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A Plague of Ignorance Regarding the Ignorance of a Plague

© Copyright 2004, Dr Scott Taylor, DVM, All rights Reserved

My objective for writing this report is to help inform the layman and the medical community about the extremely complex infection called Lyme disease. I have recently been infected with Lyme disease and I will share my experience and what I have learned about the complex nature of Lyme disease in this report. I continue to update this report and I foresee many revisions of it in the future as more information regarding Lyme disease surfaces. I have recently been introduced to a major medical breakthrough discovered by Dr. Trevor Marshall, research director at the Autoimmunity Research Foundation in Thousand Oaks, CA. I have updated this version of the report to include this vital information.

Lyme disease (LD) is a seriously complex multi-system inflammatory disease that is triggered by the bacterial lipoproteins (BLPs) produced by the spiral-shaped bacteria called Borrelia. Borrelia are difficult to isolate, grow, and study in the laboratory. So, our technical knowledge of this pathogen is poor compared to our understanding of most bacteria that cause disease. Transmission of Borrelia occurs primarily through the bite of ticks. The disease affects every tissue and every major organ system in the body. Clinically, it can appear as a chronic arthalgia (joint pain), fibromyalgia (fibrous connective tissue and muscle pain), chronic fatigue, immune dysfunction and as neurological disease. LD may even be fatal in severe cases.

The diagnosis of Lyme disease is primary based upon clinical evidence. There is currently no laboratory test that is definitive for Lyme disease. Many tests give false negative results. Physicians not familiar with the complex clinical presentation of Lyme disease frequently misdiagnose it as other disorders such as: Fibromyalgia or Chronic Fatigue Immune Dysfunction Syndrome (CFIDS), Multiple Sclerosis, Lupus, Parkinson's, Alzheimer's, Rheumatoid Arthritis, Motor Neuron Disease (ALS, Amyotrophic Lateral Sclerosis -Lou Gherig's disease), Multiple Chemical Sensitivity Syndrome (MCS) and numerous other psychiatric disorders such as depression and anxiety.

Lyme disease is a familiar name to most people, but their knowledge of it is very limited. Unfortunately, this is also true for most professionals in the medical community. There have been numerous reports in the media about it in the United States over the past 25 years. These superficial articles report something about small deer ticks transmitting bacteria called Borrelia burgdorferi. The tick vectors are said to be mainly restricted to certain endemic areas of the United States, which are the Northeast and the upper Midwest. Frequently mentioned is the bulls-eye skin rash that develops following the bite of an infected tick. The disease is reported to begin with flu-like symptoms that progress to an arthritic and fibromyalgic condition. It is often said that Lyme disease can be readily treated with standard regimens of antibiotics. While these reports are partially true, they are also critically erroneous and very misleading!

This report is an urgent warning for everyone. Lyme disease is devastating the lives of hundreds of thousands of individuals and we are all at risk. Many patients are suffering with chronic Lyme disease and continue to be misdiagnosed and mistreated. In many cases of Lyme disease, a correct diagnosis doesn’t occur until after several months or more often many years of suffering with the disease. By then it has caused severe illness, disability and permanent damage. The disease is widespread and the prevalence is significantly higher than reported by health officials.

It is very unfortunate that most physicians don’t know how to recognize and treat cases of Lyme disease, especially the illusive cases of chronic Lyme disease. I’m not just talking about general MDs being ignorant; I am also referring to specialists such as: rheumatologists, neurologists, orthopedic surgeons, cardiologists, psychiatrists, and the most ignorant actually seem to be infectious disease specialists. I was extremely surprised by this plague of ignorance after I began my investigation of Lyme disease.

There are some key factors that exist in the medical community regarding Lyme disease; they go a long way in explaining why LD is often misdiagnosed and mistreated:

1. LD is frequently misdiagnosed. Physicians frequently overlook cases of Lyme disease simply because they don’t know the complex pathogenesis of the disease. They don’t understand that Lyme disease causes well over 100 different symptoms; the common arthralgia (the medical term for joint pain) is a LD symptom that most physicians are familiar with; however, it is only one of many symptoms caused by Lyme disease. The clinical presentation of Lyme disease can be very subtle and complex. Most doctors don’t know that laboratory tests are often useless and misleading. Results are frequently negative or inconclusive in individuals with borreliosis. The technology we have to deal with borrelia species is in need of significant improvement. The isolation and identification of borrelia is rarely successful; and no clinical laboratory test exists that can definitively diagnose Lyme disease. This is why a diagnosis of Lyme disease is heavily based upon clinical information such as history, symptoms, and response to therapy. There is an art to medicine when dealing with Lyme disease. Lyme experienced physicians must use keen clinical skills and judgment when dealing with suspect Lyme disease patients. They thoroughly evaluate the patient’s history and symptoms when seeking a diagnosis and are able to recognize even the subtle symptoms of complex Lyme cases. Most physicians don’t recognize the symptoms of chronic Lyme disease and will rely solely on laboratory tests to confirm a diagnosis. Frequently these lab tests are negative and mislead the physician and patient to search for another cause. Most MDs don’t know that borrelia produce a large variety of toxic bacterial lipoproteins (BLPs) and they aren’t familiar with the way these BLPs cause disease. Lyme disease specialists must use very keen clinical judgment when diagnosing cases of Lyme disease. In defense of the ignorant physicians, much blame can rest on health officials and the medical establishments that are not giving clinicians the appropriate information they need to diagnosis these difficult cases of Lyme disease. The criteria being used to report Lyme disease by physicians is often set by state health officials and is often based upon the rigid criteria established by the Center for Disease Control and Prevention (CDC). This CDC criteria was established for an epidemiological survey, which was designed to study the distribution of Lyme disease. The two-step method of the CDC uses a screening immunoassay for all patients followed by a more sensitive and specific Western blot only if the screening test was positive. Unfortunately, this approach was originally intended for surveillance of Lyme disease in potentially asymptomatic patients, not for diagnostic purposes in patients with symptoms that are potentially related to Lyme disease. This criteria was not intended to be used as a standard for the clinical diagnosis of Lyme disease; the CDC has clearly stated this. Unfortunately, ignorant health officials and physicians continue to use these criteria for the clinical diagnosis of Lyme disease.

