There are numerous factors which seem to determine how each patient will respond.
If patients are to improve I believe that doctors need to try different approaches. The one size fits all method works poorly. A 43 year old woman was seen several months ago for a second opinion. She was diagnosed with fibromyalgia and CFS. She had been very physically active. She was a personal trainer. Now she was a wreck. She had typical signs and symptoms of disseminated Lyme and neuroborreliosis. Her SPECT showed left frontal lobe hypo perfusion. The brain MRI was normal. Her exam had neurological abnormalities and her labs confirmed exposure to Lyme. She was treated with Ceftin and Minocin. There was a tolerance issue and a bad Herx. She was given a Medrol dose pack and switched to Biaxin and Plaquenil. After two months she felt even worse. We started IV Rocephin. The pain was improving but the cognitive issues were unaffected. Symptoms of sweating in cycles suggested Babesiosis. Mepron and Artemesin were added(the Biaxin and Plaqueil had never been discontinued). The sweating went away but otherwise she felt worse.She only took this regimen for a month. There was a worsening of cognitive functions- more memory loss, and an increase in neuropathic symptoms and pain. She was then treated with only Rocephin: still not better. IV Zithromax was added- then she started to improve. It was the IV Zithromax that was making a difference. The Rocephin was stopped and she continued to improve. When Flagyl was added she again felt worse. The treatment was changed: IV Zithromax. Just Rifampin was added and she was now really improving. She was tired- but able to work. Her cognitive dysfunction was clearing up. Much of her pain was gone. (I had prescribed Levaquin but she didn't take it after looking up its side effects). I saw her today 5 months into treatment. The hangdog look was gone. She agreed to try the Levaquin. I hope it helps.
She had Lyme with neurocognitive deficits and an abnormal SPECT scan.
The only lab data I will add is that she had a high C6 Lyme peptide index and that her blood smear at Clongen showed motile gram negative coccobacilli.
What have I been treating her for?
Do people really have Herx reactions which go on for months?
If a patient Herxes for more than one month I think it is time to change the treatment. The immunological consequences of a prolonged "Herx" can't be good.
Bacteremic. Yes. With what? Has Fry found the answer before Clongen: We shall see.
Babesia- or an immitator like Toxoplasmosis, as exists in immunosupressed HIV patients? This has been suggested as a possibility.
Is there really Bartonella and or Mycoplasm. We don't know.
Why didn't Rocephin work while Zithromax did?
There are lots of questions and still few answers.
As a clinician all I can do is report my clinical results.
Again, one size does not fit all.
Wednesday, November 26, 2008
Tuesday, November 25, 2008
Sexual transmission
A single patient who is CDC positive for Lyme, symptomatic and off antibiotics for four months agreed to have his semen tested. An ultrasensitive culture was performed at Clongen labs. Diptheroids, thought to be a contaminant grew. No Borrelia grew in the culture medium. This is only one case. So far there is no evidence to support the theory that LD is sexually transmitted. Quack watch has criticized "LLMDS" for promoting this notion, well....
DNA fingerprinting has been difficult: Clongen still expects a answer soon? Perhaps next week: we shall see.
DNA fingerprinting has been difficult: Clongen still expects a answer soon? Perhaps next week: we shall see.
Monday, November 24, 2008
Towards a unified perspective
As confusing as Lyme disease is for patients; it is more confusing for me. As I became indoctrinated into the world of "Lyme literacy" it became easy to say/think that all the text books(and doctors) are wrong- Lyme is the cause of all the ill's of the world- why can't you blind doctors see that?. If one finds himself in such a manic state he either needs to take a Xanax, or slow down- take a deep breath, and look again. Are all the rheumatologists and neurologists wrong? Have I lost my mind. Can I be so pompous as to believe that only folks who think like me are right and that everyone else is wrong? (Lets leave infectious disease physicians out for the time being.) There are a "zillion" articles and texts which validate the paradigms they work under. Perhaps a more humble approach is needed. Perhaps everyone is a little right (and a little wrong). The more you are a hammer, the more everything around you takes on characteristics of nails.
At the core is the concept of inflammation. Inflammation is primarily an immunological response. The inflammatory process always begins when a foreign protein is introduced to the body. This is called an antigen. The sentries of the immune system, such as macrophages, sniff out the protein that doesn't belong. This leads to a complex process in which the immune system becomes activated. Without this process we could not survive. Not only does the immune system remove germs: its myriad functions include responding to allergens (proteins to which we have allergic responses) and even removing mutated cells, which if left unchecked could develop into cancer. Without this system we would be doomed. The system cannot be too efficient, it has to be quite selective. It has to recognize normal tissues and leave them undisturbed- we know this is not always the case; it even has to recognize "friendly" bacteria and other microbes, such as those that live in our gut. It has to be an awfully "smart" system.
If the immune system operates normally, things are kept in a state of equilibrium. If it is over activated we can become sick. Many checks and balances are in place- there is a delicate balance required for "normal" health. Sometimes, something very small- like an infection, can disturb the natural order and make us ill. I will confine my remarks to the imbalances caused by small micro-organisms known as bacteria.
When undesirable germs (we are speaking of bacteria here) enter the body the macrophages "gobble" them up. They are processed through the lens of histocompatibility complexes and presented to cells called helper T cell lymphocytes. These T cells somehow "read" the proteins on the surface of these antigens and transmit the information to B cell lymphocytes. These B cells quickly get to work, becoming factory which makes antibodies- special proteins called immunoglobulins, which are able to attach to germs and mark them for destruction. A vigorous response may be needed with alarm bells rung. The B cells can morph into monocytes which are even better antibody (immunoglobulin) factories. Quickly the macrophages and other immune cells crank out other immune system proteins called cytokines, which mobilize the natural immune processes. The cytokines are messenger proteins known as hormones. One can visualize the cytokines as traffic cops frantically directing speeding traffic coming from all directions-performed with pinpoint precision. While this process occurs at "light speed," A complex symphony of players melds into one. The complement system is activated. Special proteins are produced through a complex cascade which also directly attack the offending bacteria. Special proteins are released in very specific ways. Some of these are called: chemokines, bradykin, interleukins, tumor necrosis factor and interferons ( the last three are considered cytokines) and many other molecules. At this time more than 100 distinct cytokines have been discovered. So call "acute phase reactants" are released. These include C-reactive protein of which many of us are familiar. Then granulocytes move in. These are the big guns which gobble up and digest those doomed germs or antigens which have been marked for destruction. In the process granuals are released shedding other inflammatory proteins such as histamine, prostaglandins and leukotriones. The inflammatory process affects many tissues. For example, it affects the lining of the blood vessels, the endothelium, leading to the leaking of fluids (serum) into the surrounding areas. Nitrous oxide is released which promotes an inflammatory response. There is an increase in the clotting pathways of blood proteins. Of course the story is much more complex than this.
