There were issues about this diagnosis even very early on in the 80s and, as tests were developed, primarily Western Blot tests were one of the first tests that were actually being used for studying purely the clinical manifestations with the disease. The University of Conneticut, where I was, the laboratory medicine group, Dr Tilton was in charge of that; he then left the University in order to establish his own commercial group and had available various tests. I became interested in the disease and being at the State University we established a Lyme Disease clinic and that is where I began to study the disease and began seeing patients and seeing what the issues were.
Now over the years, almost 20 years now, that we have been looking at the disease, I then moved to Boston University in 1993 and I was there until last year when I ‘retired’. I still am very busy seeing patients on Wednesday in Boston and on supply and on Saturdays and still doing clinical research forming our own company to look after the toxin that we have discovered and one product that the Lyme bacteria make that may or may not have anything to do with clinical symptoms but hopefully looking at ways to a better diagnosis and better treatment of the disease.
The talk today “Issues in the Diagnosis and Treatment of Lyme Disease” is designed really to review where we are with what we know about diagnosis of the disease and treatment of the disease. It raises more questions than we have answers and that is the state of play. I think we have learned a lot in the last 15-20 years but much remains to be learned about this disease. As with any other evolving illness you will have controversy about its origin and what to do about it. And certainly, Lyme Disease, and what I call the Lyme-like diseases that you may label chronic fatigue, fibromyalgia, Gulf War Illness, ME, chemical sensitivities. All of these have a lot in common in terms of being multi-symptom disorders. I am going to focus primarily on the later manifestations: the chronic manifestations. I presume if we have time in the Question and Answer period that follows or tomorrow morning that we can get into issues of tick bites, early Lyme Disease and what to do about it. I think that those are relatively easy compared to what happens once you have set into the chronic multi-symptom disorder.
So I am going to be looking at the diagnosis in terms of whether the clinical criteria of whether the laboratory tests that are available and what imaging studies are available and then we will get into treatment after that.
Now, in terms of diagnosis, the clinical criteria, many people know that there are a lot of symptoms, that if you look at the studies done primarily from the group of Nancy Shaddock that looked at Nantucket residents and the group out of Westchester County, Art Weinstein was the senior author, Nancy published papers in the mid 90s. They followed patients who had documented tick bites, documented rashes and followed them over a number of years. That 30 to 50% of them had continuing multiple symptoms of varying degrees. Now in her latest publication, Dr Shaddock observed that those symptoms had become trivial over time. That was her understanding. Dr Weinstein’s group did not do subsequent studies. But it has become clear that patients with Lyme Disease do develop the chronic fatigue/fibromyalgia syndrome which to me clinically is very difficult to distinguish one from the other.
Having also been fortunate enough to be part of the Gulf War Veterans Illnesses studies by the Veterans Affairs Department in the country, the definition of Gulf War Veterans Illness by the CDC is patterned after chronic fatigue. It doesn’t have the four out of eight symptoms that you have in addition to fatigue but basically there are three major symptoms and the major symptoms are fatigue, musculoskeletal and neuro-cognitive and just as with Gulf War Illness I believe that Lyme Disease could be characterised as a major criteria and minor criteria. This might to some of the older generation bring up the Jones Criteria for Rheumatic Fever – they were major criteria and minor criteria. Dr Burrascano has attempted to put together a points system. Whether those are correct, they have not been validated so they need to be validated as to what/how to appropriately measure this and this is part of the problem because we are dealing with symptomatology and not objective physical signs and laboratory data necessarily.
But notwithstanding if you look at the percentage of people who have Lyme Disease and have continuing symptoms, 90% will have fatigue, 80-90% will have musculoskeletal symptoms and 50-80% will have some kind of neuro-cognitive symptomology.
And, under the minor criteria – I use the word ‘minor’ carefully – that these symptoms can be very predominant as well and headaches are present in about 80% of people. I am just putting together a study of paediatric patients that we have seen and hope to publish about the results of 200 of those with chronic Lyme Disease and detail the percentage of symptoms but I think what helps with the diagnosis is not only that you have fatigue in combination with myalgias or arthralgias or neurologic symptoms - cognitive symptoms such as memory, most notably short term memory loss, but also other confusional states and if you separate cognitive from mood and then you have mood disorders as well and Dr Brian Fallon from Columbia has done, I think, the seminal work on neuro-psychiatric manifestations where patients can have predominantly psychiatric manifestations - Bi Polar Disorder. At the end of the day, you can say Lyme is the cause of everything. And that is the problem, you have to be very careful about how you bear all of this out. I think Lyme Disease is certainly the major cause of multi-symptom disorders in an endemic area but is not the only cause there are other causes remaining to be discovered.
I think that may also determine whether some are more antibiotic responsive and others are less antibiotic responsive because if you have certain viral diseases typically Epstein Barr virus is still talked about as a cause of chronic fatigue syndrome that if we really had a good anti -Epstein virus anti-viral drug then we could test that hypothesis better by using it as a test just the way we do with antibiotics in treatment of chronic Lyme patients. Is that not the ultimate test of whether you respond and whether your disease has a cause and effect relationship.
But back to the more minor symptoms, you have a variety of headaches different than migraines. Headaches that are not amenable to any relief and as you treat the patients now the headaches become more amenable to routine pain relief from aspirin or acetaminophen.
Eye symptoms varying from optic neuritis itself to blurry vision, to pain, to conjunctivitis, light sensitivity.
Ear symptoms – ear ringing, humming, buzzing, loss of hearing, increased sensitivity to sound.