 

2. Unfamiliar pathogenesis. Lyme disease has a complex pathogenesis that I’ll discuss later in this report. Only a few medical professionals understand the pathogenesis of Lyme disease. Actually, very few MDs that specialize in Lyme disease understand this pathogenesis very well. This detailed information is not taught in medical schools or even in the general medical conferences or in post-resident seminars. Thus, most clinicians practicing medicine don’t understand how borrelia causes disease. Without this knowledge, it is difficult to properly recognize, diagnose, and treat Lyme disease.

 

3. LD is caused by many borrelia species. Another major oversight by the medical community regarding Lyme disease is that Borrelia burgdorferi is not the only bacterium that causes Lyme disease; there are many pathogenic borrelia strains; many of which cause borreliosis (Lyme-like disease). The causative agent, Borrelia burgdorferi, is a type of spirochete. When Bb was first discovered in 1982 it was thought that there was just one strain. Since then, about 100 U.S. and 300 worldwide strains of the bacterium have been discovered.

In the mid-1990's genospecies were formed to group the many variations into subcategories.

Borrelia burgdorferi sensu lato is name given to the overall category. In North America there is just one genospecies variant - Bb sensu stricto. In Europe there are three categories Bb sensu stricto, B. garinii, and B. afzelii. Asia has B. garinii and B. afzelii. Japan has B. japonica and B. miyamoto. These groups are evolving as new research discoveries occur.

A new pathogen causing Lyme or "Lyme-like" disease has been reported. While not culturable, it has been named B. lonestari sp.

B. andersonii, B. lonestari and B. miyamotoi have been identified by PCR and DNA sequence analysis as likely human pathogens in the U.S. Unfortunately, the criteria for clinical Lyme are set for only Borrelia burgdorferi; they were not designed for any other borrelia species. The reason that Borrelia burgdorferi is tracked by health officials but not other species is because it’s the primary borrelia species that laboratories are able to identify and study. I admit that Borrelia species are very difficult to grow (fastidious) and work with in the laboratory. In most cases, laboratories are not even able to isolate and identify Borrelia species. Some other known strains of borrelia include: B. valaisiana,

B. lusitaniae and B. bissettii.

 

4. There are more carriers of LD than just the deer tick. There is a tremendous misunderstanding regarding the vector (carrier) that transmits Lyme disease. First of all, the familiar tick vector called the deer tick (Ixodes dammini) and black-legged ticks (commonly called deer ticks) (Ixodes scapularis) are more prevalent and spreading wider than reported. Secondly, these ticks are not the only vector able to transmit Borrelia species. Several other tick species such as the Lone Star ticks (Ammblyoma americanum), western black-legged ticks (Ixodes pacificus), and wood ticks or dog ticks (Dermacentor variabilis) can transmit it too. Unfortunately, this critical information is not being reported by health officials to the public and medical community. The widespread distribution of these tick vectors greatly increases the prevalence of Lyme disease well beyond that of official reports. The public needs to understand the potential danger of all tick bites, not only that from the deer tick.
5. LD is more common than we think. The true prevalence of Lyme disease is much higher than is being reported by health officials. It is difficult to know how many cases are unreported but estimations suggest that the prevalence is actually 10-15 times higher than what is actually being reported. I personally believe it is much higher than that. Why are health officials under-reporting cases of Lyme disease? Again, the answer is because physicians don’t recognize and report most cases. These misdiagnosed cases go unreported even though Lyme disease is a mandatory reportable disease (in the state of Iowa). So, a futile cycle exists causing numerous cases of Lyme disease to be misdiagnosed and unreported. That is, since most cases of Lyme disease go undiagnosed, health officials under-report Lyme disease; thus, physicians that read their official reports believe that the prevalence of Lyme is rare and place it low on their list of possibilities when faced with clinical cases that could be caused by Borrelia.
6. Patients need longer and more comprehensive treatment. The standard therapy of 4 -6 weeks of antibiotic treatment is not sufficient to treat chronic Lyme disease. Chronic Lyme disease is often a life-long illness. Months, years, and often indefinite antibiotic therapy may be necessary to manage the disease. Ignorant physicians often use the standard treatment and consider the patient cleared of Lyme disease afterwards. Often these patients are not treated long enough to clear the stubborn Borrelia from the body. So, when the standard regimen of antibiotics is finished, the patients relapse with Lyme symptoms soon after the residual Borrelia reemerges. Unfortunately, the relapse is often not recognized by doctors and the patients are misdiagnosed with a different disorder. Not only does treatment be directed at the infection; it must also manage inflammation, help eliminate the BLPs produced, support the immune system, and many other associated problems such as hormone deficiencies.
7. Wrong diagnosis leads to wrong treatment. Another critical point that needs to be highlighted is that Lyme ignorant physicians often administer medication that is contraindicated in patients with Lyme disease. The therapy most often prescribed that is extremely contraindicated is the use of steroidal anti-inflammatories; usually the glucocorticosteroids (such as prednisone). Lyme patients suffer with many painful inflammatory symptoms. MDs, not knowing that the patient has Lyme disease, think it is appropriate to treat these patients with steroids to reduce the pain and inflammation. Unfortunately, steroidal therapy is very deleterious to Lyme patients because it suppresses the patient’s immune system causing it to tolerate the presence of Borrelia instead of attacking and killing it. This harmful treatment significantly diminishes the prognosis of Lyme patients; it prolongs the course of the disease and makes it more severe in the long run.

