By Thomas M. Grier, M.S. ©
Lyme disease is a perplexing illness. Early in 1970s in Old Lyme Connecticut, Lyme disease was first described as a rheumatological syndrome called “Lyme Arthritis”. The symptoms of “ Lyme Arthritis” mimicked Juvenile Rheumatoid Arthritis (JRA) and many kids with Lyme disease were misdiagnosed as having JRA.
It was only a matter of a few years before “Lyme Arthritis” was associated not only with arthritis but also with causing a host of serious neurological symptoms. Further investigation soon showed that the characteristic bull’s-eye rash was associated with the bite of a new species of tick named the Ixodes dammini tick. (The I. dammini tick turned out to be the same species as the I. scapularis deer tick.)
In 1981 when the culprit of the illness was isolated both from the suspect tick and from human Lyme rashes, it was all but decided by the medical community that while Lyme disease was a real concern, it was easily treated. This assumption was based on the fact that “Lyme Arthritis” was caused by a bacterium: and with few exceptions bacterial pathogens are all successfully treated with just a few weeks of antibiotics.
While in the test tube the Lyme bacteria Borrelia burgdorferi responded to many common antibiotics including erythromycin, tetracycline, doxycycline, penicillin and amoxicillin, the truth was that in the early days of treatment, in every human trial of antibiotic drug treatment, some patients either did not respond at all, or their symptoms quickly relapsed.
The unfortunate fact of Lyme disease is that more than twenty years later medical science has not developed any significant breakthroughs in either diagnosis of or the treatment of this disease. Despite all of what we have learned about Borrelia burgdorferi , our diagnostic tests are still poor, and our treatment regimens are for the most part unchanged for the last two decades.
The early Lyme tests that were developed made heavy assumptions that a patient’s level of antibody was a consistent marker of exposure and active infection. More distressing is that most early treatment studies considered a drop in antibody levels during antibiotic treatment as a quantitative marker for indicating a cure. Researchers inappropriately accepted a negative antibody titer as an absence of active infection. It was not considered that the bacteria was surviving beyond the reaches of the bloodstream’s immune system.
Despite the overwhelming evidence that seronegative Lyme is common and that infection can persist despite treatment, today’s researchers and manufacturers of these tests still squabble over patents and royalties and spend more time thinking up clever ways of making their indirect tests more competitive in the drug market rather than creating better direct tests.
An example of this was when a new PCR test by the U of MN was compared not to other PCR tests but to culturing Lyme rashes. Assuming only a 4 % success rate of culturing rashes the press release for the new test was complete with cost for the test and boldly stated that this test was 4 times more accurate than culturing. To the lay person this sounds good but it really meant the new PCR test was accurate only in 1 out of every 5 patients with a bull’s eye rash. This kind of research is not in the best interest of the patient.
So what research needs to be done that isn’t being done?
In the last twenty years the goal of medical research has become so economically competitive that so much of the work being done is secretive and proprietary, many institutions won’t even pursue research that doesn’t look economically rewarding. In today’s bottom line medical system, most institutions will not do work in an area that might duplicate the work of a competitor who may already own patents on the end product. Yet work on endless “me-too” versions of existing tests continues simply because manufacturers see more money in patient testing and vaccines than in treatment.
I have said it many times before and still believe that Lyme patients would be better off if no test had ever been developed, and Lyme treatments were based entirely on symptom response to therapy. I don’t have a quick solution to the problem of the current patent-or- parish mentality of universities, but I do think more time needs to be spent on some old technologies such as blood smears and tissue stains before we listen to any more press releases from universities and drug companies telling us how their new test is better than that of their competitors.
In truth I have little hope in ever developing a quick easy reliable blood test for Lyme and feel we are better off without the ones currently being demanded by insurance companies and HMOs.
My first suggestion for research is to spend less money developing tests for the living, and spend more money investigating the disease process in the dying. Understanding the pathology of this disease is paramount to making any significant advances in the treatment of this illness.
We have seen in animal models going back to the 1980s that the blood brain barrier of mammals is quickly breached by this bacterium. (4) What role does early invasion of the Lyme spirochete into the human brain mean to patients? Is there long-term sequela to CNS invasion? These are questions are left wholly unanswered and require a deeper commitment to research than what has been allocated to Lyme disease!
In the 1990s we learned that the Lyme spirochete has a predilection for and attaches to the lining of blood vassals. When this occurs the endothelial cells break down and creates blood vessel holes. No one has suggested or pursued any receptor site research. Perhaps one form of treatment might be finding a way to block these attachment sites?
