Dr Ray Stricker - York 2004 LDA Conference
American television has a top ten list, a top ten list of just about everything
This is my top 10 list of the top ten myths about Lyme Disease:
(and just substitute whatever country you are from for California)
10. There is no Lyme Disease in California
9. Only deer ticks carry Borrelia the cause of Lyme Disease
8. All patients with Lyme Disease have a skin rash
7. Arthritis is the only symptom of Lyme Disease
6. A negative ELISA test rules out LD
5. Men and women react the same on Lyme Western Blots
4. All laboratories do a good job with Lyme Disease testing
3. Two weeks of antibiotic therapy cures all Lyme Disease
2. The neurological treatment of Lyme Disease are easy to treat
1. There is no such thing as Chronic Lyme Disease (the number 1 myth)
Now, unfortunately, I have heard these sentences, every single one of these sentences, from a physician in the United States at one time or another so, unfortunately, we have a long way to go to convince the medical community that Lyme Disease is a serious problem. So I am going to talk a little bit about generally the diagnosis and treatment of Lyme Disease with perhaps a little bit different a perspective and also talk about where we can go with diagnosing and treating this infection.
1.DEFINITION AND PATHOGENESIS
2. SYMPTOMS
3. TESTING
4. TREATMENT
5. HERXHEIMER and CO-INFECTIONS
6. Q & A SESSION
As you all know, Lyme Disease is caused by the spiral bacteria, Borrelia burgdorferii, and its variants in Europe the tendency to other strains garinii and afzelii that are more common and unfortunately also cause more neurologic disease than what we see in the United States but all of these strains of Borrelia have the potential to cause serious chronic infection.
It was sort of ironic to hear Dr Wainwright say that microbiologists don’t know how to look through microscopes any more and actually kind of shocking but even if they are focussed on genetic aspects of microbes, Borrelia presents a very interesting array of genetic problems and it is shown pretty much on the following slide:
Characteristics of Borrelia burgdorferi
· Over 1500 gene sequences
· At least 132 functioning genes (in contrast T Pallidium has 22 functioning genes)
· 21 plasmids (three times more than any known bacteria
· “Stealth” pathology: evades the immune response
Borrelia has over 1500 gene sequences so this is a very, very complex bacteria. Now, unfortunately, we really don’t know what over 1400 of those genes do or if they do anything but when you talk about not having the gene for something in this bacteria, the answer is, well you don’t really know that, I mean, the gene might be there, we just haven’t found it yet. However, we do know that there are at least 132 functioning genes in Borrelia and this is in contrast to Treponema pallidum which is the spirochaete that causes Syphilis. This bacteria has only 22 functioning genes so Borrelia is a much more complex organism from a genetic point of view compared to the organism that causes Syphilis.
Now, in addition, to all of these functioning genes, the structure of Borrelia is quite interesting because it has 21 plasmids and plasmids are these extra chromasomal strands of DNA that are kind of the early response mechanism for bacteria.
So if a bacterium wants to do something very quickly, if it has a plasmid, the plasmid can make a protein very quickly to do things like avoid the immune system or enter cells or do whatever the bacteria needs to do to survive. 21 plasmids is three times more than any other known bacteria. I think that Chlamydia has the next greatest number - that’s 7. So this is an organism that has a very, very adaptable and effective gene structure in terms of infecting people.
In addition, Borrelia qualifies as an organism that has true stealth pathology and what is meant by that is that the bacteria can evade the immune system by making different types of proteins that do things such as complement the immune response or get into cells with different types of cell receptors and this stealth pathology is one reason why Borrelia can persist in humans and cause the type of chronic problems that we see. I should also mention that a lot of this work comes from the Lab of Sherwick Casjens who is at the University of Utah and also Tom Schwan at his Lab at the Rocky Mountain Labs in Montana. Dr Casjens has been working on this for a number of years and if you want to look at the complexity of the genetics of Borrelia you should look at his work and it has been extensively published even though very few people pay attention to it.
Now, you also know that Borrelia is transmitted by the deer tick and these are pictures of the different stages of the deer ticks, larva, nymph, and female and male; the female is usually bigger than the male. What is interesting, of course, is that when you see a nymphal tick like this up on the screen, it looks like it’s about 10 feet tall and most physicians expect that when someone has been infected with Lyme Disease that they have this thing sitting on their arm that kind of looked like Godzilla and they got bitten and that is why they got the disease and if didn't have that then you couldn’t possibly have Lyme Disease but, in fact, what makes the most impression on a physician is when you show them this picture.
This is a picture of a nymphal tick on the arm of Jim Bosey, who is a microbiologist at Berket, New Jersey. Jim is a very interesting guy, his hobby is to go out to the State parks in New Jersey in the dead of winter and then wait there until the snow cover melts and then go pick up ticks which start running around as soon as the temperature hits a certain level and the snow melts and even in winter in New Jersey these ticks are very active and they do get on his arm and if you can see the nymphal tick here it is this tiny little dot here which is a nymphal tick on his arm.