Lyme Wise Medical Doctors: The Few, the Knowledgeable, the Harassed

Lyme disease has a relatively young history in the U.S. The first reported case of borreliosis in the U.S. was made by Dr. Rudolph Scrimenti in 1970. He noticed a skin lesion called erythema migrans (EM), a rash that Borrelia can cause soon after a tick bite. Scrimenti diagnosed and treated the patient who had been bitten by a tick and acquired LD while hunting in Wisconsin. Lyme disease was later rediscovered in the well-known Lyme, Connecticut outbreak that began in 1975 by Dr. Allen Steere. He misdiagnosed this outbreak as juvenile rheumatoid arthritis near the community of Lyme, Connecticut. At that time the condition was named 'Lyme arthritis.’ Then, in the early 1980s, B. burgdorferi was recognized as the causative agent of the Lyme outbreak and the name was later changed to Lyme disease.

Although the disease was named for the town in Connecticut, Lyme disease (borreliosis) actually has a long history taking it as far back as the 1800s. The first reported case of clinical Lyme disease was made in Germany by Dr. Alfred Buchwald in 1883. He described a degenerative skin disorder now called acrodermatitis chronica atrophicans (ACA) that is known to be caused by Borrelia. Thus, a great deal of information was already known about Lyme disease prior to its rediscovery as Lyme disease in the United States. However, most of this early medical history of LD comes from the European scientific literature. The U.S. still lags behind the Europeans regarding their understanding of borreliosis.

The terminology used to describe Borrelia infections and the disease caused by them is not clearly defined. The name "Lyme disease" has been used to describe the illness specifically caused by only B. burgdorferi, not other Borrelia species. However, the term Lyme disease or Lyme borreliosis is commonly used to describe the infectious diseases that are caused by many Borrelia species. More appropriately the name for the disease caused by borrelia infections is borreliosis. However, borreliosis isn’t commonly used and is not familiar to most, so I will often use the more familiar name, Lyme disease. However, please note that I will use borreliosis, Lyme disease, or Lyme borreliosis interchangeably to describe the complex disease caused by borrelia infections.

The Spirochete Called Borrelia: What Makes Lyme Disease Tick

Borrelia species, like the human pathogen Treponema pallidum, (the cause of syphilis) are placed in the spirochete family of bacteria. Spirochetes are long, thin, spiral-shaped bacteria that have flagella (tails), (see figures 1 & 2 below). Other familiar humans diseases caused by Borrelia species include: 1) relapsing fever, which use soft ticks or lice as vectors, and 2) gum disease. The genus Brachyspira is a spirochete that commonly causes colitis in swine in Europe and has recently been discovered to cause colitis in humans.

Spirochetes are very difficult to grow (fastidious), identify, and study in the laboratory. In the laboratory we still cannot grow the spirochete that causes syphilis, Treponema pallidum. This makes it very difficult to perform research and develop better diagnostic tests and therapies for borreliosis. Borrelia species grow extremely slowly; they even grow slower than many fungi and mycobacteria. Their growth rate is also slower than Mycobacterium tuberculosis, which causes tuberculosis. Borrelia’s slow growth partially explains its ability to cause chronic disease and the difficulty identifying it in the laboratory.

Borrelia exists in three different life forms: 1) the cyst, 2) the spheroplast or "L form", which doesn’t have a cell wall (commonly called: cell wall deficient (CWD)), and 3) the typical spiral-shaped bacteria form that has a cell wall and flagella as seen in figures 1 & 2. Spirochetes have a unique mode of motility that allows them to easily travel through tissues of the body. By rotating their axial filament (endoflagella) the flagellum rotates causing the spirochete to actually move in a cork-screw fashion. This mode of motility allows spirochetes to literally "screw" themselves into and through the tissues of the body. They can also contract like a spring and move through tissue as they uncoil. Spirochetes hide their flagella from the host’s immune defenses, which are normally antigenic and would trigger an immune response if detected.

Figure 1

In 1982 the brilliant entomologist, Willy Burgdorfer, discovered the etiologic agent of Lyme disease. He was investigating ticks at the United States Rocky Mountain Laboratories located in Montana, part of the National Institutes of Health, when he isolated spirochetes from the mid-guts of Ixodes ticks. He showed that these spirochetes reacted with immune serum from patients that had been diagnosed with Lyme disease.

Consequently, the etiologic agent was named in his honor, Borrelia burgdorferi (Bb). It is interesting to note that Dr. Burgdorfer was familiar with European literature regarding borreliosis and was able to connect that information to the Lyme outbreak. I wish the rest of our medical establishment would be as diligent as he.

 

Figure 2: Borrelia burgdorferi, the bacteria that causes Lyme disease, left picture seen at 400x magnification. Right picture is a scanning electron micrograph of Treponema pallidum, the cause of syphilis.

Justified Arachnophobia: Ticks, the Vector of Borrelia

Figure 3

The Life Cycle of TicksTicks have a life cycle of 2 years that includes the egg, larvae, nymph, and adult stages, (see figure 3). Nymphs and adults appear to be primarily responsible for transmission of the borrelia to susceptible large animal hosts including humans; however, larvae can transmit borrelia to humans also.

In the spring, eggs hatch into a larvae ("seed" tick) that have six legs. Larvae feed and molt into nymph that have eight legs and no sex differentiation. Nymph feed and molt into adults that are differentiated into male or female. Similar to the mosquito, the adult female tick requires a blood meal before she can lay eggs.

A tick seeks a blood meal at or slightly above ground level by climbing onto vegetation and using its forelegs to feel and grab a host. They are usually found between ground level to three feet above the ground. To locate a host, a tick detects carbon dioxide, scent, body heat, and possibly other stimuli generated from the host’s body. Ticks generally feed once during the spring, but they may feed in the fall and anytime during the year. They are active at temperatures above 42° F. Although the incidence of Borrelia induced erythra migrans (EM) skin rashes is highest during the spring and early summer, symptoms of LD may occur anytime during the year.

Ticks cannot survive long exposure to the sun and are therefore typically found in shaded areas. Tick habitats must contain both small animal hosts for tick larvae and large animal hosts for tick adults. A relative humidity of greater than 65% is required for hatching eggs and larvae survival. This cool, wet spring of 2003 has been ideal for producing ticks. This means that there will be a large crop of feeding nymphs this fall and next spring; followed by a large crop of feeding adults throughout the year 2004.

