness of not only our study, but the other study that was released at the same time, the single dose prophylaxis study, just before the summer season, when we’re all being bombarded with tick bites and what to do about them
So, I think that that was an editorial decision, we didn’t have much to do with it. But I think that it was appropriate given the timing of year and [garbled] that we’ve had, and the risk that patients
Are put at.
Questioner 4: Given your own earlier work of the intracellular persistence of Borrelia burgdorferi
in spite of antibiotic treatment, how do you know that some of the patients in your study didn’t have persistent intracellular Borrelia burgdorferi that were evading detection and might respond to more aggressive or longer term treatment?
Klempner: Uh, Let me separate those two points. Uh you refer to work that we did in vitro in fibroblasts, where we demonstrated that Borrelia burgdorferi in the presence of fibroblasts was, uh, could be recovered in the presence of ceftriaxone that was present there for several days. Um,
That is very different that what is, we did in patients, which is 90 days of antibiotics all told, and I don’t think that one can immediate translate finding in [silico?] to in vivo findings.
Questioner4: But you know that there are other in vivo works?
Answer: Yeah, Um, I will tell you, so let me now address the second part, and that is that there are only a few modalities that we have for detecting microorganisms. They come down really, as you all know, to culture and, uh, PCR for detecting dead or living organisms. There’s only one way that we actually detect living organisms and that’s culture. I think that’s the gold standard. This is an organism that is relatively easily culturable from acute patients, for sure. We know that from the EM lesion we can isolate the organism from probably on the order of 80-90 % of patients who’ve never received a dose of antibiotics. The bottom line is that to the best our ability, which is culturing and PCR we did 740 different tests on this 129 patients that had a zero positivity rate both at the outset and during therapy. So, all I can tell you is that that is the best that is currently available to do. If there is a new test to do, We’ll do it!
Um, we have a freezers full of all of those specimens and we’re prepared to do better tests if they’re available. When, uh, there was a report of a very uncontrolled trial, um, using hypertonic medium, um that perhaps that’s what you are referring to of being able to recover organisms. We used hypertonic media. I will tell you that, which by the way, that paper was, distanced themselves from the main author that did the culturing. And by the way They hypertonic media was required to be using Detroit tap water, in the original paper. We did, we tried to send for some Detroit tap water and uh, didn’t get any. Em, so, the bottom line is it’s the best that you can do!. And um, those are the best tests that are out there and they were negative over 750 times.
Questioner4:… In the blood…
Questioner5: Since you excluded who were positive, who probably would have been the population that would most benefit from quote intensive therapy, you can’t really be surprised that your had zero % PCR positivity in that population, correct?
Answer: We excluded patients who we thought it would be inappropriate to do a placebo controlled trial.
Questioner5: Being PCR positive?
Answer: And that included people who were PCR positive. If we could have had culture data first, we would have had culture data, the problem, is as you know you can’t you can’t call a culture after six weeks, So it was very difficult to screen people and wait six weeks before you can enroll. And so we used a surrogate and the surrogate was PCR. And Um, that was the reason that that was done because you certainly wouldn’t want to have people in your study who were culture positive. Um, let me take it one step further, and say, that we screened 2000 people for this study to see how many people who would qualify. Of those 2000, there were zero positive cultures or PCRs.
[There was no report on primers used in the study, in the report. This is FRAUD- See the Wormser and Schoen methods for detecting spirochetes. The whole thing is a DNA shell game. OspC is associated with invasiveness, and there are plenty of valid DNA and RNA primers, 16S and 23S RNA that detect more infections than culture methods. The best test for infection is the Mouse Infectivity Test. These bastards know this.]
Questioner6: And do you have any evidence of if there’s upregulated… indirectly.
Answer: The question is, is there evidence of an upregulated immune system. Um, there’s a lot of different ways to approach that question, as you might imagine,. Um one could do it at the most basic level and say is there evidence of an ongoing inflammatory reaction. And surrogate markers at that. Um probably the one that we’re all most familiar with a surrogate for an inflammatory reaction is the sed rate. I know that that doesn’t sound very sophisticated but
the bottom line, of that is, that they were normal. And we did look at, we have not measured things like IL-12, and IL6- and IL-4 and etc. There is a cytokine profiling quote study going on with patients that are enrolled at an NIH intramural study that looked at exactly that. If the hypothesis is that this is an autoimmune reaction, then, um, heightened reactivity of T cell clones, would be something we would expect to find, and that’s exactly what we intend to look for, if we can confirm, that these patients do have a genetic cluster. But at the moment, none of the limited number of markers that have been looked at can profile these patients in a different way.
Questioner6: Because that would seem to answer the skepticism about negative cultures, you would expect that if there was some kind of response going on, we would find indirect evidence on a cytokine level if there was.