Since perhaps millions of pages have been written about the above topic, keep in mind that this represents a vast oversimplification, and that the author is a simple country doctor- trying hard to make sense of a disease many of my colleagues insist does not exist.
How are all these proteins made? They are made in cellular structures called ribosomes of which you have heard much. The ribosomes in our cells, (eucariotic) are quite different from those in bacteria, (procariotic). Antibiotics know which ones to attack. Protein synthesis in each case is directed by RNA, which comes directly from DNA, the blueprint for everything that transpires in our bodies.
Like everything in the universe: the immune system if not infallible. Sometimes mistakes are made.
Let us turn our attention to what rheumatologist know. They actually know quite a lot. They know that variations in histocompatibility complexes, genetically mediated, are associated with various illnesses. These genes have names like: DR and DQ. Small mutations in these genes are associated with differing autoimmune diseases.
Numerous auto-antibodies have been discovered. Theses include rheumatoid factor, ANA, Anti-Sm, Anti-RPN, Anti-Ro, Anti-La and numerous others. These antibodies have special relevance with regard to well characterized rheumatological disorders. Autoimmune disorders are defined based on various clinical and laboratory criteria. There is a great deal of overlap. Symptoms from column A and antibodies from column B are combined in various complex ways to make the diagnosis. Lupus, rheumatoid arthritis and scleroderma constitue only a small fraction of these varied autoimmune disorders. Sometimes these disorders are broken down into those which respond to steroids and those which do not. Rheumatologists and rheumatological literature prominently claims that these disorders are of unknown cause.
Now let us take a look at what rheumatologists have forgotten.
Rheumatic fever is a autoimmune rheumatolgical disorder. It occurs after a Streptoccal infection, usually in the throat (pharyx). It occurs some time after the initial infection. It is an autoimmune disorder because it affects organs which are distant from the site of infection. Typically in affects the skin, the joints, the heart, the kidneys and the brain. Although early treatment generally prevents its occurrence, it can occur despite the lack of signs of ongoing Strep infection (the infections may be considered occult) Recurrent or persistent infection is associated with a relapse of the disease. In some cases indefinite use of antibiotics is recommended to prevent recurrence of the disease.
Another disease associated with Strep infection goes by the name PANDAS. This is an autoimmune disorder affecting the brains of children. It is associated with occult Strep infection. The sufferers have psychiatric symptoms including obsessive compulsive disorder and tics(not ticks). Patients can frequently be taken off psychotropic medication and successfully treated with antibiotics.
Many disorders diagnosed by rheumatologists are called reactive. They follow an infection. The paradigm is that the infection has resolved but that an autoimmune disorder, triggered by the infection remains. Rheumatologic sources point to evidence that continued antibiotic therapy does not influence the outcome. What have they forgotten?
Continued antibiotic therapy does influence the course of rheumatic fever and PANDAS.
Let us consider a little microbiology. Strep is an easy germ to kill. It has no known ability to develop resistance to antibiotics; it replicates quickly and it does not form spores.
How about rheumatoid arthritis? Studies have demonstrated M. fermantans in the synovial fluid of patients with RA. This has been confirmed by 16S rDNA. Viable organisms have also been demonstrated in the synovial tissues. Treatment with antibiotics hasn't helped- or has it. Numerous studies show that Doxycyline and Minocyline are in fact effective drugs for RA. I have observed that rheumatologists tend to avoid these drugs preferring agents which are much more toxic in my opinion.
And unlike the case with Strep- Mycoplasmas are very difficult to eradicate.
Inflammation is bad- so we are constantly told. It in the media all the time. C-reactive protein is a stronger indicator of heart attack risk than cholesterol measurements. Chlamydia pneumonia and other bacteria have been shown to be present in atherosclerotic plaques inside the walls of arteries which can rupture and lead to heart attack and stroke. Some studies have been with drugs like Doxycyline. Is this going to work? Stratton has shown that this organism is very resistant to eradication and that complex multi-drug regimens are needed.
Let us go full circle. Why are people sick who have contracted Lyme disease? We know the causative germ is invasive and nearly impossible to eradicate. We know patients have co-infections which aggravate the disease. Still, some folks who are infected remain relatively unaffected. They are mildly ill or altogether well. The immune response must be a key part of this mystery. For example, the most commonly measured autoimmune antibody is the rheumatoid factor. This is an IgM antibody directed against IgG antibodies. IgM antibodies represent the acute response to an infection. They are made quickly but are not all that effective. In general, they should be supplanted by the more effective, second phase IgG antibodies. Some physicians are troubled by the fact that so called chronic Lyme patients primarily have an IgM response, not an IgG response. If the disease were chronic they reason, one should see IgG responses in the blood. (Actually it turns out that patients who have a robust IgG response to Lyme infection are healthier and respond better to treatment). Is this logical? IgG responses indicate a full immunological/antibody response. These responses are seen in patients who are no longer ill but are in fact recovering from an infectious disease. These are smaller antibodies which bind better to the target sites. So this is not the response one would expect to see in patients with chronic Lyme disease- if such an entity does indeed exist? If the infection is active one would expect IgM antibodies- there is active inflammation. Is this not analagous to the phenomenon which observed with rheumatoid arthritis? Remember, the rheumatoid factor is an IgM antibody. The sickest Lyme patients in fact never have a good IgG response. For some reason the sickest patients are unable to mount a protective immune response. Such patients may suffer and endless cycle of infection and inflammation which becomes very difficult to treat.