Jaw pain is a particularly interesting and telling symptom. Of all these symptoms, the most discriminating ones are paraesthesias, palpitations, jaw pain. I mean Bells Palsy makes it easier, although for some physicians it’s a little tougher because Bells Palsy is caused because you left your window open whilst riding in the car and so you get a Bell’s Palsy. And Herpes is not the cause of all Bell’s Palsy but there are multiple causes probably, and so Lyme Disease has to be thought of now routinely and the impulse to treat the Bell’s Palsy with steroids I think should be avoided now that we know that an infection is responsible for some of these cases and the Bell’s Palsy will basically go away anyhow, or not go away, steroid or no. But nonetheless I don’t want to be too critical about the use of steroids in Bell’s palsy. I would prefer that it be done under the umbrella of antibiotic use just in case you are dealing with it. In the Bell’s Palsy, it can occur in children as was demonstrated earlier by Dr Ross, and I think that is a very telling thing. It is very unusual for children and youngsters to get Bell’s Palsy so once you think of Lyme Disease as a major cause. Bell’s Palsy at its earliest can occur about two months after the tick bite but may occur years after the original exposure.
I think one of the other things clinically that needs to be appreciated is not all patients with Lyme Disease have severe Lyme Disease. That many who are out there because they are so distressed by their symptomatology would make it appear that in order to have Lyme Disease you have to have a severe form of it. Whereas, as with any other illness you have mild disease that never gets worse, you may have moderate disease, you may have asymptomatic disease. And we need to study that. The only study that was done about asymptomatic disease was with titres in the 80’s and no Western Blot studies have been done in the United States of asymptomatic background and I would like to do that on the Cape where there is an endemic area as well as in non-endemic areas. And we need to organise those kind of studies that are rather easily done to get more awareness.
There was a publication a few years ago from the Munich area that said there was a 20% background reactivity. I think from a publication from Warsaw, if I am not mistaken, apologies if I have that wrong, when they looked at a psychiatric hospital 30-50% were sero-positive versus 5% of the control population. So we need, just as in the early days, it’s like medieval times come back, and people were in psychiatric institutions and they discovered that they might have organic disease be it syphilis, be it tuberculosis, be it a variety of illnesses. I think we are back to the future if you will. We need to come back to this and examine people who have psychiatric disorders from other than a psychosomatic point of view. I am still amazed there is a journal of psychosomatic medicine. I don’t know how much more progress we need to make in medicine to realise that psychiatric symptoms are most likely going to follow some other organic driver from that point of view.
But it is easy when you have complex of symptoms and you have additional baggage, as I call it, you have had accidents, psychological trauma, losses in your life and then you have these symptoms, to say ‘Oh it must be due to that’. But most patients with Lyme disease don’t want to have these symptoms. There are a few that you question whether there isn’t this additional input that makes it difficult for the diagnosis but we have that as an issue.
But the palpitations are interesting and I can put tachycardia there. They can have skipped heart beats, they can have racing heart, pounding heart and they almost all end up in the emergency room where they go to the cardiologist, they get an echo, they get a stress disorder. We are talking about 20 year olds, 30 year olds, people who are not in a position to get coronary artery disease.
And the parathesias are not just because you had your arm hanging over a chair but you have numbness, tingling, burning is a particular interesting clue and you go to the neurologist and you have neuropathy. This is the diagnosis. Well that is a nice circular argument that you have something wrong with your sensory nervous system.
This is an interesting one. Shortness of breath. I have become aware that phrenic nerve palsy may be a cause of this so maybe in some patients where there is a shortness of breath there ought to be a radiographic examination to see if there is an elevated diaphragm or a poorly responsive diaphragm which may give a clue.
Tremors – I won’t put Parkinson’s Disease into this picture. I think Parkinson’s is a separate disease but Lyme Disease can produce coarse tremors and fine tremors as well, but usually not produce rigidity, or a bobbing head or a shuffling gait and I think one of the issues and one of the errors, if you will, is to try and overly lump everything into one disease that all MS, all ALS, all neurologic diseases are due to Lyme Disease and I think the mainstream Lyme Disease is typically sensory neuropathy. The animal experiments that support the idea as well as the clinical picture that these patients suffer from a sensory neurone disease and, if you think about it, it must be that these bacteria, the Borrelia, localise at the sensory nerve roots as opposed to the motor nerve roots which are typical in Polio and Lou Gehrig's Disease. Most Lyme Disease don’t actually have a paralysis, the Bell’s Palsy being a little bit unusual. There are a few circumstances that they might have motor problems but by and large it is a sensory neuropathy and thereby all these sensory symptomology. You have an autonomic problem and I think palpitations. The cardiac issue does not mean that the cardiac tissue is involved. Yes, there can be a myocarditis earlier on but this is rare. Heart block can be present and it doesn’t have to be a third degree heart block, a complete heart block, that was the original description but you can have first, second degree or varying degree blocks that are caused by Lyme Disease as well.
GI symptoms. I am not saying that ulcerative colitis and Crohn's Disease is due to Lyme Disease but you can get an irritable bowel type of picture with some minimal inflammation in the intestine on colonoscopy or by small bowel study. Seeing we don’t know the cause of Crohn's disease, there are interesting theories about atyptical micro-bacteria being responsible. I think we still have something to learn but I consider some of the irritable bowel part of the autonomic neuropathy of Lyme Disease and it is corrected as you go through the successful treatment so it seems like it is coincident with it. A lot of this is circumstancial evidence and as I tell patients as well as lawyers that Lyme Disease, especially as with other parts of medicine, is like the law: circumstantial evidence can be very strong or it can be very weak when you have it, it is helpful, when you don’t have it, it just makes the case tougher to go through.