A favorite tick habitat is the transitional zone between woods and lawns or meadows. Ticks become stimulated by the warmth and carbon dioxide that is produced by a host that spends a considerable amount of time in the ticks’ environment. Ticks will grab a passing host or drop to the ground, find the host, and climb onto it. They will travel upward until they reach the head or are obstructed. It is important to remember that humans can be hosts for all stages of ticks.

The deer tick is the size of a pinhead in the larvae stage. It is tan, and feeds on small animals like the mouse where it can pick up the spirochete. During the nymph stage the tick is the size of a poppy seed. It is beige or partially transparent and feeds on larger animals such as cats, dogs and humans. Adult deer ticks are black and/or reddish and will feed on cattle, deer, dogs and humans.

Figure 4: Left is the Amblyomma americana (Lone Star tick) nymph, adult, and larva. Center is the Dermacentor variabilis (American dog or wood tick) adult. Right is the Ixodes scapularis (black-legged tick) larva, adult, and nymph.

Figure 5: Lone Star tick, Amblyomma americanum

Figure 6:

Comparison of the Capitulum (head/mouth) of the lone star tick (Amblyomma americanum) which clearly has a different size and shape than that of the American dog tick (Dermacentor variabilis).

Below-Magnified mouthparts of the deer tick (I. dammini)

Figure 7

Figure 7 is a CDC chart showing the distribution of the deer (Ixodes scapularis) and western black-legged (Ixodes pacificus) ticks. Unfortunately, this chart doesn’t show the large distribution of the Lone Star tick, American Dog Tick, Black-Legged Tick and other tick vectors of Borrelia. Again, according to the deficient reporting by the CDC there are three main focal points in the eastern half of the country, (see figure 8).

Ticks are carried by a number of different host animals, not simply deer. The hosts for adult ticks are numerous and include: fox, coyote, dogs, cats, cattle, rabbit, skunk, raccoon, rats, squirrels, white-tailed deer, wild turkey, and humans. Nymphs get on many of these same animals as well as larger animals typical for adults. Ground nesting birds including bobwhite quail, pheasants, turkeys and chickens are also tick hosts. Forty-nine species of migrating birds have been found to carry ticks, transporting them large distances and contributing to the national spread of Lyme disease. Potential minor vectors for Borrelia species include: chiggers, mosquitoes, biting flies and fleas. Cases of LD being contracted from infected pets are well documented; likely due to the pet bringing infected ticks into the home. Borrelia can also be transmitted in utero from an infected mother to a child during pregnancy. Congenital transmission can cause miscarriages, severe neurological disabilities, or other major system dysfunctions to the baby. Other modes of transmission probably exist that we are not aware of. I am personally concerned that transmission may occur through blood transfusions without authorities knowing about it.

Lyme Disease in the U.S.A.

Figure 8

By looking at this map, it is interesting to highlight certain points:

• The Northeast is the traditional place when you think of Lyme and is quite evident in figure 8.

• The Midwest is a rapidly emerging area of Lyme activity recently and is unfortunately poorly recognized in this map. Dr. Masters, a Lyme expert in Cape Girardeau, has shown that Borrelia is causing Lyme disease in Missouri.

• The South; from Texas to Florida, and from Georgia to Virginia, where knowledge of the disease is still very limited, tick populations are large, and vector-borne disease cycles are still poorly understood and under reported.

Figure 9

In 1996, there were 16,455 new cases reported in the U.S. The number dropped in 1997(see table above), but in 1998 there were 16,801 cases, and in 1999 there were 16,273 new cases reported to the CDC. In 2002, 18,000 cases of Lyme disease were reported in the U.S.

Reported cases of Lyme disease in 2002 were up nearly 40 percent from 2001,
according to the CDC. The phenomena does not appear to be regional, as 95 percent of
reporting states showed an increase in reported cases, with a one year doubling seen in some states. The northeastern and northcentral states remain a focus of concern, accounting for
approximately 90 percent of all cases.

With 23,000 new cases of Lyme reported last year, it is becoming apparent that the disease is a much larger problem than many had originally thought. CDC statements acknowledge the prevalence of Lyme disease.

The Iowa Department of Public Health criteria for Lyme disease is actually much more restrictive than the CDCs criteria. A Lyme disease case must have three out of these five criteria:

• Live in an endemic area (Iowa is not listed as an endemic area)
• Known tick exposure
• A bulls-eye EM rash
• Early symptoms of Lyme
• Laboratory confirmation

Since 1982, 220 cases that fit the above criteria have been reported to the Iowa Department of Public Health. Twenty-six cases were reported in 1998. Wisconsin (5,970 cases since 1982), Minnesota (2,385 cases since 1982), and Missouri (1,060 cases since 1982) are all CDC endemic areas for Lyme disease.

Although Lyme is a mandatory reportable disease, physicians will often treat patients with early Lyme without getting positive serology tests and avoid reporting it to the Dept. of Public Health.

Pathogenesis of borreliosis: How Borrelia Cause

a Self-Perpetuating Inflammatory Disease

Understanding how borrelia causes disease is the key to successful diagnosis and treatment.

Regarding borreliosis, the molecular component of the pathogen that appears initiate the pathogensis are the bacterial lipoproteins (BLPs) which are found within the outer surface proteins of the borrelia cell membrane.

BLPs are fat-soluble toxins that are part protein and part lipid. They are often a structural part of the borrelia cell membrane and can be found within the outer surface proteins of borrelia. They are very potent immunomodulators even in small amounts. Thus, a few borrelia can produce enough BLPs to initiate significant disease.

These BLPs trigger many harmful responses in any tissues and organ system of the human body. These responses, produce complex symptoms of fibromyalgia, arthritis, neurological signs, psychiatric disorders, immunologic dysfunctions, and endocrine deficiencies.