What I often hear from my patients is that they had a mole on their arm that was there for three days and then it fell off. Of course moles don’t do that but nymphal ticks certainly do. Now in contrast to that, this is a fully fed, I believe it is a dog tick, and this tick has been fed for two weeks on a rabbit. You can see that it gets to a very huge size. What is interesting about these ticks is that the tick saliva has become a very interesting substance and there are several companies that are now trying to make bio-technology products based on tick saliva, for example, tick saliva has a natural anaesthetic which is why the tick can get on your arm and feed for hours or days and you don’t feel anything and tick saliva also has some immune evasion proteins that are important in terms of letting Borrelia get into the system once the tick has attached and is feeding. So tick saliva is becoming a big issue.
Now, where do ticks bite? Well, Bart Simpson knows. I know you have him here because I saw him on TV when I got here. He knows that the most common place for tick bites is round the arms and legs. 30% on the legs, 23% on the arms but almost any part of the body can, of course, have a tick bite and there is some evidence that tick bites around the head and neck are more often associated with neurologic symptoms of Chronic Lyme Disease.
How do ticks get around? Well, you’ve heard all about a deer, you saw the deer in Dr Kroun’s backyard. These are the deer in Yosemite National Park which has an altitude of 7,000 feet and ticks supposedly don’t do very well at 7,000 feet and last year I got a call from the director of the medical clinic at Yosemite who said “Gee, I don’t understand it but we are getting all these people coming in with rashes this year who have Lyme Disease and you know there is not supposed to be any here” and the answer is well, there is deer and wherever there is deer there is Lyme Disease and these are some deer and these are my kids and they are being followed by a very anxious dad taking pictures!
Now, one question that came up last night was why is Lyme Disease spreading as rapidly as it is and why do we have so much of it? And I think this is a very instructive figure. In 1900 at the turn of the last century, there were a total of 500,000 deer in the United States. In the year 2000, there are between 35 and 40 million, so the deer population in the United States has grown tremendously and with the deer has come the mass transit system for ticks to go all over the place and expose people to Lyme Disease.
So, why else should Lyme Disease be so widely spread? Well, there are studies from Sweden that have shown that birds such as the red winged thrush can be infected with Borrelia and also can have ticks on them which can then migrate with the birds and the birds can either drop the tick off wherever they happen to be going or they can be bitten by a tick when they get there and then transmit Borrelia to that location and these are trans-migratory birds, they can fly thousands of miles and that is also a very good explanation of why Lyme Disease is so widespread around the world and certainly it is a good explanation for why Lyme Disease is so widespread around the United States because this is a map believed from 1998 showing the major areas of Lyme Disease in the United States mainly on the east coast and also the upper mid-west but you can see there is also this area in California where I am that has quite a bit of Lyme Disease especially the northern part of the state but now even in Southern California. The area in the middle that doesn’t have very much is mostly the Rocky Mountains so there isn’t that much Lyme Disease in the mountainous regions but the rest of the country is becoming fairly endemic for the disease.
Now, what’s happened – just to show you in statistical form – this is the recorded cases of Lyme Disease until 1998. There has been this progressive rise in recorded cases of the disease which has continued to rise in 2002, the last year for which we have the statistics there were over 23,000 recorded cases. It is estimated that Lyme Disease is under-recorded by a factor of at least 10 so that means there were at least 250,000 new cases of Lyme Disease in the year 2002 so this is not an inconsequential disease it is something that is spreading and it is getting worse.
Now the month in which people report Lyme Disease is shown on this slide. This is mostly for the east coast where the peak incidence is between May and September but in fact Lyme Disease can occur at any time of the year and it is important to keep that in mind and a lot of physicians really don’t. One of my favourite stories is I saw a 10 year old boy who was out on a golf course near San Francisco and was playing in the leaf litter and came in with a bull’s eye rash that was basically his entire abdomen with a tick stuck in his belly button and he went to a paediatrician and the paediatrician said, well, you know, this can’t be Lyme Disease. Why? It was October and there is no Lyme Disease in October so that’s the kind of thinking that we also have to overcome in getting people to be aware of the disease.
Now Professor Bob Lane, who is a professor of entiomology at the University of California at Berkeley recently turned the Lyme community on its ear by doing this study and what Professor Lane did was that he took his graduate students up to this beautiful oak grove in Medicino California, which is in northern California, and he had them put on this spacesuit contraption and then wander around this oak grove and do certain things and then he looked at the risk of acquiring different types of ticks, particular nymphal ticks with these activities and what he showed was the following:
When the people were either sitting on logs or gathering wood or were sitting against trees, the risk of acquiring a nymphal tick was a total of 70% of the total ticks acquired. In contrast to that, the people who were either sitting in leaf litter or stirring leaf litter, the risk of acquiring a nymphal tick was only 21%. So what this study showed was that your risk of getting a nymph on you was significantly higher when you were exposed to wood and this goes against the conventional wisdom of tick exposure from leaf litter and grass being the biggest risk and really shows that exposure to wood is the most common way that people get exposed to nymphal ticks and this has really changed our thinking about the epidemiology of Lyme Disease because most of those studies are based on flagging the leaf litter or looking in the leaf litter for the disease and not based on looking at wood and wood exposure.