And what do we see in chronic Lyme patients? They have an increased incidence of autoimmune antibodies. They have elevated CRP and sed rates. They have elevated complement levels including C3a, C3b and C4a. They have increased circulating immune complexes. They have increased levels of cytokines. They experience inflammatory hematologic abnormalities: the white blood cell count is low. An increased, lymphocyte response may be present, platelet levels may be decreased and abnormalities of blood coagulation may be seen. Alterations in vitamin B12, folic acid and vitamin D may correspond to an active inflammatory process.
Is it post Lyme syndrome? Are the germs gone and we are simply seeing an autoimmune disorder as suggested by the IDSA? This begs the question: What are autoimmune disorders? We have seen evidence that they are in fact promoted by ongoing infection. Autoimmune disorders occur because auto-antibodies are produced. Antibodies are produced when macrophages are activated by foreign proteins. For some yet unexplained reason, sometimes auto-antibodies are produced rather than normal antibodies which would target the offending antigen(protein). The distaff argument then becomes, auto-antibodies are produced because memory cells are activated. When B cells and plasma cells "learn" how to make a particular antibody memory cells are created. These cells "remember" how to make the antibodies and quickly kick into gear when the offending antibody is present. This is why vaccines work. However, there is no reason to believe that these memory cells make antibodies spontaneously. It makes sense that the process is triggered by new antigen exposure. This would explain for example, why rheumatic fever flares up with new exposure to Streptococcal bacteria. The immune system is activated by continued exposure to antigen. In Lyme disease, this dovetails with the observation that IgM antibodies predominate. The immune pump is constantly being primed. I would suggest that a theory of autoimmune disease should include the notion of repeated antigenic stimulation and therefore persistent infection. There is good experimental evidence that patients with "autoimmune" disease, such as rheumatoid arthritis, do in fact show persistent infection.
What do rheumatologist do with their patients? They use steroids. These medications are immunosuppressive. They damp down the entire immune cascade. They reduce activity of macrophages, lymphocytes, granulocytes and cytokines. Patients certainly feel better. The underlying infections may be unchecked with an undesirable effect.
Patients with Lyme who are pregnant feel better. Pregnancy is associated with an immunsuppressed state. After delivery the patients generally have severe relapses as the immune system returns to baseline. Rheumatologists typically prescribe a wide array of immune suppressing drugs. These medications have serious side effects such as life threatening infections and cancers. Concerns regarding the overuse of antibiotics seem less significant in this context.
Are antibiotics bad? Readers of my blog seem very preoccupied with this question.
Antibiotics are neither good nor bad. They are very useful tools essential to the treatment of disorders such as chronic Lyme disease.
A second question is: are alternative and complementary therapies bad? I am concerned about this issue. Many patients who use such therapies claim they help; however, the same patients speak about chronic suffering- the implication: Lyme disease cannot be cured. I am concerned that a focus on these therapies can deprive patients of more effective therapies which offer improvement and a high likelihood of long term remission.
Severe Lyme disease is very bad and must be treated with the most effective tools at our disposal.
Are there ways to make the immune system work better? This question is oft raised. At this time there are no great answers. But perhaps there may be some clues. The relaxation response improves immune function. Exercise improves immune function. A positive mental attitude improves immune function. Correction of sleep disturbances, especially sleep apnea improves immune function. Not being obese improves immune function. Certain diets may improve immune function. Gluten sensitivity and food allergies may stress the immune system and compound the effects of Lyme disease. It is possible that a stressed immune system may experience a tipping point. Removing some of those stressors may allow for quicker overall healing.
What about vitamins and supplements? I am not convinced, sorry. Vitamin A deficiency can cause a decrement in immune responses- but do not take this- it is fat soluble and can be toxic. What about vitamin D. Lately I have given this some thought. In the past I have espoused the belief that vitamin D dysregulation is a pathogen induced process which increases the survival of intracellular pathogens. This theory came from my reading of Marshall's theories. Perhaps this is completely wrong. Another possibility is that vitamin D levels are raised not by the bacteria, but by the host. Perhaps this is an adaptive response to damp down an exuberant immune response which the host senses is causing harm to our bodies. I will stop criticizing doctors who give LD patients D. For now I don't know, and I will leave this topic alone.
All of these ramblings- and not once have I mentioned the helper cell Th1 versus Th2 controversy. This issue has received too much press. The same can be said for the natural killer T cell issue. These immune cells are probably down regulated by a cytokine response. But I have not found the CD57 marker to offer clinical benefit.
Let me finally return to the title of this entry: Towards a unified perspective.
Rheumatologists are right in their characterization of autoimmune disorders. They claim that the cause of such disorders remains unknown. I am simply suggesting that one can take the process back a notch, and posit that the precipitating causes are infection(s), of which Borrelia burdorferi- the Lyme bacteria may be one. And to the neurologists who asked me: "Are you trying to tell me the patient has Lyme disease, not MS." My response would be the same. MS is a well characterized autoimmune disorder associated with destruction of the protective myelin sheath of neurons. You say it is of unknown cause. I am simply offering a theory which provides an explanation of the underlying cause. Such an explanation may also offer therapeutic considerations. So you see- we can all agree, can't we?
As I said early on- I am omitting infectious disease specialists for the time being.
At the core is the concept of inflammation. Inflammation is primarily an immunological response. The inflammatory process always begins when a foreign protein is introduced to the body. This is called an antigen. The sentries of the immune system, such as macrophages, sniff out the protein that doesn't belong. This leads to a complex process in which the immune system becomes activated. Without this process we could not survive. Not only does the immune system remove germs: its myriad functions include responding to allergens (proteins to which we have allergic responses) and even removing mutated cells, which if left unchecked could develop into cancer. Without this system we would be doomed. The system cannot be too efficient, it has to be quite selective. It has to recognize normal tissues and leave them undisturbed- we know this is not always the case; it even has to recognize "friendly" bacteria and other microbes, such as those that live in our gut. It has to be an awfully "smart" system.