GU symptoms are also prevalent: frequency, urgency. We are not talking about a 70 year old man with prostatitis or with prostatic hypertrophy, we are talking about someone with urgency. Interstitial Cystitis- that other illusive disorder in the animal models – bladder, especially in the hamster model, involvement with active spirochaetal growth in the bladder epithelium, haemorrhagic cystitis is common and there are a number of Lyme patients who do have haematuria of unknown cause that may be part of an irritable bladder/ cystitis kind of picture.
Fevers and sweats are also part of the illness.
Cognitive, mood-wise another interesting feature which I didn’t put on here. Sleep disorders. And of course, that is hard. You are tired but you cannot get to sleep, you wake, so there is disturbance in sleep and the reasons for that are not exactly clear physiologically speaking. One feature is interesting is that many patients of chronic fatigue stop dreaming and as you start improving them they start going through vivid dreams or nightmares and then as they correct themselves they go through and in and out of normal dreams.
So these are things that you begin to observe as you study these patients. If you want to study them and this is an example of a form that we use to go ahead and try and quantitate this. There are various quality of life measures and when you try to study the disease and you do control trials and observations – how do you quantify these symptoms? Do you rely on the patient entirely? Is there a better way to do it? We don’t have a better way right now other than to record the symptoms and these are just the first six there is another page that goes through this and it’s actually on one page.
We did factor analysis of our Gulf War Veterans Illness patients and of our Lyme Disease patients and I haven’t put that information together again - in another life I’ll publish a few more studies. But I think we can probably reduce the list – Dr Burrascano’s list is about 30 to 40, you don’t need to do that. I think we can probably reduce it to about 10 or 12 maybe 5 and then focus on those and grade the frequency and where the severity. It turns out you probably don’t need both. You just need the severity and forget the frequency. And the reason to forget the frequency is that when you ask a patient whether its chronic fatigue patient, Lyme Disease patient to record their answers to these particular questions I can’t help but think that they are influenced by how they are feeling that day. So if I ask them ‘please indicate whether you have had any of the following symptoms over the past two weeks and how severe they have been’. First of all, they may not remember what happened the week before and if they are feeling better that particular day they will answer in the more positive. So these forms are flawed but they are the best we have.
Whether you have a fatigue score sheet – in the Gulf War Veterans Illness study we actually use 4 or 5 forms. In the Quality of Life survey adapted for veterans use, there are 4 or 5 pages of questions that are interspersed to try keep you from focussing on one particular type of symptomatology. And then there are individual cognitive, fatigue and pain questionnaires. I think we need to try and get a simpler multi-symptom questionnaire and then use that in doctors’ offices as a routine to go ahead and get patients as they come in. Not to go ahead and give your entire medical history the way it is prominent in some physicians’ offices but specifically if you are dealing with this disorder and then this becomes more computer friendly and you can begin to store this information and access it later on. I do not access this information this way so I have to go back to my own dictated report and clumsily if you will, ferret it out and see how many have had what, which makes it very cumbersome. So as far as the clinical picture, you have multiple symptoms that are very difficult to distinguish from any other multi-symptom disorder. What do you do? Of course, you think about other possibilities. You go through tests of anaemia, could you be fatigued because you are anaemic? Do you have metabolic abnormalities? Do you have a thyroid disorder? And everyone goes through a systematic evaluation. Do you have a rheumatologic disorder? What is your ANA? What is you rheumatoid factor? All of these various considerations.
Now moving on to laboratory criteria. I did have a slide that I am sorry I couldn’t transpose to Powerpoint presentation but at the end of one of our sessions while I was at the University of Connecticut and it was a multi-disciplinary clinic in which we had several physicians who did not agree with each other but nonetheless we agreed to study these people. And we had signs posted up like a score for a skating competition. One said at the end of the presentation one held up ‘LYME’ another held up ‘NO LYME’ another one held up a sign saying ‘IT JUST DOESN’T MATTER’ and another one held up a sign saying ‘I WASN’T LISTENING’. And it just shows you the frustration that is within the physicians as well as the patients when you have multiple symptoms that are difficult to ferret through.
So you would think the laboratory would be our saviour. Go to the laboratory. That is what you do to figure out what is wrong with somebody. And the answer is, unfortunately, we have a ways to go. And what are the problems here? I think Dr Owen reflected some of them but the first test, just because that is what we have done over the years, is to go to serology. Let’s get our immune system, our antibody system, our circulating antibody system, to tell us: have we been exposed to the agent. Yes or No. And when this was first done and we said let’s go through, we’re good at making enzyme -immuno assays. We’re good, we get these 96 well plates running through the machines. We’ll grind up the organisms. We’ll put them on the plate. We’ll get the patient’s serum. We have the anti-anti serum. It’s a nice colour, we can measure it on the machine and out it comes.
And so when this was done and the results were published both of the ELISAs and the subsequent Western Blots, there was very poor inter-laboratory co-ordination and this was published in the mid-90s and there were a variety of laboratories; University of Connecticut was one of these and they were sent blind specimens – and these were all cases of proven Lyme Disease. What we call Late Lyme Disease. Dr Steere liked to call Early disseminated with Stage 1, 2 and 3 first and then it became clear that there weren’t separate stages just a continuum of early disseminated and late as he liked to call it as apposed to chronic. And those were patients with big swollen knees with lots of robust IgG responses that the laboratory sensitivity by the titre was 50 to 55% and with the blots that he went through and published this Western Blot information that when you look at the individual bands and on Western Blot basically it is a technique of separating out the various proteins of whatever it is you are looking out. In HIV you separate out their proteins, in Lyme you separate out their proteins, you pass an electric field through a gel and then these are the various proteins and more.