So, now the staging of Lyme Disease, Dr Donta talked a little bit about the different classifications. I use a very simple classification, acute Lyme Disease being less than one month since infection and Chronic Lyme Disease being greater than three months since infection. There are other terms used to describe this but that’s kind of a simple way to think of the disease. Also, in terms of classification, there are patients who have predominantly musculoskeletal symptoms and these can be either fixed or migratory joint problems and muscle aches and also in contrast people have predominant neurologic symptoms and these can be either cranial neuropathies, meningeal encephalitis or unexplained cognitive defects and this is another simple way to kind of break down the primary symptoms of Chronic Lyme Disease.
Now, you have heard a little bit about the classic features of Lyme Disease and this is shown on this slide. A tick bite, of course, is a classic feature, but only 70 to 80% or perhaps less of patients with Lyme Disease actually recall a tick bite and often this is because as you saw the ticks can be very small and as I mentioned bites around the head and neck can be more commonly associated with neurologic disease.
The second classic feature is a bull’s eye rash or E.M. However, only 60% of patients and even less than that in some studies ever get an E.M. rash and there is also a variable appearance and location which I will show you in a minute.
The third classic feature is the frank arthritis which was described in the original cases in Lyme Connecticut but as Dr Donta mentioned only 30% of patients get actual joint swelling and this symptom can often be masked by the use of anti-inflammatory medications which we use pretty commonly now and also the joint fluid in those patients may be culture - negative but sometimes PCR positive for Borrelia so it may be difficult to make the diagnosis based on culture but sometimes PCR is helpful in that situation.
Just to show you some E.M. rashes. You can see that some of them are nice round bull’s eyes like that one, but others can be sort of polygonal or big and sort of difficult to see as a bull’s eye so there is a lot of variability in what an E.M. rash can look like.
This is a study from Nantucket and I’ll just show you this slide, actually Dr Donta alluded to it, but these were symptoms in patients from Nantucket. Now, Nantucket is this island off the coast of Massachusetts and essentially the entire population of Nantucket has Lyme Disease, I mean, they have all been bitten by ticks and gotten infected so this was a study done comparing those patients to controls from the mainland who didn’t have Lyme Disease and in virtually every category shown here except for palpitations there were significantly greater symptoms in the Lyme Disease patients than in the controls and this also shows you the joint swelling in the Lyme Disease patients only 23% of those patients had actual joint swelling but 61% of them had joint pain so joint ‘pain’ is significantly more common than ‘swelling’ of the joints in Lyme Disease. Now, what was the conclusion of this study? Well, what the authors did was they did neurological testing on everybody and they found that the Lyme patients had no difference in their neurological testing that the controls so the conclusion was well, that there was no chronic sequelae of Lyme Disease in spite of all these symptoms, interesting conclusion.
Now, distinctive symptoms of Lyme Disease, you’ve again heard most of this in terms of musculoskeletal symptoms. One very typical complaint that I hear a lot is migratory joint pains. A patient will say you know one day I had this pain in my elbow and it was killing me and the next day it was completely gone and there are very few things in medicine that really do that, that give you that kind of symptomology. Usually when you have a symptom it kind of stays there that is what you would expect but with Lyme Disease that’s not the case.
Temporo-Mandibular Joint disorder, where pain in the TMJ is also very common in Lyme Disease and very, very typical in that disease.
Another joint symptom is heel pain and there is this peculiar sharp heel pain that patients get and nobody really knows why but that is a very typical symptom of the disease.
And finally, myoclonus, or muscle twitching, is also very, very common in this disease. Patients come in complaining that they can’t sleep at night because their muscles are twitching and one of my favourite stories is that I had a patient who was an attorney and he came in primarily with this symptom and I treated him and his muscle twitching got better but his wife wanted him to go somewhere where they knew what they were doing so he went to Stanford University and went to the Chief of Neurology and got sort of the whole work up at Stanford and finally the Chief of Neurology walked into the room and sat down in front of him and said “OK now, twitch” and he said, well you don’t understand, it doesn’t work like that I can’t control my twitching and she said that well, you don’t have Lyme Disease, Lyme Disease doesn’t do this. Go away, we can’t help you. So, that’s kind of where we are with that.
Now, in terms of neurological symptoms, visual migraines are very common. These are the visual equivalents of migraine headaches. Patients often describe a kind of a saw tooth pattern in their visual field and that is actually some kind of a vascular phenomenon that is like a migraine but it affects the vision. Very common in Lyme Disease.