If the immune system operates normally, things are kept in a state of equilibrium. If it is over activated we can become sick. Many checks and balances are in place- there is a delicate balance required for "normal" health. Sometimes, something very small- like an infection, can disturb the natural order and make us ill. I will confine my remarks to the imbalances caused by small micro-organisms known as bacteria.
When undesirable germs (we are speaking of bacteria here) enter the body the macrophages "gobble" them up. They are processed through the lens of histocompatibility complexes and presented to cells called helper T cell lymphocytes. These T cells somehow "read" the proteins on the surface of these antigens and transmit the information to B cell lymphocytes. These B cells quickly get to work, becoming factory which makes antibodies- special proteins called immunoglobulins, which are able to attach to germs and mark them for destruction. A vigorous response may be needed with alarm bells rung. The B cells can morph into monocytes which are even better antibody (immunoglobulin) factories. Quickly the macrophages and other immune cells crank out other immune system proteins called cytokines, which mobilize the natural immune processes. The cytokines are messenger proteins known as hormones. One can visualize the cytokines as traffic cops frantically directing speeding traffic coming from all directions-performed with pinpoint precision. While this process occurs at "light speed," A complex symphony of players melds into one. The complement system is activated. Special proteins are produced through a complex cascade which also directly attack the offending bacteria. Special proteins are released in very specific ways. Some of these are called: chemokines, bradykin, interleukins, tumor necrosis factor and interferons ( the last three are considered cytokines) and many other molecules. At this time more than 100 distinct cytokines have been discovered. So call "acute phase reactants" are released. These include C-reactive protein of which many of us are familiar. Then granulocytes move in. These are the big guns which gobble up and digest those doomed germs or antigens which have been marked for destruction. In the process granuals are released shedding other inflammatory proteins such as histamine, prostaglandins and leukotriones. The inflammatory process affects many tissues. For example, it affects the lining of the blood vessels, the endothelium, leading to the leaking of fluids (serum) into the surrounding areas. Nitrous oxide is released which promotes an inflammatory response. There is an increase in the clotting pathways of blood proteins. Of course the story is much more complex than this.
Since perhaps millions of pages have been written about the above topic, keep in mind that this represents a vast oversimplification, and that the author is a simple country doctor- trying hard to make sense of a disease many of my colleagues insist does not exist.
How are all these proteins made? They are made in cellular structures called ribosomes of which you have heard much. The ribosomes in our cells, (eucariotic) are quite different from those in bacteria, (procariotic). Antibiotics know which ones to attack. Protein synthesis in each case is directed by RNA, which comes directly from DNA, the blueprint for everything that transpires in our bodies.
Like everything in the universe: the immune system if not infallible. Sometimes mistakes are made.
Let us turn our attention to what rheumatologist know. They actually know quite a lot. They know that variations in histocompatibility complexes, genetically mediated, are associated with various illnesses. These genes have names like: DR and DQ. Small mutations in these genes are associated with differing autoimmune diseases.
Numerous auto-antibodies have been discovered. Theses include rheumatoid factor, ANA, Anti-Sm, Anti-RPN, Anti-Ro, Anti-La and numerous others. These antibodies have special relevance with regard to well characterized rheumatological disorders. Autoimmune disorders are defined based on various clinical and laboratory criteria. There is a great deal of overlap. Symptoms from column A and antibodies from column B are combined in various complex ways to make the diagnosis. Lupus, rheumatoid arthritis and scleroderma constitue only a small fraction of these varied autoimmune disorders. Sometimes these disorders are broken down into those which respond to steroids and those which do not. Rheumatologists and rheumatological literature prominently claims that these disorders are of unknown cause.
Now let us take a look at what rheumatologists have forgotten.
Rheumatic fever is a autoimmune rheumatolgical disorder. It occurs after a Streptoccal infection, usually in the throat (pharyx). It occurs some time after the initial infection. It is an autoimmune disorder because it affects organs which are distant from the site of infection. Typically in affects the skin, the joints, the heart, the kidneys and the brain. Although early treatment generally prevents its occurrence, it can occur despite the lack of signs of ongoing Strep infection (the infections may be considered occult) Recurrent or persistent infection is associated with a relapse of the disease. In some cases indefinite use of antibiotics is recommended to prevent recurrence of the disease.
Another disease associated with Strep infection goes by the name PANDAS. This is an autoimmune disorder affecting the brains of children. It is associated with occult Strep infection. The sufferers have psychiatric symptoms including obsessive compulsive disorder and tics(not ticks). Patients can frequently be taken off psychotropic medication and successfully treated with antibiotics.
Many disorders diagnosed by rheumatologists are called reactive. They follow an infection. The paradigm is that the infection has resolved but that an autoimmune disorder, triggered by the infection remains. Rheumatologic sources point to evidence that continued antibiotic therapy does not influence the outcome. What have they forgotten?
Continued antibiotic therapy does influence the course of rheumatic fever and PANDAS.
Let us consider a little microbiology. Strep is an easy germ to kill. It has no known ability to develop resistance to antibiotics; it replicates quickly and it does not form spores.
How about rheumatoid arthritis? Studies have demonstrated M. fermantans in the synovial fluid of patients with RA. This has been confirmed by 16S rDNA. Viable organisms have also been demonstrated in the synovial tissues. Treatment with antibiotics hasn't helped- or has it. Numerous studies show that Doxycyline and Minocyline are in fact effective drugs for RA. I have observed that rheumatologists tend to avoid these drugs preferring agents which are much more toxic in my opinion.
And unlike the case with Strep- Mycoplasmas are very difficult to eradicate.
Inflammation is bad- so we are constantly told. It in the media all the time. C-reactive protein is a stronger indicator of heart attack risk than cholesterol measurements. Chlamydia pneumonia and other bacteria have been shown to be present in atherosclerotic plaques inside the walls of arteries which can rupture and lead to heart attack and stroke. Some studies have been with drugs like Doxycyline. Is this going to work? Stratton has shown that this organism is very resistant to eradication and that complex multi-drug regimens are needed.