At the molecular level, the BLPs cause a dysfunction in the immune system by triggering a complex imbalance of chemical immune mediators (cytokines). These cytokines regulate the immune system and when they are over stimulated, they produce harmful reactions from the immune system, such as pain, inflammation, and even apoptosis (cell death). Some of the cytokines involved include: tumor necrosis factor-alpha (TNF-α), interleukins-6 (IL-6), fatty acid products (eicosanoids such as inflammatory prostaglandins, thromboxanes, and leukotrienes) that have potent inflammatory/physiological properties and many other cytokines play a role in the pathogenesis of borreliosis.

These BLPs have a key component, Pam3cys, which triggers an innate immune response that cascades into the disease borreliosis.

The inflammation triggered by the fat-soluble BLPs toxins is responsible for most, if not all symptoms of borreliosis.

So, the innate immune system and the acquired immune system are strongly triggered by the presence of the borrelia BLPs.

BLPs activates the innate immune system through what are called Toll-like receptors. Many cell types throughout the body carry the TLR receptors. It's a basic innate immune response that even invertebrates have. These receptors are able to recognize molecular patterns that are unique to microbial pathogens. The body uses TLRs to detect the prescence of many microbial pathogens, not just borrelia. The figure below shows how TLRs can detect several molecular patterns of different microbial pathogens. The TLRs that are most likely involved in borreliosis are TLR 2, 6, & 1, but TLR-2 likely plays the major role.

For a thorough review of the TLR signaling pathway see this reference: Seminars in Immunology 16 (2004) 3–9 ,TLR signaling pathways, by Kiyoshi Takeda, Shizuo Akira. Here’s the abstract from this manuscript:

Toll-like receptors (TLRs) have been established to play an essential role in the activation of innate immunity by recognizing specific patterns of microbial components. TLR signaling pathways arise from intracytoplasmic TIR domains, which are conserved among all TLRs. Recent accumulating evidence has demonstrated that TIR domain-containing adaptors, such as MyD88,

TIRAP, and TRIF, modulate TLR signaling pathways. MyD88 is essential for the induction of inflammatory cytokines triggered by all TLRs. TIRAP is specifically involved in the MyD88-dependent pathway via TLR2 and TLR4, whereas TRIF is implicated in the TLR3- and TLR4-mediated MyD88-independent pathway. Thus, TIR domain-containing adaptors provide specificity of TLR signaling.

We know that BLPs are potent activators of Toll-like receptor-2 (TLR2). Thus, through TLR2, BLPs induces the synthesis of the precursor of the pro-inflammatory cytokine interleukin -1B (IL-1B). As shown in the figure below, TLRs can activate a transcription factor known as NF-kappa B which stimulates the gene expression for inflammatory cytokines.

BLPs also activates caspase 1 and potentiates apoptosis (programmed cell death) via this route.

The lipid moiety of the BLPs contains a part that is responsible for triggering the TLRs. A synthetic analog of this moiety is called: tripalmitoyl-S-glyceryl-Cys-Ser-Lys4-OH (Pam3Cys).

Other important inflammatory mediators triggered by BLPs in immune cells are tumor necrosis factor-alpha (TNF-α), IL-6, IL-12, INF-γ, and nitric oxide (NO).

A Major Medical Breakthrough; Dr. Trevor Marshall’s Angiotensin Discovery

The Angiotensin Hypothesis

Authors:

We have concluded that sunlight fuels the inflammation of sarcoidosis, via 1,25-D and Angiotensin II, in the following manner:

Normally this inflammatory cycle is self-limiting, but, in the case of sarcoid patients, 1,25-D levels are poorly controlled, leading to upregulated production of monocytes, and their upregulated differentiation into the macrophages and epithelioid giant cells characteristic of sarcoid granuloma.

Reichel, et al, demonstrated that lipopolysaccharide from gram-negative bacteria stimulated the generation of 1,25-D within pulmonary alveolar macrophages from sarcoid patients. A bacterial pathogenesis is therefore consistent with the initial increase in paracrine 1,25-D concentrations needed to trigger the run-away inflammatory biochemistry described above.

The blockade of A-II Type 1 receptors has been shown (in-vitro) to reduce production of the Th1 cytokines, including TNF-α, an action which would interdict this inflammatory process.

Angiotensin Receptor Blockers are currently indicated for hypertension. There is thus a simple clinical test of this hypothesis available for patients who are suffering both from Sarcoidosis and mild hypertension.

We have found that Benicar (Olmesartan Medoxomil), administered as 40mg every 6 to 8 hours, provides a very effective angiotensin blockade.

There are two issues in the selection and dosage of the ARB. As you can see from the pressor effect vs. dosage for Benicar (Figure 1), about 90% of the ultimate pressor effect can be achieved with only 40mg, once per day. But this dose is not well tolerated by sarcoid patients. Partly this may be the result of the additional Angiotensin receptors in the inflamed tissues, all of which have to be blocked, and partly it may be due to an increased production of serum ACE by macrophages in response to the partial blockade. Sarcoid patients experience symptoms ranging from increased fatigue to psychedelic dreams when prescribed ARBs just once daily, the customary prescription for hypertension

To be fully effective, we found that Benicar must be prescribed to sarcoidosis patients as 40mg every 6 to 8 hours. We found the ARB Diovan (Valsartan) to be less effective than Benicar, but it may be used at the 80mg q8h described in our earlier paper. Two patients reported sinus congestion with the Diovan blockade, which was not present after changing to Benicar. Controlled studies are needed to accurately define the blockade capability of each ARB, individually and in combination.

Vet Immunol Immunopathol. 1999 Feb 22;67(3):271-84.

Up-regulation of inducible nitric oxide synthase mRNA in dogs experimentally infected with Borrelia burgdorferi.

Harter L, Straubinger RK, Summers BA, Erb HN, Appel MJ.

James A. Baker Institute for Animal Health, College of Veterinary Medicine, Cornell University, Ithaca, NY 14853, USA.