Answer: Yeah, this is a pretty stealth organism, so maybe, you know, I’d look for both. Which is what we were trying to do.
----
Klempner, side 2
Questioner7: How do you manage these cohorts of patients now that you’ve demonstrated that the antibiotics are no longer helpful?
This is a really critical question and I’ll tell you, what’s we’ve done is we’ve gone out to the patients first, even before we presented the paper and said, Here’s what you’ve told us, and we’ve had a 100% buy-in for the next round of study. Because they are as eager as we are to find an answer. I mean, I think it’s one thing to say, I don’t believe it.
At the moment we are really are pursuing this question of autoimmunity I mean this needs to be done based on some hypothesis. This needs to be hypothesis driven research. Our current hypothesis is that the HLA- DQB*0602 group has a certain amino acid sequence that allows that organism to sit in there in a way that then subsequently there is a mimicing molecule. We don’t know what that mimicing molecule is. If that’s true, and we don’t know if that’s true at the moment, then that would lead you down very different paths. That would lead you down the path of perhaps immuno[block?], or immunosuppression. Or perhaps, even better, would be peptide oriented therapy. Peptoidometic [<phonetic] therapy. These are down the road. So I think you guys know the hypothesis. At the moment, we’re recommending that these patients be treated symptomatically. I don’t think that I feel comfortable giving them a placebo even though I know that’s as good as the antibiotics that they’ve gotten so far. So at the moment we’re really still in the phase of developing the next hypothesis.
Questioner8: I just have one more question for Dr. Klempner. Um, being that there are inadequacies, inaccuracies in the tesing methods, seropositivity, etc, and the surveillance criteria that you used were just that, surveillance. And the CDC recognizes that there are so many more people that have Lyme disease who do not meet the CDC criteria. What’s your feeling on what percentage of patients who have Lyme disease because they have not met the criteria for diagnosis?
Klempner: I, um, I think there are a number of inaccuracies in what you just said. The CDC does not recognize that there are patients who have, um, that are seropositive that don’t meet seropositive criteria. What they say, is that these are the criteria. I think what, the question, if I could reinterpret the question a little bit, is are there patients who are out there who had Lyme disease who continue to have symptoms and um, wouldn’t fall into these categories. And the question is, how do you define patients who have had Lyme disease? You’ve gotta, you’ve gotta start with some agreed upon cohort, so what are the agreed upon criteria? And what we were trying to do, since we know this was a controversial topic to start with a group of patients who no one would doubt had had Lyme disease. And that was really the point of the study. Are there other patients who fall into equivocal groups that one could say, it’s difficult to document that they had Lyme disease? Sure, but remember we were about to do a study that was very risky. Um, meaning giving people parenteral antibiotics, doing lumbar punctures, doing huge numbers of studies on these people. It was very important to start patients that everybody agreed had had acute Lyme disease. Are there lots of other people out there who say they have Lyme disease where the documentation is lacking? You know that better than I do. Of course, there are lots of people out there who says they have lots of things that you can’t document.
Questioner8: But, but according to what I’ve read is that not everyone is going to, number one, see an EM rash, um, so when you’re are using entry criteria, diagnostic criteria, that you need to have an EM rash, and physician diagnosed…
Klemper: If you’re’re seronegative
Questioner8: Right, okay, but there are seronegative people that don’t have the initial EM rash, And if they do, they may not see it, being on the back…
Klempner: So, then how do you know what they have, that is anybody who walks in the door who says, “I don’t feel well”, with this set of symptoms. Um, that is not a group of people that I would be comfortable putting an intravenous catheter in, an LP on, doing all this very complex study. I needed to be assured that those patients had had Lyme disease. You’re describing a group of patients who cluster by virtue of symptoms. No different from the symptom complex that was given here [previous (Fibromyalgia) talk]. This is a very different symptom complex, very different patient population. Very well documented Lyme disease. And I just wanted to be sure. Um, that’s where I started my talk, at that point. That is, there are a lot of people all over this world that claim to have lots of different things. But for doing studies, I think it’s very important that we cluster patients by objective findings, strict criteria.
Questioner9: (can’t hear)… you have to be careful… (can’t hear) You can’t make the assumption that people who don’t meet that criteria would respond the same way.
Klempner: I don’t agree.
Questioner10:….(can’t hear) would this be the 30% improvement.. was that a placebo effect or is the natural course of 30% of the people..
Klempner: This is a very, very important question. What, It strikes at the heart of What is the Placebo Effect. You know there’s an awful lot of controversy now that’s been raised that there is no such thing as a placebo effect. I view, and I wrote in the paper, that I believe that the placebo group and identifies and gives us a window into the natural history. And so I think that people, patients have told us for years, that they get better, and they get worse, at times, that their symptoms fluctuate. And it may very well be, that the so-called placebo effect really explains the natural history which is a waxing and waning symptom complex.
END