Let us go full circle. Why are people sick who have contracted Lyme disease? We know the causative germ is invasive and nearly impossible to eradicate. We know patients have co-infections which aggravate the disease. Still, some folks who are infected remain relatively unaffected. They are mildly ill or altogether well. The immune response must be a key part of this mystery. For example, the most commonly measured autoimmune antibody is the rheumatoid factor. This is an IgM antibody directed against IgG antibodies. IgM antibodies represent the acute response to an infection. They are made quickly but are not all that effective. In general, they should be supplanted by the more effective, second phase IgG antibodies. Some physicians are troubled by the fact that so called chronic Lyme patients primarily have an IgM response, not an IgG response. If the disease were chronic they reason, one should see IgG responses in the blood. (Actually it turns out that patients who have a robust IgG response to Lyme infection are healthier and respond better to treatment). Is this logical? IgG responses indicate a full immunological/antibody response. These responses are seen in patients who are no longer ill but are in fact recovering from an infectious disease. These are smaller antibodies which bind better to the target sites. So this is not the response one would expect to see in patients with chronic Lyme disease- if such an entity does indeed exist? If the infection is active one would expect IgM antibodies- there is active inflammation. Is this not analagous to the phenomenon which observed with rheumatoid arthritis? Remember, the rheumatoid factor is an IgM antibody. The sickest Lyme patients in fact never have a good IgG response. For some reason the sickest patients are unable to mount a protective immune response. Such patients may suffer and endless cycle of infection and inflammation which becomes very difficult to treat.
And what do we see in chronic Lyme patients? They have an increased incidence of autoimmune antibodies. They have elevated CRP and sed rates. They have elevated complement levels including C3a, C3b and C4a. They have increased circulating immune complexes. They have increased levels of cytokines. They experience inflammatory hematologic abnormalities: the white blood cell count is low. An increased, lymphocyte response may be present, platelet levels may be decreased and abnormalities of blood coagulation may be seen. Alterations in vitamin B12, folic acid and vitamin D may correspond to an active inflammatory process.
Is it post Lyme syndrome? Are the germs gone and we are simply seeing an autoimmune disorder as suggested by the IDSA? This begs the question: What are autoimmune disorders? We have seen evidence that they are in fact promoted by ongoing infection. Autoimmune disorders occur because auto-antibodies are produced. Antibodies are produced when macrophages are activated by foreign proteins. For some yet unexplained reason, sometimes auto-antibodies are produced rather than normal antibodies which would target the offending antigen(protein). The distaff argument then becomes, auto-antibodies are produced because memory cells are activated. When B cells and plasma cells "learn" how to make a particular antibody memory cells are created. These cells "remember" how to make the antibodies and quickly kick into gear when the offending antibody is present. This is why vaccines work. However, there is no reason to believe that these memory cells make antibodies spontaneously. It makes sense that the process is triggered by new antigen exposure. This would explain for example, why rheumatic fever flares up with new exposure to Streptococcal bacteria. The immune system is activated by continued exposure to antigen. In Lyme disease, this dovetails with the observation that IgM antibodies predominate. The immune pump is constantly being primed. I would suggest that a theory of autoimmune disease should include the notion of repeated antigenic stimulation and therefore persistent infection. There is good experimental evidence that patients with "autoimmune" disease, such as rheumatoid arthritis, do in fact show persistent infection.
What do rheumatologist do with their patients? They use steroids. These medications are immunosuppressive. They damp down the entire immune cascade. They reduce activity of macrophages, lymphocytes, granulocytes and cytokines. Patients certainly feel better. The underlying infections may be unchecked with an undesirable effect.
Patients with Lyme who are pregnant feel better. Pregnancy is associated with an immunsuppressed state. After delivery the patients generally have severe relapses as the immune system returns to baseline. Rheumatologists typically prescribe a wide array of immune suppressing drugs. These medications have serious side effects such as life threatening infections and cancers. Concerns regarding the overuse of antibiotics seem less significant in this context.
Are antibiotics bad? Readers of my blog seem very preoccupied with this question.
Antibiotics are neither good nor bad. They are very useful tools essential to the treatment of disorders such as chronic Lyme disease.
A second question is: are alternative and complementary therapies bad? I am concerned about this issue. Many patients who use such therapies claim they help; however, the same patients speak about chronic suffering- the implication: Lyme disease cannot be cured. I am concerned that a focus on these therapies can deprive patients of more effective therapies which offer improvement and a high likelihood of long term remission.
Severe Lyme disease is very bad and must be treated with the most effective tools at our disposal.
Are there ways to make the immune system work better? This question is oft raised. At this time there are no great answers. But perhaps there may be some clues. The relaxation response improves immune function. Exercise improves immune function. A positive mental attitude improves immune function. Correction of sleep disturbances, especially sleep apnea improves immune function. Not being obese improves immune function. Certain diets may improve immune function. Gluten sensitivity and food allergies may stress the immune system and compound the effects of Lyme disease. It is possible that a stressed immune system may experience a tipping point. Removing some of those stressors may allow for quicker overall healing.
What about vitamins and supplements? I am not convinced, sorry. Vitamin A deficiency can cause a decrement in immune responses- but do not take this- it is fat soluble and can be toxic. What about vitamin D. Lately I have given this some thought. In the past I have espoused the belief that vitamin D dysregulation is a pathogen induced process which increases the survival of intracellular pathogens. This theory came from my reading of Marshall's theories. Perhaps this is completely wrong. Another possibility is that vitamin D levels are raised not by the bacteria, but by the host. Perhaps this is an adaptive response to damp down an exuberant immune response which the host senses is causing harm to our bodies. I will stop criticizing doctors who give LD patients D. For now I don't know, and I will leave this topic alone.
All of these ramblings- and not once have I mentioned the helper cell Th1 versus Th2 controversy. This issue has received too much press. The same can be said for the natural killer T cell issue. These immune cells are probably down regulated by a cytokine response. But I have not found the CD57 marker to offer clinical benefit.