Comparing the number of borrelia-positive tissues in dogs within Group A (acute

lameness) it was interesting to note that the dogs investigated on the first day of lameness

showed more borrelia-positive tissues than dogs from Days 2±4 of lameness. The mean of

the seven dogs with 1-day lameness was 72%, whereas the mean of the 3-day lameness

dogs was 36% (the single value for the 2-day lameness is 48%, for the 4-day lameness is

36%). This apparent decrease of the borrelia load during an episode of acute Lyme

arthritis may be a result of the host's inflammatory response. In contrast, the number of

iNOS-positive tissues increased from 40% for dogs with 1-day lameness to 64.3% for the

dog A96-2/3 with the 4-day lameness. While this might suggest the role for NO in

clearing B. burgdorferi from the infected tissues, the number of dogs investigated was not

sufficient to establish a reliable relationship between the borrelia load and the number of

iNOS-positive tissues during lameness. Further studies should clarify this point. The

milder and generally subclinical chronic Lyme arthritis, as represented by dogs from

Group B, is characterized by a lower number of borrelia-positive tissues and a lower

number of iNOS-positive tissues as well.

Immunol Lett. 1994 May;40(2):139-46.

Killing of Borrelia burgdorferi by macrophages is dependent on oxygen radicals and nitric oxide and can be enhanced by antibodies to outer surface proteins of the spirochete.

Modolell M, Schaible UE, Rittig M, Simon MM.

Max-Planck-Institut fur Immunbiologie, Freiburg, Germany.

Interaction of B. burgdorferi organisms with mouse bone marrow-derived macrophages (BMM phi) leads to phagocytosis of microorganisms, induction of nitric oxide (NO) and superoxide radicals (O2-) by BMM phi and killing of spirochetes. Destruction of spirochetes by BMM phi was quantified by a new method based on the release of radioactivity from spirochetes pre-labelled with [3H]adenine. Uptake of B. burgdorferi by BMM phi, which mainly occurs by coiling phagocytosis, generation of NO and O2- radicals as well as killing of spirochetes were significantly enhanced by pre-opsonization of spirochetes with monoclonal antibodies (mAb) to the outer surface proteins A and B but not with those to the periplasmic flagellin. Addition of inhibitors specific for NO and O2- radical synthesis either separately or together to cultures of BMM phi and spirochetes resulted in only partial reduction of the killing potential of effector cells. The data indicate that NO and O2- radicals are necessary, but not sufficient, for complete elimination of B. burgdorferi by macrophages. Together with previous findings that protection against B. burgdorferi infection is conveyed by humoral immune responses the present data indicate that one of the important functions of specific antibodies is their participation in macrophage-mediated control of spirochetes.

Decreased nitric oxide-mediated natural killer cell activation in chronic fatigue syndrome.

Ogawa M, Nishiura T, Yoshimura M, Horikawa Y, Yoshida H, Okajima Y, Matsumura I, Ishikawa J, Nakao H, Tomiyama Y, Kanayama Y, Kanakura Y, Matsuzawa Y.

Osaka University Medical School, Osaka, Japan.

BACKGROUND: L-Arginine (L-Arg), one of the essential amino acids, has been reported to have an immunomodulatory effect. The precise mechanism of the L-Arg-induced natural killer (NK) cell activation remains unresolved,and the effect of L-Arg on NK cells in chronic fatigue syndrome (CFS) patients has not been estimated. METHODS: NK cell function was evaluated in 20 subjects with CFS and compared with that in 21 healthy individuals. RESULTS: In healthy control subjects, NK activity was significantly increased after treatment with L-Arg, an NK function enhancer, for 24 h, whereas the same treatment failed to enhance NK activity in the CFS patients. We thus focused on L-Arg metabolism, which involves nitric oxide (NO) production through NO synthase (NOS). The expression of inducible NO synthase (iNOS) transcripts in peripheral blood mononuclear cells was not significantly different between healthy control subjects and CFS patients. The L-Arg-mediated NK cell activation was abolished by addition of NG-monomethyl-L-arginine, an inhibitor for iNOS. Furthermore, incubation with S-nitroso-N-acetyl-penicillamine, an NO donor, stimulated NK activity in healthy control subjects but not in CFS patients. CONCLUSION: These results demonstrate that the L-Arg-induced activation of NK activity is mediated by NO and that a possible dysfunction exists in the NO-mediated NK cell activation in CFS patients.

Infect Immun. 1994 Sep;62(9):3663-71.

The outer surface lipoproteins of Borrelia burgdorferi, OspA and OspB, stimulate the production of nitric oxide (NO) by murine bone marrow-derived macrophages from BALB/c, C3H/HeN, and C3H/HeJ mice. Gamma interferon (IFN-gamma) caused a three- to fivefold enhancement of this production of NO, and the L-arginine analog N-guanidino-monomethyl L-arginine inhibited it. Activation of transcription of the inducible NO synthase gene in stimulated macrophages was demonstrated by reverse transcriptase rapid PCR. Although IFN-gamma increased the amount of NO produced in macrophage cultures, it did not cause transcription of the inducible NO synthase gene greater than that seen with the Borrelia proteins. OspA and OspB also induced the production of high levels (40 to 150 ng/ml) of IFN-gamma in cultures of macrophages incubated with interleukin-2 (IL-2)-elicited cells from normal (T and NK cells) and scid (NK cells) mice but not in macrophages or IL-2-elicited cells cultured individually. This suggests that OspA stimulated macrophage production of cytokines, which, in turn, stimulated the production of IFN-gamma by NK and T cells. Reverse transcriptase rapid PCR demonstrated that OspA and sonicated B. burgdorferi stimulated production of several inflammatory cytokines in macrophage cultures, including IL-1, IL-6, IL-12, IFN-beta, and tumor necrosis factor alpha. As tumor necrosis factor alpha, IFN-beta, and IL-12 are potent activators of IFN-gamma production by T and NK cells, their presence in these cocultures could be responsible for the IFN-gamma production. Lymphocytes from infected C3H mice also produced IFN-gamma when stimulated with B. burgdorferi; thus, immune cells may also modulate NO responses. The generation of NO during infection with B. burgdorferi may be important, as NO has potent antimicrobial properties. NO can also be involved in pathological inflammatory processes in which its generation is detrimental to the host. Thus, the colocalization of B. burgdorferi lipoproteins, NO-producing cells, and regulatory cytokines may determine the outcome of infection.

