Editorial by Thomas M. Grier, M.S. ©
In 1975 the term “Lyme Arthritis” first entered the vocabulary of the physicians in America. Since that time Lyme disease and Lyme-like diseases have become recognized worldwide. But in the 28 years since “Lyme Arthritis” was first described: What do we actually know? And what do we yet need to learn about
Why is it that in the three decades since Lyme disease was first described that
it still perplexes us and vexes us with controversy and puzzlement?
In a nutshell it comes down to the inescapable fact that victims of Lyme disease all too often have lingering symptoms that remain or return even after aggressive and multiple antibiotic treatments. They remember wellness, but with each passing year the fog that fills their brain, the palpitations that shake their hearts, and the fatigue that plagues their bodies becomes the ever present reminder that they were stricken with a poorly understood and often underestimated pathogen.
Here are some things we know: The pathogen that causes Lyme disease is Borrelia burgdorferi and it is a highly motile spirochete that belongs to a genus of bacteria that are notorious for giving rise to variant strains. Borrelia are bacteria that are associated with dozens of tick and louse-borne Relapsing Fevers that are found throughout the world. These related illnesses range in symptoms from cases of mild fevers to rapidly fatal encephalitis’. The hallmark attribute that most Borrelia bacteria have in common is their ability to adapt, change and infect host animals that in turn infect many species of ticks and lice.
We know for example that if you rank all the known Borrelia pathogens in a phylogenetic tree based on related genetics, you will find many disease causing pathogens that cause similar symptoms will often end up close together in related
groups on the phylogenetic family-tree.
In other words Borrelia burgdorferi, Borrelia afzellii and Borrelia garinii that cause Lyme disease in America and Europe are all genetically similar to each other and have similar tick vectors. It is believed that they are closely related and variations occurred as separate tick populations over thousands of years migrated with animal populations and the bacteria became isolated populations. At one time all Borrelia had a common ancestor.
Exactly how long ago we don’t know, but the evidence of common ancestry is in their related and similar genes. This year when the genomic sequence of Borrelia burgdorferi was determined, it came as quite a shock that most of the genes in this large bacterium had no known counterparts or similarities to other known bacterial genes. This means the function of the majority of the genes in the Borrelia species has yet to be determined.
What we don’t know: The Lyme bacteria Borrelia burgdorferi likes to preferentially express certain genes and suppress others. This allows the bacteria to adapt to new environments. But what does it take for Borrelia burgdorferi to express one of the suppressed genes of an ancient pathogen cousin? Borrelia burgdorferi like all Borrelias have genes that are latent but intact. If a gene is expressed or triggered by the environment as it is suggested by research done of Relapsing Fever strains, then could a latent but deadly gene be triggered in one individual with unique genetic markers and not expressed in another patient? Could pathogen-host interactions based on patient genetic markers explain why some Lyme patients have persisting symptoms?
What we know: Dr. Andrew Pachner infected mice with Borrelia burgdorferi and later extracted the bacteria from the blood and from the brains of the infected mice. What he found was basically that the Bacteria in the brain changed: they now expressed a new set of genes. The result was bacteria so different from what he started with, that the antibodies from the peripheral blood could no longer detect the bacteria isolated from the brain.
This is bad news as the CNS is isolated from the rest of the body. If the Lyme spirochete can adapt to the human brain and circumvent the immune system, it is less likely to be inhibited by our natural immune defenses. Further studies by Pachner in primates using PCR suggested persistent infection post-antibiotic treatment. This is more bad news as this suggests that the CNS of primates is an isolated and protective incubator for Borrelia bacteria.
What other gene expressions of these bacteria do we need to understand better?
What we need to find out: Occasionally patients infected with Relapsing Fever will report a Bull’s-Eye rash identical to Lyme disease, and experience symptoms similar to Lyme without a recurring febrile states (Recurring fevers). If Relapsing Fevers can behave like Lyme disease, does this mean Lyme could suddenly cause an aggressive encephalitis in a patient similar to East African Relapsing Fever? Since we don’t know or understand the reasons for patient variation in symptoms, it is something we need to investigate and learn. We know for instance from early work done by Dr. Patricia Coyle M.D. PhD that the Lyme bacteria can get into the CNS of a lyme patient very early , but only a small fraction of these patients develop serious mennigo-encephalopathies.
Understanding the recently sequenced genomic sequence of Borrelia burgdorferi and gene _expression is essential to understanding both chronic and acute Lyme disease. In patients with HLA-DR4 tissue type, are there markers in the joints responsible for chronic Lyme arthritis ? We need to study the role of genetics, and receptor sites in both humans and within the Lyme spirochete. How the bacteria interacts with one person may be radically different than how it acts in another patient.
What we don’t know: One of the most frequent complaints from Lyme patients is the loss of cognitive abilities. Their minds are fuzzy, foggy and they complain of short term memory loss and poor word retrieval. Their fear is: How permanent is this memory impairment? And will it progress? We don’t know why so few bacteria can cause such a profound affect on conscious thought, but unlike Syphilis a related and similar spirochetal infection, the Lyme bacteria is found in the human body in extremely low numbers?
Why are there so few bacteria in a Lyme infection? Are there other forms (sphereoplasts or cell-wall deficient forms) of the bacteria in greater numbers that we just aren’t recognizing? How can so few bacteria cause such horrible symptoms like cardiomyopathy, encephalitis, hepato-spleenamegaly, heart arrhythmias, rheumatoid-like arthritis, optical neuritis, Bell’s Palsy, muscle spasms, fibromyalgia, and multiple sclerosis-like presentations. Can it be that a small number of bacteria initiate cascade responses of inflammation and autoimmunity in the human body? If autoimmunity is playing a role, how does it affect the various tissues?