Let me finally return to the title of this entry: Towards a unified perspective.
Rheumatologists are right in their characterization of autoimmune disorders. They claim that the cause of such disorders remains unknown. I am simply suggesting that one can take the process back a notch, and posit that the precipitating causes are infection(s), of which Borrelia burdorferi- the Lyme bacteria may be one. And to the neurologists who asked me: "Are you trying to tell me the patient has Lyme disease, not MS." My response would be the same. MS is a well characterized autoimmune disorder associated with destruction of the protective myelin sheath of neurons. You say it is of unknown cause. I am simply offering a theory which provides an explanation of the underlying cause. Such an explanation may also offer therapeutic considerations. So you see- we can all agree, can't we?
As I said early on- I am omitting infectious disease specialists for the time being.
Friday, November 21, 2008
Odds and Ends
I don't use alternative therapies. Sometimes C.diff and other issues make standard therapy impractical. Patients can try protocols described by Buhner, Coweden and others. I have not found such therapies to be terribly effective in my patients. Salt and C: I don't use it. Anecdotal reports of its efficacy exist. This dove tails with one of the weirder aspects of the disease. Some patients with Lyme claims to see worms in their stool. It has been suggested that this is an unknown microfilaria species. Patients have in fact brought me stool specimens with visible worms. Labs have not IDed the organisms . The first thing the Willie Burdorfer saw in tick guts was worms. I don't know if this species has been characterized. High levels of Na in the gut may have an osmotic effect and act as a de-wormer as has been suggested by some. For such patient, Ivermectin has been tried. Sometimes it seems to help- I am reluctant to recommend this therapy at this time. Dr. Stricker who treat many Morgellons patients uses this anti-parasitic medication with some success. There is some connection between Morgellons and Lyme disease. This is outside my comfort zone.
My expertise(if I have any) has accrued over time. The combinations of drugs I used two years ago were more empiric then systematic. My approaches now are more regimented. I am not sure this has improved the results. For example, when I first read about LD treatments, I noted that Jemsek reported success with Cipro and Doxy. It didn't occur to me that I might also be treating "Bartonella." I used Rifampin because many patients reported that it had been effective; maybe this too was treating something other than Borrelia. The treatments were more hodgepodge. So when I review the cases of patients I have treated over time it may reflect an evolution in my general approach. It is still evolving.
IVIG sound great: I can't prescribe it because of standard of care limitations.
Invanz is a 24 hour drug with a broad spectrum of coverage. There are variable responses of drugs within the same class. I mentioned it based on one anecdote. It might be a great addition to the available arsenal. Most antibiotics require more complex dosing strategies. Unfortunately we have no data regarding the use of many antibiotics including this one.
Whether patients get very ill probably depends on a host of factors. Some strains of Bb may be more pathogenic. The mix of co-infections varies. Individual immunological responses based on genetics may play a large role. Some of this may be medicated by major histocompatibility molecules(genetically determined). Some patients only have IgM responses which made bode poorly versus those patients who develop a robust IgG response. So far we cannot do much about individual genetic based immune responses, but such things may have prognostic and or treatment value.
My expertise(if I have any) has accrued over time. The combinations of drugs I used two years ago were more empiric then systematic. My approaches now are more regimented. I am not sure this has improved the results. For example, when I first read about LD treatments, I noted that Jemsek reported success with Cipro and Doxy. It didn't occur to me that I might also be treating "Bartonella." I used Rifampin because many patients reported that it had been effective; maybe this too was treating something other than Borrelia. The treatments were more hodgepodge. So when I review the cases of patients I have treated over time it may reflect an evolution in my general approach. It is still evolving.
IVIG sound great: I can't prescribe it because of standard of care limitations.
Invanz is a 24 hour drug with a broad spectrum of coverage. There are variable responses of drugs within the same class. I mentioned it based on one anecdote. It might be a great addition to the available arsenal. Most antibiotics require more complex dosing strategies. Unfortunately we have no data regarding the use of many antibiotics including this one.
Whether patients get very ill probably depends on a host of factors. Some strains of Bb may be more pathogenic. The mix of co-infections varies. Individual immunological responses based on genetics may play a large role. Some of this may be medicated by major histocompatibility molecules(genetically determined). Some patients only have IgM responses which made bode poorly versus those patients who develop a robust IgG response. So far we cannot do much about individual genetic based immune responses, but such things may have prognostic and or treatment value.
Thursday, November 20, 2008
Ivanz- who knew
A new Lyme med?
This 48 year old female was not one of my best success stories. Despite this, I had helped her a great deal. Two years ago she came to me a train wreck. She had incapacitating total body pain, cognitive impairments and abdominal pain. She had seen rheumatologist who had treated her with immunomodulators including gold and prednisone. Nothing had helped. Antibiotics had caused strange reactions- numbness and tingling in her mouth. Numerous doctors had no idea what was causing her abdominal pain and myriad other symptoms. She had been sick for over 20 years and was at the end of her rope.
The abdominal pain was easy. I have found that gastroenterologists and surgeons make this same mistake over and over again. She had classic right upper quadrant abdominal pain with a tender gallbladder(positive Murphy sign). She had had numerous CT scans and ultrasounds which were negative. Her HIDA biliary scan was normal. The CCK injection given during the test reproduced her symptoms. This is key. If hormonal stimulation of the gallbladder reproduces the pain- the gallbladder is diseased. A clinical rule which has served me well over the years is simple: Treat the patient, not the labs or ancillary tests. The first surgeon I sent her to refused to consider surgery. She was an obvious hypochondriac. Besides, the GI specialists didn't think she had gallbladder disease: IBS. The second surgeon performed a laparoscopic cholecystectomy. Bingo. Path showed chronic cholecystitis.