Some of the outer surface proteins - basically what you are measuring of the Lyme bacteria, the Lyme Borrelia, and then analysing how many of these are shown, that is, what antibody reactions to these are shown, in various patients groups. And in the Journal of Infectious Disease report in 1994, Dressler and Steere, you could see that if you had reactions against what you consider highly specific proteins, that is what they looked at, you only needed one reaction. But somehow this got convoluted so that when they met in Dearborn in Michigan in 1994 they declared that you needed to have 5 or more reactions by IgG or 2 reactions by IgM in order to have a positive test. And for the life of me I have not been able to figure that out because in their actual study - let alone that they did not look at any chronic patients, they did not look at any late Lyme Disease patients really other than the big swollen knee, so we have no information from them. The information as I have presented it – there have been a few people from Europe who have said that it isn’t that way for the Late Lyme patient and I will try to explain why I think this is the case.
Question from floor:
Q You mean they looked at Lyme Arthritis patients rather than Neuro-borreliosis patients?
A Yes, they said they looked, and if you look at the numbers of the meningitis what they called meninlo- encephalopathy it is like 5, 10…
Q I understand that Lyme Arthritis people get far more bands than others.
A Yes, they do, they have robust responses and they actually do quite well and there may be an important part of why the chronic Lyme patient who was immune responsive before does worse.
Q But the neurological person tends to get a lot of bands above and between 60 and 93?
A There may be and this now raises the issue of whether (inaudible interruption) the European strains are any different than the American strains and I think this is still an open question as with the old Rheumatic Fever and Rheumatic Heart Disease - that licked heart and bit the joints or bit the heart and licked the joints. Do you have different strains that are more rheumatogenic and other strains that are more neurotrophic and I keep that open but I think we have appreciated that in the United States because Rheumatologists were looking at this disease that they emphasised the rheumatologic manifestations and did not seem to appreciate the neurologic manifestations whereas in Europe it was a neuro-Borrelia or neurologic disease sort of syndrome and neurologic disease to begin with, and now you realise that a lot of the European patients do have arthralgias/ myalgias. In fact, in chronic Lyme Disease patients – I didn’t show you that separately – arthritis itself, which by definition is a swelling, as apposed to arthralgias which is an aching without any swelling, occurs in about 25% of the chronic Lyme patients so that means 75% of the patients have joint pains mostly pains without any swelling. And we have swelling in the chronic patient. You can have the knee involved but atypically it is also other places, the elbow or a finger or the wrist and it makes it very difficult as you go through the differential diagnosis of each of these disorders.
But what we have been finding is that when you look at the Western Blot this is a more sensitive technique. To look at it, it is still not a perfect technique because it only uses one dilution. You take a particular amount of the patient’s serum and you dilute it one hundred fold and you use that particular dilution against this strip of paper that contains all of the antigens on the paper and ask the question: is there antibody that recognises any of these specific proteins which numbers are according to size, molecular weight as it is called, chemical weight, in size and if you see a reaction, you say it has seen this particular protein and if you don’t you then you don’t have that evidence for it.
But looking at this, what we have been finding is that patients with the chronic phase have IgM reactivity, preferentially IgG reaction. Now some of this has been then thrown out as saying well this has to be a false positive. There is no such thing as a false positive blot, I mean, you either have the reaction or you don’t have the reaction. The interpretation is something else and you can argue about its significance and I will show you some information about that and I will return to the DNA culture in the spinal fluid. Let me just show you what we found in our patients and this is in the first tetracycline paper that I published in 1997 that here is the ELISA being either positive or negative and Western Blot being positive or negative and in this case my definition was 2 or more reactions, one of which had to be specific either IgM or IgG, and according to that when you have an ELISA that is positive, you only have a negative blot in 1% of people. When you have an ELISA that’s negative, you have a Western Blot that is positive in about 50% of people. So you are missing half the people if you just stop at an ELISA that is being negative. And both are negative in about 18-20% of people. So that means, well wait a minute, that must mean that they don’t have Lyme Disease or it must mean the test is not as sensitive as it might be because in some of these patients they have had other compelling evidence being a tick bite, the erythema migrans rash partially treated, some PCR DNA evidence.
Nonetheless, one is, I think, authorised to question whether these people then do or do not have Lyme Disease. One of our later studies that appeared in a recent publication of Medical Science Monitor a year ago on macrolide treatment of chronic Lyme Disease is showing there are more details. Here you have ELISA positivity or negativity in this column and this is IgM or IgG reactivity and what you see just jumping here is that when the ELISA is positive the blot is negative in only 6% of people. When the ELISA is negative, the blot can be negative in up to 33% of patients.
So, even with the best of intentions, you come out with a population which appears to fit the criteria of chronic Lyme Disease who are sero-negative a third of the time. What do you do with those patients? Well, in the beginning, when I first started to practice, I dealt with the sero-positive people and then I began to enroll, if you will, the sero-negative people and it became clear to me afterwards that either I was stupid or I could not tell the difference between the two of them because the reactions did not depend upon their Western Blot reactivity. They seemed to react more because of the duration of the disease and the type of treatment we gave them than according to this blot. But when you look again a little closer, you see that IgM and IgG reactivity is common in these patients together but you will get some isolated IgM reactivity especially in this ELISA negative group here and these are reactions to 23kD protein which is the outer surface ‘C’ as it is called, that a group in Austria that are trying to generate a vaccine and a group in Maryland is also trying to get a vaccine against this outer surface protein ‘C’ so we know it is a highly specific protein.
Before I get into the Imaging Studies, I am going to say a few words about the other techniques. Direct culture has been very difficult. Why has it been difficult? You can actually culture the organism. You can culture it from skin, from the erythema migrans and in a SmithKlineBeecham study of a vaccine where they found that half the patients had atypical rashes (so it was one value of that study showed that erythyma migrans, bull’s eye rashes, were present in about 50%, maybe less, other rashes 50-60%. ) When they cultured those rashes, they were able to culture the bacteria.