What we know: Since 1911 dozens of papers have associated spirochetes with Multiple Sclerosis. The most dramatic and convincing of these papers were all published prior to 1954 which was decades before the numerous controversies of Lyme disease would appear. Recently in experiments using a rat-brain model, one researcher showed that Borrelia burgdorferi was directly neuro-toxic to neurons and caused the death of brain cells on contact. This happened rapidly and consistently. This means there is an evolved mechanism within the Borrelia bacteria when in contact with the CNS to not only change it’s antigenic identity but to paralyze and destroy neurons and glial cells.
In recent years the incidence of Alzheimer’s disease has risen sharply. Even more recent research has shown that the incubation of Borrelia burgdorferi in mouse brain cultures for eight weeks resulted in creating many of the laboratory markers for Alzheimer’s disease. We see the synthesis of amyloid precursor protein and the rapid conversion to amyloid and beta sheet amyloid. We see the hyperphosphoralation of Tau protein, we see similar fibrillary tangles and fibrin deposits. In other words we can essentially create a laboratory model of Alzheimer’s in-vitro simply by virtue of adding Borrelia to living brain cells. An animal model of Alzheimer’s was something researchers dreamed of for decades, and now that it is within our technical abilities almost no one is exploring this model of Alzheimer’s pathology.
What we need to know: What receptors are on the Borrelia membrane that triggers neuron destruction? What causes the cascade of Amyloid synthesis in brain-cell cultures? If we knew these things we could develop potential new treatments to prevent amyloid production in Alzheimer’s patients, and perhaps a way to stop neurological damage in Lyme patients.
What we need to do? If even a few percent of the cases of M.S. and Alzheimer’s disease were caused by spirochetes, we could save countless people from the morbidity and disability of these diseases, and millions in health care dollars. But we need much more money and research to explore a link between Borreliosis and dementia in humans. Clearly if it turns out that spirochetal infections are playing a role in some dementias, we need to find out Who to treat? and How to treat?
The first is advanced and thorough research to establish whether a link between M.S. and Lyme disease does or does not exist. Even a 1 % incidence would be an important finding. But before we can give M.S. and Alzheimer’s patients that 1 in 100 chance of an effective treatment, we need to do the basic research, and frankly while monies are currently being spent on more Deer studies, almost nothing with respect to Lyme disease is being spent on Dementia research . We need millions of dedicated research dollars to study a link between Lyme-related-spirochetes and Alzheimer’s disease and M.S. To do these studies we need more than just money.
We need human brain tissue from dementia patients and M.S. patients. To obtain these samples we would need to pre-enroll affected patients into a nationwide autopsy study and create a tissue bank for the tissues, and then make them available to researchers to specifically look for spirochetes and the markers of Borrelia. Prior to this however we need to train pathologists in techniques to detect spirochetes. Unfortunately if you don’t know how to detect them, the spirochetes are virtually invisible on a normal autopsy.
With a national annual budget of a mere seven million dollars to study Lyme disease and to educate the public, we are about 100 million dollars short of an effective Lyme disease research program in America.
What we know: We know that many Lyme patients with established disease can test negative on serology tests. Seronegative Lyme has been reported in the medical literature and has been confirmed in patients with Erythema Migrans rashes, it has been confirmed by PCR, it has been confirmed by culture, and even by biopsy and staining of surgically removed tissue. So we know antibodies do not always manifest in all Lyme patients and cannot be the sole determinant of diagnosis. We also know by all the same methods of confirmation that some patients remain actively infected with the live bacteria even despite antibiotic treatment. Treatment failures have been reported in all treatment studies that required a follow-up of patients.
What we don’t know? Why do some patient’s not express adequate antibodies against this bacteria? If a patient is infected and has low or no detectable antibodies are they more sick than patients with a high natural immunity? Why do some patients maintain an active infection when they receive the identical treatment as patients who recover? Why do symptoms remain in so many Lyme patients despite aggressive therapy?
What we need to do: To answer these questions we need research that includes a budget for extensive pathology and histology. We need studies that look at the modes of action of the various antibiotics against spirochetes. We need more pharmacological studies and newer and better antibiotics. We need studies that investigate adjunct therapies that address patients lingering symptomatic sequela post treatment. If nothing else we need better delivery systems for the medicines
we already have.
In the 1950s it was recognized that penicillin did not consistently get into the brains of Tertiary Syphilis patients. Only when the CNS was extremely inflamed or if the drug was given in gigantic single doses did penicillin enter the brain in therapeutic levels. So some clinicians in desperation tried to inject penicillin directly into the brain only to discover that this induced seizures. Now fifty years later we are faced with a very similar dilemma.
How do we get amoxicillin and other inexpensive and readily available drugs into the CNS? One potential answer is more research in better delivery systems to deliver the drug into the CNS. Another option is to add fat soluble carrier molecules or to use micronized antibiotics encapsulated in lipids. Of course there is no uarantee of success with these and other methods, but drug companies do not pursue this area of research, the market is perceived as being too limited. But if you expand these delivery systems beyond Lyme for such diseases as fungal infections of the brain, then the market is much larger! Once again the World Health Organization may be a source to stimulate this kind of research.
Conclusion: To do these studies that have never been done, we need to put a stop to the impediments hindering good research. Until the studies are done no one has the answers. And we won’t find the answers if we don’t invest more money into more and better designed studies. What Lyme disease has lacked in the past twenty five years has been research dollars that focus on the pathological disease process.