Bell’s Palsy you have heard about. We will talk about that.
Holmes-Adie Pupil is another complication of Lyme Disease which we described several years ago. This is a pupil that is very sluggishly reactive and this is probably a type of neuropathy that occurs in the eye and it is due to Lyme Disease.
Acute Psychosis can be seen and also any psychiatric syndrome can be seen in this disease.
Another very peculiar thing that we described recently was musical hallucinations in this disease. I have had several patients who had formed musical hallucinations. One heard the Star Spangled Banner. She heard this over and over and over again and it would wake her up from sleep and was really very annoying. Another patient heard Italian Opera. She could remember that this was one of the earliest things that her parents would play for her and this was quite a pleasant memory. Usually these things come from sort of way back in the subconscious and they are brought out by this infection. And they got better, by the way, when they were treated with IV antibiotics.
Cardiac manifestations of Lyme Disease. Interestingly, much more common on the east coast of the United States than the west coast, we don’t see this very often at all. On the east coast, patients can get palpitations, that is the most common symptom, and also frank arrhythmias with atrioventricular block, this can lead to serious consequences including cardiac arrest. Also pericarditis, inflammation around the heart, can be seen and frank heart failure but again we don’t see this very much in California; this may have to do with the strain of Borrelia which we have. There are about 300 different strains of Borrelia throughout the world so it may be that ours don’t do this.
Sleep Disorders. Also mentioned by Dr Donta. I am sure you can’t read this, but this is a study done by Eileen Hilton in New York showing that every single patient with Lyme Disease which she looked at had some problem with sleep even when they weren’t aware that they had a problem with sleep they either had a delayed sleep, they had trouble getting to sleep, or trouble staying asleep or staying in deep sleep and this is a huge problem of Lyme Disease that probably is responsible for a lot of the fatigue that patients have in that disease. If you can’t get good quality sleep at night, you are going to be tired for the rest of the time.
Laboratory testing for Lyme Disease, you have heard a little bit about this, the ELISA test which is the screening test, the primary screening test for the disease has less than a 50% sensitivity as Dr Donta showed you, there is also a large variation in how the labs do the test. The Lyme Western Blot is very sensitive but again, there is a problem with that and I will show you that in a minute and also men and women react differently on the Western Blot and I will show you that too in a minute. The Lyme PCR as Dr Donta mentioned is a kind of a controversial area right now. It is highly specific but it is expensive and it doesn’t always come up positive. There is a physician in New Jersey who does PCR tests on all his patients and he does for every 10 tests he may get one positive so very often this test is negative and may not be very useful.
The Lyme Western Blot as you heard – this is an Igenex Western Blot and it’s a little hard to see on here but you can see that it looks at different bands, different protein bands from the bacteria. If you count them here there are 16 bands that are tested for so this is using the patient’s serum and looking at reactivity with 16 of the bands from the bacteria.
Now the problem is though, that this is not the standard Western Blot, the standard Western Blot goes by the so called Dearborn/Dressler criteria that the CDC has adopted to look at Western Blots and what this does is that it takes those 16 bands and it says, OK, now for the IgM Western Blot we are only going to look at 3 bands, we are going to throw out 13 of those bands because they are not important and similarly for the IgG Western Blot we are only going to look at 10 bands, we are going to throw out the other six because they are not important. And then, in order to get a positive, you need at least 2 out of the 3 bands positive on the IgM or at least 5 out of the 10 bands positive for the IgG so this has created a very, very insensitive Western Blot system and, unfortunately, this is the Western Blot that is done by most routine clinical labs and it is what is accepted by the CDC as a positive surveillance Western Blot which is another issue that we can talk about later.
And in contrast to that what IGeneX and MDL and other Lyme Literate laboratories have done is they have said, Well, look, it is really stupid to throw out all of this information on the Western Blot why don’t we just look at the whole Western Blot, look at all 16 bands and then we will say that there are well 6 that are very specific for Borrelia so in order to have a positive Western Blot you either need 2 of those 6 bands positive or 5 of the total bands positive and that is going to be a Western Blot that’s positive. And this really makes a lot more sense, because it makes more physiologic sense that if someone is reacting to all of these bands firstly you don’t want to throw out the ones that are there just because you don’t think they are important you want to see if someone has reacted to that and second of all, it sorts of sets up criteria that are more consistent with what we know about the clinical aspects of the disease. We can talk about that a little later too. So, this is where we have a big problem with testing for Lyme Disease. There is this split in how to do adequate Lyme testing and until that gets resolved we are going to have consistent problems with making a diagnosis.
The other interesting difference with the Western Blot and, this is a study that was done about 10 years ago, is that it turns out that men and women respond differently on Western Blots and this was a study of patients with Chronic Lyme Disease where they did a standard 3/10 Western Blot which is CDC approved and they looked at how many positive bands they got according to whether they were testing men or women.