I hope they still have them because we would like to do some gene studies on antibiotic resistance genes, for example, because we haven’t had any antibiotic studies of Borrelia sensitivity since the early 80s and that needs to be re-done, if you will, from fresh isolates just to see if that has changed. Is that a factor in antibiotic responsiveness or lack thereof in on-going Lyme Disease patients. So the culture, thereafter, except from an isolated report from an eye or from wherever, cultures have not been very rewarding even in the animal. The primate studies from Tilain or some of the elegant dog studies done at Cornell by Strobinger, he was not able to culture the bacteria back. What he did find was in some of his models was that PCR DNA which disappeared with initial antibiotic treatment. reappeared over a series of 5 to 6 months suggesting that there was relapsing disease.
PCR DNA is a very sensitive technique in the sense of, and very specific, to the probe, the sequence, that you design it with. The problem that we have had with PCR DNA in medical practice in infectious diseases is that the technique is too sensitive in the sense why don’t we just do blood cultures and do PCR DNA on them? Why is it that we have to wait for culturing them just to get the gene material and I thought 10 years ago or more that this would have been what would have happened and I think what you will find is that the technique is so sensitive that you are probably picking up transient asymptomatic bacteriaemias. Or in the case of Legionella Disease, or Streptococcal disease or Epstein Barr Disease, you find the organism, or evidence of the organism, the DNA, for months afterwards. Does that tell you that you have carriage of the organism? Probably it does.
With Lyme Disease, I think it had been hoped, that this would now give us a more sensitive way of telling whether you have Lyme Disease. So they looked in serum, they looked in whole blood actually. Because if you are going to find the DNA, it is going to be in the scavenger cells, in the white bloodcells, it is not going to be floating free as HIV RNA can be found, or Hepatitis can be found, and the problem has been that it has been rare to find any PCR DNA positivity in blood, spinal fluid or urine.
It is there, and so now comes the issue, how do you interpret this? Is it a real thing which means that a person has been exposed. It certainly is not a marker of active disease in that the PCR DNA test does not tell you if you have an active infection. It just tells you that the DNA is there. It could have been there 20 years ago, it could have been there yesterday. You might wish to assume that it is a marker of active disease but it isn’t in the same way we have the viral load for hepatitis and HIV. We need a messenger or RNA test or we need a more active, a probe of active infection, and we don’t have it yet. And in the spinal fluid, it was so disappointing that after the first several hundred people when I was getting back negative after negative, I stopped doing that. And even though we had a paper that bounced around and couldn’t get published that PCR DNA positivity was sero-negativity; the argument came back, well, how can you be sure even in the best laboratory that it isn’t a contaminent.
And I think that is a real concern. Persing has expressed this concern ad nauseum but it is true, when we site visited labs in order to select labs to confirm our mycoplasma DNA results for Gulf War Illness, it became clear when you went into the laboratory: A technician is a human being. They store their lunch in the refrigerator that they shouldn’t be storing it in. They leave the tubes open when tubes should not be left open. There are other materials. So, they put the right controls in the racks. They have positive controls, they have negative controls and they report out a PCR DNA tests. I do not know if it is positive or not. I can use it. I can use it politically or in a particular legal case and say this means the person had Lyme Disease but scientifically I don’t know what to make of it.
Do I do PCR DNA tests? Sometimes I do. But they are not as reliable as I would like them to be. With Herpes encephalitis, for example, PCR DNA test has replaced culture and antigen detection in the spinal fluid and it is positive for about 2 weeks and then it disappears. What does that tell us? It tells us that we haven’t eradicated the Herpes virus, it is still there. And I think what the Lyme PCR DNA tests and what the antibody tests are telling us, I think what they are telling me, is that it is not where we are looking. It is like your typical story, you lose your dime in the dark, and where do you look, under the lamppost. It is elsewhere, it is probably inside cells. And this disease is such an indolent disease. It is not very surprising is it if you think about it from that point. It is not going to be an aggressive, fulminant life-destroying disease like a cancer or Hepatitis disease that is running rampant. So it is not surprising to me that it may stay intra-cellular for the rest of its life and somehow cause havoc on the individual nerve cells or the ganglia or whatever part of the brain that they have been probing for.
Whether we are ever going to be successful in finding a better marker or a better scent of the bacterium remains to be seen. But I am optimistic that we have to be able to find a metabolite of some sort that somehow comes out into the circulation, and perhaps into the urine, perhaps into the spinal fluid that will make a better test. We know that antibody tests are not good tests for ongoing disease. And whoever follows an infectious disease anymore with an antibody to tell you if you are over and, when you do antibodies for Herpes disease, to see you have Herpes as a cause of your disease you are deluding yourself because all that tells you is that you have been exposed to the antigen that may or may not have anything to do with the illness in question and I think that our antibody tests are all that we basically have and we need to have more effort devoted towards study. We have the technology, we can do MMR on bacterial filtrates metabolite to see if there is a unique form and then begin to study it. But there is very little interest at the national levels of funding research and it is one of the purposes of meetings like this is to get people together and begin organise into more effective groups to get government research to have a more serious approach to this disease.
Question from floor:
Q.Can I just ask you a very quick question? Surely, if we can actually see the bacteria under the microscope as already shown us then could we not just then use the PCR to confirm what we have seen?