Drug Therapy: While we have in the past twenty years explored the use of dozens of antibiotics and combinations of antibiotics, we have not made any real advancement in antibiotic therapy. The quick and easy answer is to say we should develop newer and better antibiotics. While this is obviously true it still falls far short of what else can be done.
One of the problems of treating Lyme disease is that the bacteria is known to penetrate difficult to reach and difficult to treat areas of the body. While the argument still persists on whether Lyme disease is an intracellular disease, there is no argument that the bacteria can get inside the joint, connective tissue and the brain which are tissues difficult to treat. In most cases you must overdose the rest of the body in order to penetrate these tissues.
A solution not currently being pursued is better drug delivery systems. In 1991 I proposed to the company I worked for at the time, Wyeth labs, that research be done on better CNS delivery systems for amoxicillin.
With the advent of diseases like AIDS and Lyme it seemed that we needed a better way to get drugs safely into the brain in higher concentrations where they were needed. While old drugs like amoxicillin can no longer be patented, the drug delivery systems can be patented for more than a decade. This could give new life to many old drugs. Better delivery systems make dozens of drugs available rather than just concentrating on a singly new drug option.
Devises that optimize direct infusion of antibiotics into joint and brain is one method of accomplishing this, and the use of fat soluble carrier molecules conjugated to or surrounding the drugs is another method (lipo-spheres, DMSO etc). The response to a 28 page proposal that I drafted in 1991 to my employer, was a single sentence in a short letter. “ Dear Mr. Grier: At this time there is no interest or economic feasibility in developing new treatments for Lyme disease …there are not enough new cases of Lyme annually to warrant development of clinical treatments. ”
Since economic interests seem to be the main concern in researchers developing better tests for diagnosis and better drugs for the treatment of Lyme disease, it appears that Lyme disease research may be left in the hands of foundations still willing to fund research directed by need and not economics. The bonus is that almost any new treatments will be economically viable because of use in Lyme and other emerging infectious diseases.
Here is a list of areas of research that have not been aggressively pursued and that I believe have potential in producing useful breakthroughs in diagnosis and treatment.
First we need to devote less monies to tick studies and urban exposure studies and more monies to basic pathology and microbiology studies. In a world filled with people traveling via SUVs and airplanes, Lyme disease can occur to anyone who travels through Lyme endemic areas. We need to put research money into science and not into the politics of boundaries.
I care less about which counties have Lyme, and more about what long term untreated Lyme is doing to our medical system? If Lyme patients have been misdiagnosed as having M.S. how many Lyme patients have in the last 50 years been draining insurance companies out of money for long term care of patients with M.S-like disorders caused by Lyme. We don’t know the answer and we will only find out by doing autopsies on enough dementia patients to establish an accurate percentage. Even if just a few percent of dementia patients are found to have spirochetes in the brain at the time of death, this translates to billions of health care dollars wasted on caring for sick patients when it would take just a fraction of that money to treat patients caught earlier.
A very simple study that has never been done but would be quite revealing about tick-borne illnesses is a quality of retirement-life study that looks at the differences between the quality of health of retirees in professions that are at high risk for tick-borne illness compared to lifestyles with professions at a low risk of contracting tick-borne illnesses. Previous studies have shown a higher incidence of M.S. among agricultural workers, owners of large dogs, and in Europe M.S. is highest in areas of high rodent infestations. Perhaps a large-scale quality of life study would tell us if outdoor living is really a healthy lifestyle? Is there a greater risk for forestry workers to get M.S. than say a secretary? A survey of this type would be simple and cheap to do.
Pathology: I am sorry to say it but the only way to get a definitive answer to the question of whether Lyme can still be an active infection post treatment, is to do autopsies and recover and test biopsies done on chronic Lyme patients that die of any other cause (cancer, heart attack etc) and do labor intensive searches for the bacteria using immuno-fluorescent tissue stains and silver stains of selected tissues. If we find it in the brain after treatment then all the arguments for not treating patients who respond to antibiotics becomes moot! Borrelia burgdorferi has been found in so many tissues that it makes sense that any autopsy study that is undertaken should investigate many tissues to determine what tissues are target tissues and are most resilient to successful antibiotic therapy.