It turns out that men with symptoms of Chronic Lyme Disease had an average of 6 positive bands on the IgG Western Blot and in contrast to that women with Chronic Lyme Disease had an average of only 4 positive bands on the IgG Western Blot. If you remember, how many bands do you need to have a positive Western Blot? You need 5 positive bands, so girls you are out of luck! Women are at a huge disadvantage doing this test because they tend to have less positive bands on the Western Blot so they tend to be diagnosed less frequently because of this difference. Why do we have this difference? I don’t know but it is also something you can get rid of if you use the IGeneX type Western Blot, it seems to disappear when you consider more of the bands.
So, other ways to test for Lyme Disease, there is the Lyme Dot Assay (LDA) which is a urine test and this has been an excellent monitoring tool if you have a patient who is positive you can actually do the test to see when the bacteria go away. It is based on finding dead bacteria in the urine, which happens when you treat the disease. It is also very useful as a diagnostic test in children where you don’t want to have your staff have to go over to the lab and hold some screaming 2 year old down to draw blood but you can in fact chase them around the house and collect the urine for 3 days and get a test that is very useful. There has been a lot of controversy over this test and we can talk about that too.
The latest rival from the Steere camp is the Lyme C6 Peptide ELISA. This is a test that is supposed to be more specific for Borrelia infection because it looks at a very specific peptide that is in the organism. The problem with it is, it is still an ELISA and as I have shown you, ELISA tests miss 50% of the Lyme patients so this test, even though it is very, very specific, will still miss 50% of the patients and it is just not a good screening test.
And then there is also immunologic testing with CD57 lymphocytes and I will show you that in a minute.
Now, in terms of Neurologic testing, you heard a little bit when Dr Donta talked about MRI and SPECT, cerebrospinal fluid, doing spinal tap, is not very useful because you usually have what is called the ?end spinal fluid. There is not much in it, there are not many proteins, no cells, usually there are no oligoclonal bands which is a diagnostic marker of Multiple Sclerosis (so it may be useful to do it for that reason to show that the patients doesn’t have MS) and Lyme antibodies and PCR are often negative in spinal fluid and I think the reason for that is that the organisms are not in the spinal fluid they are in the brain tissue so when you are looking at spinal fluid you are not really looking at where the bugs are because they are in the brain.
MRI, brain MRI, is also positive in perhaps 50% or less of patients with neurologic Lyme Disease. Often you see these non-specific so called white matter lesions and it resembles other demyelinating diseases such as Multiple Sclerosis. If you saw a brain scan from an MS patient or a Lyme patient, the patients are generally indistinguishable. So MRI has not been that useful.
Now, the SPECT brain scan, you have heard Dr Donta say that 75% of patients have a positive SPECT. It is probably even higher than that with the newer SPECT machines and also with a very important tool which is a radiologist who knows how to read them. You can see inflammatory and perfusion defects with the SPECT scan in Lyme Disease and the lesions usually do resolve with treatment which is nice because you can actually follow your treatment and see if it is working.
A more recent addition is the PET brain scan which is another version of the SPECT. This is still considered experimental.
Neuropsychological testing is also done on patients with neurologic Lyme Disease and it’s always kind of interesting to see how much abnormality there is on this test because patients often don’t even realise how neurologically compromised they are until they try doing this testing and then they see that there is really quite a bit of compromise that may be there. But it also depends a lot on how the test is done and who is doing the test in terms of getting a positive result.
So, you have seen a paediatric version of this, this is Bell’s Palsy, with a 7th nerve palsy on the left here, a very typical symptom of neurologic Lyme Disease. This is an MRI scan – what does this patient have? Anybody know? You can see there are some little white dots here, all over, it could be MS, it could be Lyme, it’s hard to tell, this actually is a Lyme patient but it could also be an MS patient.
This is what a SPECT scan looks like in a child with neurologic Lyme Disease and with SPECT the blue areas are the areas of decreased perfusion whereas the yellow and red areas are the areas of good perfusion and you can see that there is this blue-ish band here which corresponds to the frontal lobe which is over here and also the temporal lobe over here, and those are the areas that are generally involved in neurologic Lyme Disease. This child got hyperbaric therapy and you can see in contrast after hyperbaric treatment there is a lot more yellow in these areas, the blue has decreased, there is better perfusion and hyperbaric treatment does have the ability to do that but it is still an experimental treatment for Lyme and we can talk about that too.
OK, now, the reason I got interested in Lyme Disease is that I really like immunology and I was interested in these cells, this is a kind of funny cell of hair-like projections, a natural killer cell, which has the job of killing tissues and bugs or organisms and tissues that become infected with those organisms. Natural killer cells have certain markers on their surface that can distinguish self from non-self and that is how the body knows not to kill itself and also can detect infected cells and then kill the cells that have been infected.