A. We are going to get into a controversial area here but the question is that there are some laboratories who are saying well we see the bacteria and when Phillips and Macknin first looked at their studies, and I know Steve Phillips very well, and he sent me the paper at the time, and I said, Steve you have to do the DNA studies on this to correlate it. Seeing it is not enough because I don’t know what you see. I think you know you can question what you see yourself and you know, and plans are to try and validate what people see and it needs to be done with specific monoclonal antibodies or DNA tests in a blinded fashion and validated. I think if it was that easy to tell you the truth, and to jump ahead with my opinion, I think those DNA tests in the circulation would be positive all the time. There probably is transient spirochaetemia but I don’t know that. I don’t know how much spirochaetemia exists after the initial infective episode.
Q Are you saying that the load in serum is so low that the DNA can’t be measured? That it is really in the tissues and the PCR can’t get at that?
A We are not measuring tissues and are we going to be biasing spinal nerve ganglia? I don’t think so. Yes, but may be there are other ways to do it, maybe peripheral neurons. We need a registry of tissues so that post mortem they can be examined for the location of all these forms that we are talking about. Certainly bacteria once they are dead inside cells they no longer have their spirochaetal long form they curl up like most other things. Whether you want to call this a cystic form or not it something to be debated later.
Let me get on. So I said about the culture and about the PCR DNA. I am hopeful there will be new advances. We certainly need to do research into better ways of monitoring the disease in addition to just asking the patient how you feel. Which I am comfortable with, I think that ultimately is the test.
What has happened with imaging studies. Well MRIs have been done and basically they are normal in 90-95% of people. This comes from extensive numbers of studies that we have done over the last 10 or 5 years or so and I am going to be publishing this. I have presented this in abstract form already. In which what happened was the first sign of abnormality was that you had these T2 signal hyperintensities that were routinely called MS in the early 90s and then they realised that Multiple Sclerosis is not the only disease that can give you these signals and that Lyme Disease can do it. And currently, I don’t know of any radiologist who’s looked at Lyme Disease MRIs and MS MRIs and can tell the difference from the next. So when you have this, it tells you you have this realisation this kind of scarring, the demyelisation present but it doesn’t tell you what’s causing it but it is compatible.
In contrast to that, the brain SPECT scan, was a single photon emission. Its like doing a bone scan but doing it of the brain. You see abnormalities in about 75% of patients. We have been doing these now for a number of years and the technique has improved so you have these two headed scopes and you can follow patients. This is not something that is abnormal one day and normal the next day. This was trivialised initially by some of what I call the ‘early experts’ who said that this is non-specific. I don’t want my brain to look like that and I don’t think that it is non-specific. And the good news is that it is reversible with good treatment and I think that, to me, is a strong note of optimism that we can do something with even long - standing chronic Lyme Disease. If we can reverse the SPECT scan changes, I think along with the clinical changes that we can see, that we are doing some good.
Here is a graph of some of the locations of the SPECT scan abnormalities. In the temporal lobe which is the cognitive area , the frontal area which would be the mood, poriatal is a mixed bag there. There can be tremors associated… a variety. Occipital and periventricular are very uncommon and there are some other areas: Basal ganglias, singular gyrus have been a few abnormalities of patients with Lyme Disease. And, as with other elements, it ranges from mild to moderate to severe. And, I don’t have one to show you here that with treatment it moves from the severe to the moderate to the mild and it disappears with successful treatment and it doesn’t disappear if the treatment is unsuccessful.
Now to try to move ahead to treatment in the last few minutes. Is this an ongoing persistent infection or is this a Post Lyme Disease. That term always made we wonder, how can we call something ‘post’ when we don’t know and it is the same symptoms that we call Lyme Disease to begin with. So, there is a lot of illogic in this area that has been, I think, used to try and tell people that you don’t have Lyme Disease anymore and the fact that we don’t have evidence for persisting infection doesn’t mean that it isn’t there. So we still don’t know. I don’t know and I have strong circumstancial evidence that it is a persisting infection and I will show you that here in just a minute.
But if you look at the bacteria themselves, they are basically sensitive in vitro to many antibiotics: the penicillins, and we know we can use massive doses of penicillins, a safe antibiotic. If you are allergic, the cephalosporins are generally safe alternatives. It is sensitive to the tetracyclines. It’s very sensitive, perhaps most sensitive, to the erythrolites and the macrolide group and I will come back to them in just a minute. The quinalones which are an ever expanding newer group of antibiotics. Some of the earlier ones including Ciproflox, don’t have good activity but some of the newer ones that have just been released eg Amoxyflox. There was one that was taken off the market and this gets a little difficult because now you are getting into a class of drug that may have some longer term adverse effects to it. So I am already prefacing that long- term therapy is what is needed in this disorder and the reasons for it we can speculate but this appears to be the case.
When you look at in-vitro to actual clinical, it has been known for years that betalactams don’t get inside cells very well and there are a couple of animal tissue culture experiments by the Klempner group and by Dr Raoult's Group in Marseilles that showed that fibroblasts or endothelial cells that were infected with Borrelia had no change in their intracellular Borrelia counts when you use Ceftriaxone, when you used Penicillin but they were changed when you used Tetracycline or the Erythromycin group of drugs. That tends to support the idea that this chronic infection may be intracellular.
Again, we don’t have this as definitive proof that it is the case but it makes the most sense. I mean you have to begin to put this puzzle together a piece at a time and we are doing that and not all of the pieces fit very well but, to the extent that it is fitting to some degree, this appears to be an intracellular infection because it responds best to the tetracyclines and the macrolides and I will come to that in just a second. The others I kind of mentioned.
Now, there is an interesting thing here and this raises a big question about what it is that we do with treatment. And it is a little bit of a digression but I think perhaps it is an important one. Metronidazole, Flagyl, as it is called in the United States, has been used in Lyme Disease based on the idea that it might affect the cyst form but when you look at the genome of the Borrelia they do not contain any sequences to metabolise Metronidazole so there is no way the Metronidazole can have a direct effect on the Borrelia. So, how is it that clinically some patients who are on this seem to have a transient response?