In my experience, Lyme frequently causes gallbladder disease. She felt better and was impressed right off the bat that I had figured out one of the mysteries. Her labs made TBD a no brainer. She had positive Babesia serology from Labcorp. We began a long odyssey of treatment. There were ups and downs. Antibiotic side effects and intolerance led to long periods of no treatment. Symptoms invariably relapsed. The fibromyalgia and joint pains were somewhat refractory to therapy. Her cognitive improvements were steady. She suffered with bouts of serious depression which complicated her care. Along the way she had two courses of IV Rocephin. They were not as effective as I hoped they would be. Recently she came into my office very concerned. She told me that she had been coughing for two months- she smokes 2 packs per day- she knew that she had lung cancer. My intuition- its not cancer. The Chest Xray showed a mass. She was a wreck. I pointed out that it might be an infection. I ordered the CT, PET and a needle biopsy. The results were non-specific inflammation. No signs of cancer. It looked like a lung abscess. I thought it might be related to Bartonella. I started her on Cleocin and Levaquin. She collapsed in what looked like the mother of all Herxes. She was admitted to the hospital. She saw all the king's horses and all the king's men. They ultimately decided it was indeed a lung abscess. They were unable to identify a causative pathogen. The infectious disease doctor started her on Invanz. Its a new beta lactam antibiotic given once daily. It seems to kill everything that has a cell wall: gram positives, gram negatives and anerobes.
She was in the hospital for 6 days. Something magical happened. I saw her today. She was more bright and chipper than I had ever seen. There was almost a glow of wellness about her. This is the best she had felt in 20 years!. Virtually all of her symptoms had vanished.
Could this drug be a magic bullet that wipes out Lyme and the mystery bacteria crawling around in the bloodstreams of my patients?
Perhaps some other LLMDS should look at this and give it a try. I am trying to avoid more controversial therapies at the moment. This new antibiotics was only approved in the beginning of 2007.
PS: If it appears that I only write about my success stories it is because the other patients are a work in progress. I never give up- and neither do my patients.
This 48 year old female was not one of my best success stories. Despite this, I had helped her a great deal. Two years ago she came to me a train wreck. She had incapacitating total body pain, cognitive impairments and abdominal pain. She had seen rheumatologist who had treated her with immunomodulators including gold and prednisone. Nothing had helped. Antibiotics had caused strange reactions- numbness and tingling in her mouth. Numerous doctors had no idea what was causing her abdominal pain and myriad other symptoms. She had been sick for over 20 years and was at the end of her rope.
The abdominal pain was easy. I have found that gastroenterologists and surgeons make this same mistake over and over again. She had classic right upper quadrant abdominal pain with a tender gallbladder(positive Murphy sign). She had had numerous CT scans and ultrasounds which were negative. Her HIDA biliary scan was normal. The CCK injection given during the test reproduced her symptoms. This is key. If hormonal stimulation of the gallbladder reproduces the pain- the gallbladder is diseased. A clinical rule which has served me well over the years is simple: Treat the patient, not the labs or ancillary tests. The first surgeon I sent her to refused to consider surgery. She was an obvious hypochondriac. Besides, the GI specialists didn't think she had gallbladder disease: IBS. The second surgeon performed a laparoscopic cholecystectomy. Bingo. Path showed chronic cholecystitis.
In my experience, Lyme frequently causes gallbladder disease. She felt better and was impressed right off the bat that I had figured out one of the mysteries. Her labs made TBD a no brainer. She had positive Babesia serology from Labcorp. We began a long odyssey of treatment. There were ups and downs. Antibiotic side effects and intolerance led to long periods of no treatment. Symptoms invariably relapsed. The fibromyalgia and joint pains were somewhat refractory to therapy. Her cognitive improvements were steady. She suffered with bouts of serious depression which complicated her care. Along the way she had two courses of IV Rocephin. They were not as effective as I hoped they would be. Recently she came into my office very concerned. She told me that she had been coughing for two months- she smokes 2 packs per day- she knew that she had lung cancer. My intuition- its not cancer. The Chest Xray showed a mass. She was a wreck. I pointed out that it might be an infection. I ordered the CT, PET and a needle biopsy. The results were non-specific inflammation. No signs of cancer. It looked like a lung abscess. I thought it might be related to Bartonella. I started her on Cleocin and Levaquin. She collapsed in what looked like the mother of all Herxes. She was admitted to the hospital. She saw all the king's horses and all the king's men. They ultimately decided it was indeed a lung abscess. They were unable to identify a causative pathogen. The infectious disease doctor started her on Invanz. Its a new beta lactam antibiotic given once daily. It seems to kill everything that has a cell wall: gram positives, gram negatives and anerobes.
She was in the hospital for 6 days. Something magical happened. I saw her today. She was more bright and chipper than I had ever seen. There was almost a glow of wellness about her. This is the best she had felt in 20 years!. Virtually all of her symptoms had vanished.
Could this drug be a magic bullet that wipes out Lyme and the mystery bacteria crawling around in the bloodstreams of my patients?
Perhaps some other LLMDS should look at this and give it a try. I am trying to avoid more controversial therapies at the moment. This new antibiotics was only approved in the beginning of 2007.
PS: If it appears that I only write about my success stories it is because the other patients are a work in progress. I never give up- and neither do my patients.
Wednesday, November 19, 2008
17 month review
A 46 year old woman first came to me about 17 months ago. She had a history Lyme disease about 7 years before our first encounter. She had been treated with a three week course of Doxycycline. Her doctors over the years had diagnosed fibromyalgia, chronic fatigue syndrome and memory loss of unknown cause. She also had a history of unspecified colitis dating back 5 years. She was referred to me by a friend. On that occasion her symptoms included: headaches- severe, diffuse total body pain- severe, blurred vision, decreased hearing, memory loss, episodes of weakness and tingling of the extremities. She reported a prior history of Clostridia difficile colitis and an allergic reaction to Flagyl. This was reported to be a serum sickness like reaction and had caused a neurological reaction- some sort of muscle weakness. Her labs showed CDC positive Lyme antibodies. She was started on Ketek with probiotics. She had a massive Herx response. Plaquenil was added. She developed a urinary tract infection which led her to the hospital. Levaquin was given. Two months into treatment she saw improvements. Her hearing had improved. Her mental acuity was better. Her pain had decreased. A month later there was trouble. She developed some abdominal cramping, diarrhea and blood. She had chills. There was marked cognitive improvement. I was worried about C. diff and I knew she had a history of colitis. I had to stop antibiotics. With nothing else to offer, herbal therapy was recommended. One month later she was mostly better GI wise. The Lyme symptoms had neither worsened or improved. Asacol was started for colitic symptoms.