Ed Winger, who is the director of a lab in San Francisco called Immunodiagnostic Lab had been interested in looking at these cells in patients with AIDS and he developed this whole panel looking at markers on different lymphocytes and natural killer cells and when we were looking at all these AIDS patients we said, well you know, we really need some other patients to look at so why don’t we look at patients with other diseases and one of the diseases happened to be a patient with Lyme Disease. And what we found was that Lyme Disease patients had very normal T cell and T cell panels with the exception of one particular sub-set of natural killer cells called the CD57 natural killer cell subset and so we started looking at more Lyme patients and we found this was a pretty consistent abnormality that patients with Chronic Lyme Disease had this decreased subset and that is kind of how we got interested in the effect of Lyme Disease on this cell population.
Now CD57 natural killer cells are a subset of natural killer cells but they are distinct from the main subset of natural killer cells which has the CD56 marker on them. CD57 cells have the CD57 marker which is just another protein on the cell’s surface. Their function is poorly understood. We know that they are down-regulated by so-called Thl cytokines (such as IL-2, IFN-gamma, TNF-alpha) and also they are found on other cells including T cells and also interesting on nerve cells in the brain which is something that we can also discuss.
So, we looked at a series of patients with Lyme Disease and looked for CD57 cells in those patients and that is shown on the next few slides. For controls we had 10 patients with acute Lyme Disease: 5 men and 5 women. All of those patients had musculoskeletal symptoms primarily. In contrast, we had 73 patients with Chronic Lyme Disease shown here, most of those patients – most of the men had musculoskeletal symptoms actually most of both groups had musculoskeletal symptoms but some did have neurological symptoms primarily and then as another control group we had a group of 22 AIDS patients and what we found was the following:
The 10 patients with acute Lyme Disease that we tested for CD57 natural killer cells, all had normal levels of these cells - none of the patients had low levels of CD57 natural killer cells. Now in contrast, when we looked at the patients with Chronic Lyme Disease, there were 31 patients who were tested before any antibiotic treatment; all of those patients had low levels of CD57 natural killer cells. When we looked at the group of patients who were on treatment, and there were 37 of those, about half the patients had low levels of these cells and half the patients had normal levels. So there was kind of a mixed bag in the patients who were being treated. And we also had a group of 5 patients who had been treated for Lyme Disease and had recovered and all of those patients had normal levels of these natural killer cells so there seemed to be a correlation between decreased levels of these natural killer cells and active Chronic Lyme Disease.
Now, in contrast, when we looked at the AIDS patients, the 22 AIDS patients, 82% of those had normal levels of these cells and this was in spite of the fact that they virtually no CD4 T cells which is the marker of AIDS. So, even though their T cells were compromised, their natural killer cells by and large were pretty normal. So here was a defect that was very specific for Lyme Disease and didn’t cross over, by and large, to another disease which was HIV infection.
We also looked at the difference between patients with musculoskeletal symptoms versus the patients with neurologic symptoms and what we found on this slide is that patients with musculoskeletal symptoms by and large had much higher levels of the CD57 natural killer cells than the patients with neurological symptoms, so the patients with neurologic Lyme Disease seemed to be sicker than the patients with muscular-skeletal symptoms by immunologic testing.
And, finally, when we looked at patients on treatment over time, what we found was pretty much like what we found in the original data, some of these patients had increases in their CD57 cells back up to normal but some patients had persistently low levels of these CD57 cells and these were the patients who were chronically ill with Lyme Disease and generally didn’t respond to treatment.
So here we had a very nice marker of Chronic Lyme Disease and we also serendipitously found another patient who had been treated by Joe Burrascano about 10 years previously and was tested for this subset sort of by accident and I happened to inherit her 10 years later and she was still sick with Chronic Lyme Disease and over the next, its actually now up to 12 years, we have a series of the CD57 levels, the normal level by the way is 60, and starting in 1991 she had a slightly low level of these cells and she has had persistently low levels of these natural killer cells even though she tends to go almost back to normal when her symptoms improve but when she goes off treatment and her symptoms get worse her levels also go down. So, here there is evidence that this immunologic defect can persist over 10 years or more in a patient with Chronic Lyme Disease and it is pretty good evidence for the existence of Chronic Lyme Disease. I mean, here you have this immunologic defect that correlates with that entity.
So a decrease in the CD57 lymphocyte subset may be an important marker of Chronic Lyme Disease and also changes in the subset may be useful to monitor therapy in patients with Lyme Disease and of course the take home message is that the CD57 natural killer cells may be like the “CD4 T cells” of Chronic Lyme Disease just as we use CD4 T cells to monitor patients with AIDS and to see how patients with HIV infection are doing monitoring CD57 natural killer cells can be useful for patients with Chronic Lyme Disease.