Borrelia lack the microbial toxins called lipopolysaccharides (LPS) however, they have over 150 genes that encode for the BLPs that are the key to their pathogenicity. This is over 50 times greater than other pathogenic bacteria. That is, other bacteria usually only have 3 genes for lipoproteins, while borrelia have 150!

With this many BLPs triggering an imbalance of the immune system and other innate responses in the body, it’s not hard to see how a cascade of chronic problems can arise from this.

For example, when we look at psychological problems of neuroborreliosis, it’s clear that the cause of these symptoms arise from BLPs triggering encephalitis and that this inflammation not only causes imbalances in numerous neurotransmitters, it also causes vasculitis which leads to hypoperfusion and hypoxia of the brain.

These toxins also cause a channelopathy, which lead to a dysfunction of signals along neurons, muscles and cells making them easily excitable, but not able to discharge correctly…since the electrical potential across the cell membranes don't function normally.

This can attribute to numerous symptoms such as anxiety, paresthesias, hyperacusis, tremors and even susceptibility to static shock that many LD patients have.

Thus, the evidence is pretty clear that BLPs plays a large role in the pathogenesis of borreliosis and is a key to understanding this disease.

IMO, without BLPs, borrelia would not be virulent.

Some questions I’ve received regarding the pathogenesis of borreliosis:

Q: I don't see anything so far that would describe why these inflammatory mediators, which would be activating the T-cells, would not be phagocytized by these and other macrophages.

A: Initially it does. The initial infection of borrelia can be acute and flu-like or it may not even be noticable. Unfortunately, this initial immune response doesn't completely rid the body of borrelia.

I don't think we have the complete answer to why this happens. But there are probably several factors involved. Borrelia can adapt and be very stealthy. Another reasonable theory is that apoptosis of monocytes, macrophages, neutrophils and other immune cells triggered by TLR-2 stimulation may account for immune dysfunction and supression.

This makes a lot of sense to me since we see immune dysfunction & suppression in chronic LD and in CFIDS, which I believe have a very similar pathogenesis.

Q: Also, if it's somehow a more severe activation of these mediators, especially if caspase and IL-12 are involved, why is there not more obvious toxic shock-like symptoms apparent early on?

A: I wouldn't say that it's a more severe activation of these mediators, but more of a long term chronic/relapsing imbalance of them.

It may also have to do with borrelia's ability to grow slowly and not trigger an acute toxic shock.

It also may have something to do with borrelia's ability to hold on to it's BLPs and not release them into the surrounding tissue until they are killed.

We know that when we kill borrelia (such as with abx tx) the BLPs are released from them and we experience a herx reaction. In severe cases this response can be quite acute.

There are probably several other factors such as lipid depot effect and slow release.

The immune supressing effect of BLPs likely plays a role here too.

Q: It seems that many people are not even symptomatic until years after the original tick exposure.

A: This is true with borreliosis...(this happened in my case). It's also true with syphilis.

This may be due to borrelia's ability to code for so many different BLPs. They have the genetic code for over 150 different BLPs.

Depending on which ones and how strong the expression of these BLPs genes are may determine how virulent the borrelia is at different times.

We know that borrelia change the expression of these genes when exposed to different environmental factors such as temperature.

They express different BLPs in ticks since they are in ambient temperature, but once inside a mammal, they begin to change the BLPs that they express.

They also have an effective ability to accept plasmids and pick up other pathogenic genes in this way.

Work has shown that removing certain BLPs from virulent strains makes the borrelia avirulent.

The evidence is very suggestive that BLPs determines the pathogenesis of borrelia.

This work has appeared very timely for this discussion:

J Infect Dis. 2004 Jan 1; 189(1): 113-9. Epub 2003 Dec 22

Gebbia JA, Coleman JL, Benach JL.

Center for Infectious Diseases, Centers for Molecular Medicine, and State of New York Department of Health, Stony Brook University, Stony Brook, New York, USA.

Regulation of secretion of matrix metalloproteinase (MMP) underlies the basis of numerous physiological and pathological processes in multicellular organisms.

The Toll receptor family, which is conserved from Drosophila species to humans, mediates pattern recognition of a diversity of ligands involved in morphogenesis and innate immunity. Here, we show that secretion of MMP-9 is selectively induced through Toll-like receptor (TLR) 2 in human and murine monocytic cells stimulated with Borrelia burgdorferi.

Secretion of MMP-1 was shown to be stimulated through a pathway other than TLR2, under identical conditions. Analysis of nuclear extracts indicated that activator protein (AP)-1 was reduced in TLR2-neutralized monocytic cells, suggesting that AP-1 plays a role in the transcriptional activation of MMP-9 through TLR2.

The specific induction of MMP-9 through TLR2 provides direct evidence of a new role for this ancient receptor family in regulating secretion of MMPs and demonstrates evolutionary convergence between invertebrate morphogenesis and the vertebrate innate immune system.

Gulf-War-Syndrome (GWS) has very similar symptoms to chronic borreliosis.

Mycoplasma fermentans is being considered to be the likely pathogen...whether it is or not, it's likely some BLP producing microbe is.

Since the symptoms are similar, I'd expect the pathogenesis would be similar.

Work such as this indicates that this may be the case:

Into T, Kiura K, Yasuda M, Kataoka H, Inoue N, Hasebe A, Takeda K, Akira S, Shibata KI.