I was going through my experimental "CAM" phase. I even tried the vit C and Na protocol. It may have helped a "smidgen." Three months later I bit the bullet. Ramping up the probiotics she started Zithromax and Rifampin. No diarrhea. A herx: fatigue, increased numbness and now orthostatic dizziness. Adrenal insufficiency? I started low dose cortef, 5mg twice daily. Her insurance wouldn't cover Zithro and we switched to Biaxin. Now 5 months into treatment things were gradually improving. She had crawling sensations- saw worms in her stool and had small fibers extruding from her skin.(I have a patient with severe Morgellons- I didn't want to think about this). I added low dose Cipro and gave her a couple doses of Ivermectin. These weird things improved. I switched gears and put her on Minocin. We were 7 months in. The cortef had been a success and was stopped. A strange pruritic rash improved with antihistamines. A stool test for gluten sensitivity was suggested. She couldn't afford it, so she tried an empirical gluten free diet. Colitis symptoms improved. The original symptoms were about 50% better. 9 months in her antibiotics were ramped up again: Amoxil 3gm per day and Zithromax 500mg per day. It worked. She made steady progress. Plaquenil and Questran were used as well. Vitamin D was avoided and Benicar was added to balance out high levels of vit D dihydroxy 1,25. This helped as well. About 15 months in she was 85% better. I did elicit a history of sweats. I reviewed her chart and realized she had not been treated for Babesia. Two months into Zithro, Mepron, Tidamax (which she tolerates well) and Atemensisn she is 95% better. Admittedly I did some things along the way which I might be hesitant to try now. We were able to get past C. diff and plug away. Her colitis is in remission. Her memory and cognition are normal. Her pain is gone. She exercises and functions normally. She is a new person. We are not quite done yet. It is looking good.
I was going through my experimental "CAM" phase. I even tried the vit C and Na protocol. It may have helped a "smidgen." Three months later I bit the bullet. Ramping up the probiotics she started Zithromax and Rifampin. No diarrhea. A herx: fatigue, increased numbness and now orthostatic dizziness. Adrenal insufficiency? I started low dose cortef, 5mg twice daily. Her insurance wouldn't cover Zithro and we switched to Biaxin. Now 5 months into treatment things were gradually improving. She had crawling sensations- saw worms in her stool and had small fibers extruding from her skin.(I have a patient with severe Morgellons- I didn't want to think about this). I added low dose Cipro and gave her a couple doses of Ivermectin. These weird things improved. I switched gears and put her on Minocin. We were 7 months in. The cortef had been a success and was stopped. A strange pruritic rash improved with antihistamines. A stool test for gluten sensitivity was suggested. She couldn't afford it, so she tried an empirical gluten free diet. Colitis symptoms improved. The original symptoms were about 50% better. 9 months in her antibiotics were ramped up again: Amoxil 3gm per day and Zithromax 500mg per day. It worked. She made steady progress. Plaquenil and Questran were used as well. Vitamin D was avoided and Benicar was added to balance out high levels of vit D dihydroxy 1,25. This helped as well. About 15 months in she was 85% better. I did elicit a history of sweats. I reviewed her chart and realized she had not been treated for Babesia. Two months into Zithro, Mepron, Tidamax (which she tolerates well) and Atemensisn she is 95% better. Admittedly I did some things along the way which I might be hesitant to try now. We were able to get past C. diff and plug away. Her colitis is in remission. Her memory and cognition are normal. Her pain is gone. She exercises and functions normally. She is a new person. We are not quite done yet. It is looking good.
Monday, November 17, 2008
Three Legged Monster
I have been treating this critically ill 45 year old man for 2 1/2 months. He had previously been treated by ID specialists with 21 days of Doxycycine. He had been critically ill for 18 months with a rapid downhill spiraling course. He had 3 spinal taps, (I would have said no thank you after the first). Two were negative. The third time he was diagnosed with viral meningitis. He was given a second course of Doxy- thank you. His body is racked with pain. He has unremitting shooting pains and burning of his entire body. Every joint and muscle hurts. His body is weak and he is unable to function. His cognitive deficits have progressed to the point of global dementia. He has restless legs, fevers and chills and soaking sweats. I started him on oral anti Bb meds. He herxed severely. A break in therapy was needed. Low dose malarone was added and his chills and fevers became unbearable. This was put on hold. Despite my concerns, the family was desperate for a more aggressive approach. I was leery, but agreed to give it a try. One month in I started Rocephin. The neuro and musculoskeletal Herx was severe. The decision was made to tough it out. Mepron was added. The Herx was worse: the patient developed a delirium. This abated with a lowering of narcotic analgesics and a reduction in dose of Rocephin. When the Rocephin was ramped up again the Herx returned and was intolerable.The dose of Rocephin was lowered once more and his symptoms settled down. His mental status was at least back to baseline. The soaking sweats of the Babesia Herx persisted. The Mepron was stopped. Malarone one tablet daily was re instituted. The sweats and chills abated. Two legs of the monster were at least being held at bay: Borrelia and Babesia. His blood smear is swarming with the mystery bacteria. It was a stalemate, The patient was circling the tarmac. His pain was minimally improved. His mentation was stable. The drenching sweats were gone. He was also encouraged that the restless leg syndrome had quieted down with Mirapex. His wife was certainly grateful since he had belted her in the face during sleep. I know the Lyme and Babesia were only being tamped down. Every time I upped the ante things got worse. Is it better to treat only one thing at a time as is oft stated? That approach so far had failed. Perhaps it is better to hack away at all three legs at once. Today I set out a trap for the third leg of this dreadful monster. I don't know what the mystery germ is, nonetheless, I cautiously added Zithromax and Rifampin in an effort to throw it off balance. Hopefully the monster will fall. I know if it does I will have to return to the work of chopping away at the other legs.
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