So, let me talk a little bit about treatment, you have heard a little bit about antibiotic therapy for Lyme Disease. The range of antibiotics that are useful for this disease continues to expand and the usefulness of different combinations also continues to expand and basically it is the principles of antibiotic therapy. This is something that probably is useful. Generally, oral antibiotics are useful for musculoskeletal Lyme Disease or disease which is primarily musculoskeletal. In contrast, intravenous antibiotics are more useful for patients with neurologic Lyme Disease and, as you have heard, prolonged treatment may be necessary to treat Chronic Lyme Disease, and also it is important to rotate therapies in order to avoid getting resistant bugs that may not respond any more to treatment that you have been using for some time.
In terms of oral antibiotics, there is mono therapy and also combination therapy.
With intravenous antibiotics, there are daily intravenous regimens, and also staggered regimens that are becoming more popular now.
And finally there is a third approach, which is using intramuscular Penicillin which is kind of the old way to treat Lyme Disease which you know fell out of favour because intravenous therapy was less painful but the fact is that intramuscular Penicillin is coming back into style because it is very hard to get intravenous therapy in some places and also the intramuscular Penicillin seems to work for neurologic Lyme Disease.
So in terms of oral mono therapy: Doxycycline and Minocycline and also Tetracycline have been the primary means of treating this disease. These drugs have very good tissue penetration and they also cover Borrelia and Erhlichia. Interestingly, both of these drugs have anti-inflammatory properties which is why they are also used in patients with rheumatoid arthritis because in addition to their antibiotic therapy they also decrease inflammation from joint disease so that is another useful aspect in Lyme. Unfortunately, they can also cause significant photo - sensitivity and intestinal upset and that has limited their use. In San Francisco, when I have patients on high dose Doxycycline, they often come in with what I call Doxy Knuckles and that is because everybody in California loves to drive cars so they are out driving their car and they get this rash along their knuckles where their hands are on the steering wheel so, yeah, that is a very typical give away.
Other mono therapy agents, Amoxycillin and Augmentin are less effective in general against Chronic Lyme Disease but they do have less side effects and are more tolerable and also they are cheaper than other agents so they are also used especially with children.
Now, combination therapy has evolved over the last few years. The principle of combinations is generally to use a macrolide such as Clarithromycin or Azithromycin combined with something like a Cephalosporin such as Ceftriaxin and more recently Omnicef. The idea being that these are really synergistic antibiotics, the Cephalosporin gets into the cell and kills the bugs in the cell whereas the macrolide works outside the cell and can kill the bugs when they come outside the cell. In particular, Omnicef with Biaxin or Zithromax has become a very, very effective treatment for Chronic Lyme Disease and this should probably be the treatment of choice for patients who have primarily musculoskeletal disease except for the fact that they are relatively expensive and that’s limited their use over Doxycycline.
Another combination that you heard about this morning, is the combination, again, of a macrolide plus Metronidazole or Flagyl. As you heard Flagyl kills the spore forms of Borrelia and again the reason for using this combination is that Flagyl gets into cells and can kill the bugs in the cells but it has no activity outside the cells so you need something else to go with it such as a macrolide to kill the bugs when they come out of the cyst form and get outside the cell. There are some side effects such as GI upset and neuropathy from Flagyl, and Flagyl interestingly can give these prolonged Herxheimer reactions that can be very difficult for patients. You are not just getting a Herxheimer reaction (I haven’t talked about that much) but you are not just getting it for a few days you are getting it for weeks and you have to sort of deal with that and say look, this shows that the drug is working, and you have to bear with it, and often after patients go through that, their symptoms improve.
Intravenous antibiotics are listed on this slide. Ceftriaxone or Rocephin is still the standard intravenous therapy for neurologic Lyme Disease. It’s convenient, its once daily dosing, it gets very good CNS penetration and the question was asked before well maybe why would this cure cysts? Well, you are getting such high levels in the central nervous system that you may be actually affecting the cysts even though the drug doesn’t directly cure them and also the cysts can’t stay in the cyst form forever so when they transform into another form the Ceftriaxone may be killing them. It does have a gall bladder toxicity which has been a problem but not an insurmountable problem.
An alternative intravenous treatment is Cefotaxime or Claforan and this is less convenient, it has to be dosed twice a day at least and it can cause the same kind of liver toxicity interestingly although people think that it doesn’t.
Intravenous Doxycyline is extremely effective against neurologic Lyme Disease but unfortunately it has a prolonged infusion time about four hours a day and it also tends to cause more of the sun sensitivity than the oral Doxycycline so side effects have been a problem.
And more recently, intravenous Azithromycin or Zithromax has also been used. It is also convenient with once daily dosing but we have limited experience of that at the present time.
Adjunctive Therapy – there are some other medications which are helpful for the symptoms of Lyme Disease and I think it is important to treat the symptoms of this disease because patients come in with a symptoms list that Dr Donta showed you and they are very, very unhappy and very miserable with that, and while you are waiting for the antibiotics to work I think it is important to try to control those symptoms to make people more functional and a little happier.