Receptor site research : It appears that the Lyme spirochete has an affinity for certain tissues. It seeks out connective tissue and may use N-Acetyl Glucasamine as a food source. Borrelia burgdorferi also attaches to specific cells in animal models of Lyme disease including endothelial cells, B-cells, fibroblasts, peripheral nerves, and specific brain cells. It may be that the bacteria has receptor sites that can be blocked by new and specialized therapies? If so this may be both an effective treatment and a preventative.
To do this we need more and better animal models including mammalian brain models that investigate the pathologic mechanisms of Borrelia.
In Switzerland a Neuropathologist Judith Miklossy showed that when she looked for spirochetes in the brains of Alzheimer patients that she found them in an alarming percentage of Alzheimer’s patient’s brains. Since this is a bacteria that is invisible in human tissue unless you look for it and stain for it post-mortem, we need to do more dementia based autopsies to determine the role and frequency of spirochetes in debilitating neurological, and neuromuscular diseases. Part of Miklossy’s work showed an association of the location of the spirochetes in the patient’s brain with amyloid plaques. What role can this bacteria or other bacterial pathogens play in producing amyloid in mammalian brains? Better animal models of brain cell metabolism and infection are needed to find out.
In summary we are still essentially diagnosing and treating patients in the same manner as we did in the 1980s and the bulk of Lyme disease research seems to be oriented around everything except pathology, and treatment. I believe to make significant strides in patient treatment we need to devote more time and money to pathology, better drug treatments and better drug delivery systems. I also believe privately funded foundations are the best hope of directing and funding these kinds of projects.
References:
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Miklossy Judit. Alzheimer’s disease a spirochetosis? Neuro Report 1993;4:841-848 Miklossy J, Kuntzer T, Bogousslavsky J, et al. Meningovascular form of neuroborreliosis: Similarities between neuropathological findings in a case of Lyme disease and those occurring in tertiary Neurosyphilis. Acta Neuro Pathol 1990;80:568-572
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Schmutzhard E, Pohl P, Stanek G. Borrelia burgdorferi antibodies in patients with relapsing/remitting form and chronic progressive form of multiple sclerosis. J Neurol Neurosurg Psych 1988;51:1215-1218
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Abstract #D646 – 1995 Rheumatology Symposia Texas chaired by Alan Steere P.K. Coyle, et al, Multiple Sclerosis vs. Lyme disease a diagnostic dilemma. Forty-seven patients were identified as possible MS patients. Many had brain lesions on their MRIs, consistent with MS 61%. CSF was constant with MS in 46 % of the patients. The final breakdown of the 47 patients was: 21 MS, 15 LD, 7 had findings constant with both LD and MS. Thirteen patients responded to antibiotics but only those who had CSF findings consistent with LD.
Abstract # D657 – 1995 Rheumatology Symposia Texas chaired by Alan Steere J. Cimperman, F. Strle, et al, Repeated Isolation of Borrelia burgdorferi from the CSF of two patients treated for Lyme neuroborreliosis. Patient 1, was a twenty year old woman who presented with meningitis but was sero-negative for Bb. Subsequently six weeks later, Bb was cultured from her CSF and she was treated with IV Rocephin 2 grams a day for 14 days. Three months later the symptoms returned and Bb was once again isolated from the CSF. Patient 2 was a 51 year old female who developed an EM rash after tick bite. Within two months she had severe neurological symptoms, her serology was negative. She was denied treatment until her CSF was culture positive nine months post tick bite. She was treated with 2 grams of Rocephin for 14 days. Two months post antibiotic treatment Bb was once again cultured from her CSF. In both these cases the patients had negative antibodies, but were culture positive, suggesting that the antibody tests are not reliable predictors of neurological Lyme Disease. Also standard treatment regimens are insufficient when infection of the CNS is established, and Bb can survive in the brain despite Intra venous antibiotic treatment.
Goodman JL, Sonnesyn SW, Holmer S, Kubo S, Johnson RC.: Seroprevelence of Borrelia burgdorferi in patients with severe heart failure, evaluated for cardiac transplantation at the University of MN. Abstract # 49, presented at the Fifth International Symposia on Scientific Research on Lyme Borreliosis, Arlington, VA, 1992 * The presence of Lyme antibodies is present in a large percentage of myocardopathy patients awaiting heart transplants.
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[Letter/Comments] Lancet, August 1, 1992;340(8814):317-18, From Lancet May 9, 1992;339(8802):1174-5
– Schmutzhard E, Pohl P, Stanek G. Borrelia burgdorferi antibodies in patients with relapsing/remitting form and chronic progressive form of multiple sclerosis. J Neurol Neurosurg Psych 1988;51:1215-1218