I have thought about this for a while and it takes me about 4 or 5 years to figure things out but whether I have figured it out or not but what I think may be happening and here is the analogy: When you have a patient who has cirrhosis of the liver from either alcoholism or from Hepatitis, one of the things that they do is to go into a coma or not necessarily a coma but confusional state and that is thought to be due to the absorption of some metabolic products of the intestinal bacteria.
So what do we do in that case, we give them Neomycin, an antibiotic which just stays in the intestine, and it reduces the amount of the intestinal flora and thereby decreasing the metabolic products which have to be detoxified by the liver and in that case the liver is impaired. Well how do I jump from that to the Lyme patient and Metronidazole and let me put Cholestyramine in the picture too and perhaps any antibiotic, scary as that may be. What if we are, in the Lyme patient, that in the non- Lyme patient the metabolic products don’t make any difference. Not as far as we know. This is our brain, this is our state of confusion, our state of memory.
What if the Lyme patient is sensitised because we know the Lyme patient is sensitised to wherever their focus is they are sensitised to stimuli, they may be de-sensitised too, but what if some of the metabolic products with an intact liver are creating a problem with the sensitivity of the neurons and maybe what we are doing with the Metronidazole or Cholestyramine in the case of binding metabolic products and temporarily making a person feel better. What if some of our antibiotic therapy is reducing some of the other microflora and we are transiently then reducing some other. In other words, what if this is a secondary effect. How do we know that it is a direct effect on it. So that is one of the issues that we have to still sort out. It seems like it is a direct effect in most of the cases but back now to what we found when I first started to do this in the late 80s is that the first few patients had been on doxycycline, they started to get better, they were relapsing. I was old enough that I knew about tetracycline to begin with. I knew enough pharmacology and pharmacokinetics that I started to question well doxycycline has some distinctly different properties from the parent tetracycline molecule. One is, it is highly protein bound in serum which is why you can give it once a day. But also, that may be a liability that means that most of it is bound in the serum and the free drug is much less and even though it might be more lipophilic, there may not be enough of it to get to the tissues to get inside the cells if that what is needed and tetracycline is not highly protein bound, it is absorbed at least as well, and you are getting 1500mg tetracycline versus 200mg or even 300mg Doxycycline, that maybe that was the difference.
I have not done any control studies but it is pretty clear over the years that tetracycline is much more effective than Doxycycline and Minocycline. Even then, you need to use it over several months. You don’t begin to really get the effect unless 4 to 6 months have passed. So what I do, I cycle it every 6 months and once we came up with our findings with the macrolides that I will show you shortly.
Gender also influences outcome. Why is that? There is probably a hormonal influence on the disease and I know in the chronic fatigue literature it is like a 2 to 1 ratio of females to males and in chronic Lyme it is about the same too where females seem to have a higher incidence and perhaps more of a severity. Just to digress, Herpes viruses shuttle into the nucleus of nerve cells on oestrogen receptors. Glial cells and neural cells have progesterone and oestrogen receptors and Herpes simplex and Herpes zoster viruses are also in sensory ganglia and we have an inordinate number of young people with Shingles who have Lyme Disease and my simplistic thinking is that maybe the neuron is challenged by having more than one organism to deal with and the Lyme expresses itself. Again, idle thoughts, if you will, about what might be happening. However, women do have a harder time, both being cured and having a higher fail rate than men in our studies of both tetracyclines.
Now with macrolide treatment. Macrolide is Erythromycin, Arythromycin, Azithromycin, I did not study Dirythromycin and most of our studies were with Clarithromycin. Before 1992, I really only had tetracyclines and the intravenous treatments. It became pretty clear to me that the intravenous treatments were not curative and so despite the protestations of a number of people, of physicians and patients. that we needed longer term intravenous cetriaxone, I was happy to do that, I did that in a number of cases, six months, nine months, worth and I was unimpressed that we got any substantial sustained recovery compared with what we were getting with tetracycline and when people got intolerant of tetracycline I stopped it for two or three days, put them back on it, and when we reached the plateau after four, five or six months we’d stop for a month or two and then re-start it.
And by doing that sequentially, we would get people better and better and it took 2 or 3 years to do that. I tell patients we average 18 months of treatment but if you have been sick for 10 to 20 years, hopefully, it is not year for year, but we need 2 or 3 years to get you as good as we are going to get you. And most people respond. 75% of people, taking all comers, respond to the tetracycline/macrolide treatment. Now the secret, I think, of the macrolide treatment came after I saw an article, again from Dr Raoult's lab, he is one clever guy. He has this Department of Rickettsiology at the University of Marseilles and I was fortunate to visit him a few years ago and I hope to continue some collaborations. He put us on to the idea and he published in-vitro and tissue cultures. He showed that when you added what is called a lysosomotropic agent that de-acidifies, that alkalises, a compartment inside a cell called an endosome, a late endosome, a lysosome or a late endosome which is naturally acidic, a low pH, that allows the doxycycline that he was using in there against a completely different organism, in that case the Q Fever organism, which is related to Erhlichia, the Coxiella burnetii. He found the kill was much enhanced. So a light bulb went off in my head knowing that the macrolides whilst tremendously powerful in-vitro against the Lyme bacteria don’t work in an acid environment. So I knew we had hydroxychloroquine as the most powerful alkalising agent, Plaquenil in the United States as a brand name, and I said let me start using this. There had been a report by somebody and, I apologise he had died, he had used Plaquenil on 2 or 4 patients. I don’t really remember who that was from the West Coast and he said he had got some transient response.