So, one thing that has been very useful is the older anti-depressants such as Amitriptyline and Nortriptyline which are interesting because for a depression they are used in the doses of about 100mg but Lyme Disease patients tend to be exquisitely sensitive to these drugs. I went to a conference up in Northern California and there were a bunch of Lyme patients there who were talking about their Elavil and how they would sort of grind the Elavil up into these little pieces and sprinkle some on their tongue and then they would be knocked out for another whole night and so there is this exquisite sensitivity to these drugs that is very useful for improving sleep and also for pain control because it helps with neuropathy.
Another group of drugs that is very useful is the Cox-2 Inhibitors, the longer acting anti-inflammatories such as Celebrex, Mobic, Vioxx (NB Vioxx and Vioxx Acute were withdrawn on the 1st October 2004 due to increased risk of confirmed thrombic events) and others. These are also good for controlling musculoskeletal pain mostly because they are long acting so you don’t have to keep popping an ibruprofen every five minutes but you can take one of these and it works for a whole day and also there is less intestinal problems with them.
Now, you have heard a little bit about vitamins and minerals, supplements, and I am not going to get into that. These probably do have their place in treating the disease but I think at this point they are pretty much unproven and some of them are fairly expensive and we can talk about that later.
Now Herxheimer reaction, I have mentioned, this occurs usually at the start of antibiotic therapy. It can mimic Lyme Disease symptoms. It may occur in cycles and it basically represents a die off of Borrelia caused by the antibiotic treatment and probably due to the release of certain toxins and cytokines by the dying bugs. This is a good sign because it shows that your treatment is working. It is killing the bacteria and symptomatic treatment with the adjunctive medications that I showed you are usually what is needed to control the Herxheimer’s and reassure the patient that this is really a good sign.
Let me just mention co-infections. There is a growing list of tick-borne co-infections that play a significant role in Lyme Disease and they are shown on this slide particularly Babesia, Ehrlichia (which now goes by Anaplasma) and Bartonella are the three types of organisms that can exacerbate the course of Lyme Disease and there is evidence from animal models, particularly mouse models, that a) these organisms can cause chronic disease and b) when you infect a mouse with both, for instance, Babesia and Borrelia, you get a much, much sicker mouse and you also get a mouse that is significantly immuno-suppressed. So co-infections seem to have a significant role in Lyme Disease and you really need to address these in order to address the Lyme Disease and it is very important – at least, based on the animal models.
Babesia – you have heard that the most common is Babesia microti, however, we have some new strains. One is called WA-1 from the West Coast. WA stands for Washington State, that was where the first case was described. MO-1 is from the Mid-West, MO is Missouri. Interestingly, I have a number of patients with WA-1 infection who got infected in Missouri and we still haven’t figured out how Missouri got to the West Coast but probably these strains are more widely distributed than we know. Vasomotor symptoms are very common including sweating and flushing with Babesia. Antibody testing is still the standard for looking for these co-infections but now IGeneX is doing a fluorescent in-situ hybridisation test (FISH) which is very useful and seems to be much more effective than PCR for Babesia.
The treatment for Babesiosis, the old treatment, is a combination of Clindamycin and Quinine. This was very difficult to tolerate and has pretty much been abandoned by most people now. A combination of Zithromax and Mepron or a macrolide plus Atovaquone is pretty much the standard treatment for this infection since an article by Krauss came out in the New England Journal. The problem with that article is that Krauss treated his patients with this combination
Babesia – the symptoms are a lot like Lyme
Ehrlichia – there are two types of Ehrlichiosis – granular Ehrlichiosis, which is now called Anaplasmosis, and monocytic Ehrlichiosis. The symptoms of both are similar to Lyme, including neuropathies. The treatment of choice is Doxycyline. However, recently some strains have become resistant to Doxycycline which is a problem because nobody knows what to do.
Bartonella – this is the latest co-infection to be reported. Bartonella henselae is the most common strain. It has Lyme like symptoms, including significant neurological symptoms. The treatment is zithromax, doxycycline, or ciprofloxacin. The latter seems to be the most effective.
Conclusion
Lyme disease is difficult to diagnose and treat.
The symptoms are highly variable.
Laboratory tests for chronic Lyme disease are unreliable.
Treatment requires patience and persistence.
There was a Lyme vaccine produced by GlaxoSmithKline, but it was taken off the market 2 years ago because a number of patients developed a syndrome that looked like Lyme disease after having the vaccine. The case is now going through the courts in the U.S. now. We are unlikely to see another vaccine in the near future because pharmaceutical companies get shy when a vaccine gets taken to court. So we have to rely on treatment.
This photo (lots of people lying in rows outside) shows how they used to treat TB – people were put to lie outside in the fresh air for hours. Today we treat TB with 2 antibiotics for 18 months and that is the accepted treatment. Hopefully, we will see similar changes in the treatment of Lyme. But to achieve this we need a lot more research – at the moment we are in the Stone Age! And I think we'll need more activism from patients too.
Lyme Disease Action, Registered Charity Number 1100448, Registered Company Number 4839410
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