From the Floor:
Oliver? Baltimore
Professor Donta’s response: Yes, Yes
And the first patient I ever tried this on actually was on Plaquenil for so called sero-negative rheumatoid arthritis and she had been on it for two years without going anywhere. Her Western Blot showed specific reactions. I added Clarithromycin to her regime and she started to improve for the first time. So I enlarged and over the years now I have seen a few thousand people that we have done this with. With macrolide usually I use Clarithromycin because I can use 1000 to 1500mgs as apposed to the Azithromycin where I can only use 250/500 mgs. Erythromycin itself is OK too. It is not as well tolerated but in those who don’t have insurance coverage 1500 to 2000mgs a day and you have to use enough of the hydroxychloroquine which is not a big dose 200mgs twice a day, or 400mgs once a day. But what it does is it allows the lysosomes to be alkalised to allow the macrolide antibody to work. Whether that is what is happening or not, I don’t know. I would like to have a tissue culture model where I actually do this.
Question from floor:
?? the in-vitro studies have shown that it is quite good, very good But some people say it doesn’t work very well … but you are saying that to add the Plaquenil makes it work. (Difficult to hear).
Professor Donta:
Yes, and that has been our observations over the years and all of our patients who have been on Clarithromycin or Azithromycin and had a partial response and then we add the hydroxychloroquine and boy do they have what we call a Herxheimer Reaction and they worry it is a reaction against the hydroxychloroquine and I have to hold their hands with this and not to be condescending but there are a lot of these reactions that are so powerful that it is frightening for the patient to go ahead and go through. So what we learned is that with time, and one has to be patient with this and listen to the patient, that you will get improvement. But for how long you have been sick before, you get treated helps to determine the outcome. I am sorry this has got mushed together. If you have been sick for longer than three years your cure rate, and by cure rate I mean you haven’t had any symptoms at all for a year or more, so these are long term studies that we have been doing. 11% versus 28% and the failure rate 18% versus 5%. This is not subject to statistics, this is not a controlled study, these are observational studies but 75% or more of patients will improve and maintain that improvement after they have been on it even if they are partially improved.
How long they have been sick also determines how long it takes to even begin to have symptom improvement not a Herxheimer worsening but improvement. So if you are sick less than a year most people start to begin to improve within a couple of weeks. This is the percentage of people improving after 2 weeks, 3 weeks, 4 weeks. If you are sick for more than 3 years only 26% begin to see a response in 2 weeks. It takes more than 4 weeks to get a 50% plus response rate. So these are observations that we put down that are kind of known to people in practice.
Now what happens to the Western Blot just to kind of finish off on that tone. If you have symptomatic disease, this is from our first tetracycline paper, we found IgM reactivity in 36% of people. IgG alone 6% and the combination 58%. Once we treated them they became asymptomatic. The IgG sero converted if you will and the IgM reactivity went down to 9% and the IgM and IgG is down to 16% , and then no reactivity. I would be surprised if this would be getting 22%. Why would this be the case? Is this so unusual to have IgM reactivity in a chronic disease? I think not. I think that in Hepatitis you can maintain IgM reactivity, it’s like antigen antibody excess imbalance and I think that IgM can be a marker of chronic active disease and doesn’t have to be just a marker of early disease.
Well my time has gone on but let me say a word or two, sorry about that, but I never wanted to get involved in the supplemental issues but I have observed several things that I think made me get involved in this so I merely get into this because I think there have been well intentioned advice about you need to take this, you need to take that, don’t do this, don’t do that and I think that kind of advice can be counter-productive to a field like this that is a fledgling field that some other physicians think we are dealing with quackery here. And so if we are dealing with other things that aren’t based on strong science, we need to be very careful. I am all for trying to improve yourself. I’m all for cognitive behavioural therapy, exercise therapy, if that helps but I am not sure if that helps much. I am not sure symptomatic treatment by itself by taking the Neurontin or Elovil for sleep. All of these things are important but they won’t cure the disease.
What about vitamin supplements? Neurologists have used vitamins for years. What we noted in the beginning was that some patients weren’t getting better whilst others were and they seemed to be about the same type of patient and that one group of patients seemed to be having the supplements and the other ones not. Around that same time, information came out from the genome of the Borrelia Burgdorferi that no sequences synthesized their own vitamins and almost all bacteria have to synthesize their own vitamins. And, it began to occur to me, are they stealing the vitamins? And the third factor was if you look at chronic infectious diseases, what the body tries to do is to starve the invader to death. It withholds iron, so people get the aenemia of chronic disease, it tries to withhold metals, it tries to withhold various things.
I don’t know if it withholds vitamins I don’t have that answer but if you measure a person’s blood it will be a rare person who doesn’t have normal B1, B2, B6 levels. So I ask patients to humour me and not take any supplemental B or C vitamins. The reason for C is that it counteracts the effects of the hydroxychloroquine. It is a strong acidifying agent. So I tell them to go about your business. Eat or drink whatever you want but don’t be doing any special supplementation until we are done. It appears we are getting better on that. How am I going to measure that I can’t measure that so I am reluctant to even talk about it.
And what do we do about hypobaric oxygen? The patients who have done it say they transiently get better and they have up and downs but it doesn’t appear to be curative.
Heat therapy – I don’t think we can fry this organism. I don’t think we can heat up the body enough to get rid of it.
I welcome other approaches to try and help this disease but these are the issues. Future directions – we need to identify Lyme specific products, we need controlled clinical treatment trials and God only knows how many times I have tried to get support for this. But we are talking about several million dollars basically, this is not a $30,000 project. And we need vaccines eventually that can work.
Apologies for taking this amount of time and thank you for listening.
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