Departments of Oral Pathobiological Science and Oral Health Science, Hokkaido University Graduate School of Dental Medicine, Nishi 7, Kita 13, Kita-ku, Sapporo 060-8586, Japan. Department of Host Defense, Research Institute for Microbial Diseases, Osaka University, 3-1 Yamada-oka, Suita, Osaka 565-0871, Japan.

Mycoplasmal membrane diacylated lipoproteins not only initiate proinflammatory responses through Toll-like receptor (TLR) 2 and TLR6 via the activation of the transcriptional factor NF-kappaB, but also initiate apoptotic responses.

The aim of this study was to clarify the apoptotic machineries. Mycoplasma fermentans lipoproteins and a synthetic lipopeptide, MALP-2, showed cytocidal activity towards HEK293 cells transfected with a TLR2-encoding plasmid.

The activity was synergically augmented by co-expression of TLR6, but not by co-expression of other TLRs. Under the condition of co-expression of TLR2 and TLR6, the lipoproteins could induce maximum NF-kappaB activation and apoptotic cell death in the cells 6 h and 24 h after stimulation respectively.

Dominant-negative forms of MyD88 and FADD, but not IRAK-4, reduced the cytocidal activity of the lipoproteins. In addition, both dominant-negative forms also downregulated the activation of both NF-kappaB and caspase-8 in the cells.

Additionally, the cytocidal activity was sufficiently attenuated by a selective inhibitor of p38 MAPK.

These findings suggest that mycoplasmal lipoproteins can trigger TLR2- and TLR6-mediated sequential bifurcate responses: NF-kappaB activation as an early event, which is partially mediated by MyD88 and FADD; and apoptosis as a later event, which is regulated by p38 MAPK as well as by MyD88 and FADD.

In regards to this and other work showing that BLPs stimulates MMP-9, what this means is that the BLPs of borrelia have the ability to turn our own immunes system against the extracellular proteins of our body.

Extracellular proteins (ECP) make up the "mortar" between our cells, ie, it’s what holds the cells together in tissues.

There are several proteins in ECP: collagen, elastin, gelatin, and several others.

BLPs have the ability (thru TLR-2) to trigger our immune system to produce and release protease enzymes that digest these important ECPs. These include proteases such as collegenase, and elastase.

This protease activity is very damaging to tissues and itself can stimulate even more inflammation.

Borrelia takes advantage of these protease enzymes to penetrate through the tissues of the body. As ECPs are digested in tissues it is easier for borrelia to move through it.

This portion of the pathogenesis of borrelia explains a lot of the fibromyalgia symptoms in LD.

IMO, FMS/CFIDS and borreliosis/Lyme disease have a similar pathogenesis, which is TLR triggering by the BLPs or LPS of pathogenic microbes.

Borrelia also have an affinity for the endothelial cells lining the inside of blood vessels. They attach and infect the endothelial cells of blood vessels and trigger inflammation in these infected blood vessels (vasculitis) wherever they reside in the body. In other words, once the Borrelia infects the endothelial cells, they stimulate vasculitis of the blood vessel. Vasculitis of the nervous system, skin, muscle, tendons, and connective tissue explains much of the disease and clinical symptoms caused by Borrelia.

Borrelia species have several other characteristics that make them a challenging pathogen. They can reside and grow intracellularly (inside the cells); out of reach of the host’s immune system. By rotating their filaments, the spirochetes are able to move throughout the body in a corkscrew fashion; invading tissue, penetrating cells, replicating, and destroying the host cells they infect. The spirochetes hide their flagella, which are normally antigenic, from the host immune defenses. As Borrelia emerge from host cells they can wrap themselves with the membrane of the host cell, thus concealing themselves from the hosts immune system.

Borrelia’s ability to grow slowly and avoid attack by the host’s immune system makes it a difficult pathogen to destroy. Not only can borrelia evade the host immune system, but often will suppress it as well.

It’s also important to remember that borellia can go dormant in the body for lengthy periods of time. Then it can return to cause disease at any time.

The Early Symptoms of Lyme Disease

It’s important to remember that fewer than 50% of patients with LD will initially have the skin rash called erythema migrans (EM). An EM rash with a round red ring and a central clearing (see figure 10) is called a bulls-eye rash and it is diagnostic for Lyme disease. In other words, a bulls-eye rash is enough evidence to confirm a diagnosis of LD. However, I emphasize that EM is seen in less than 50% of infected individuals with Lyme disease. The reason I stress this is because many physicians think they must see an EM rash and have laboratory confirmation before they will make a diagnosis of Lyme disease. But, if less than 50% of LD cases have an EM rash, physicians misdiagnose these early clinical cases of Lyme disease and the prognosis for these mistreated patients deteriorates with time.

Figure 10: The presentation of erythema migrans in early borreliosis

If present, the EM rash appears between 3 days to 1 month following the bite of an infected tick; however, the rash typically resolves itself spontaneously over a 2-4 week period. The EM rash grows concentrically over the following 5-10 days and without treatment may last for up to several weeks. The rash can vary from very small to very large (up to twelve inches across). Unfortunately, the EM rash is not the only rash associated with Lyme. Various other rashes associated with LD have been reported. One tick bite can cause multiple rashes. The rash can mimic such skin problems as hives, eczema, sunburn, poison ivy, fleabites, etc. The rash can itch, feel hot or it may even be asymptomatic and go unnoticed. The rash can disappear and return several weeks later. I recommend taking a photograph of any rash, especially if associated with a tick bite. The photos will help the Lyme knowledgeable physician make a proper diagnosis and prescribe the appropriate treatment.

All rashes that occur at the site of a tick bite are not due to Lyme disease. An allergic reaction to tick saliva often occurs at the site of a tick bite. This rash can be confused with the rash of Lyme disease. Allergic reactions to tick saliva usually occur within hours to a few days after the tick bite; they usually do not expand and disappear within a few days. EM rashes caused by Lyme disease persist longer, but usually subside within a few weeks.

The occurrence of multiple EM skin rashes is indicative of systemic spread of the organisms. Multiple EM lesions usually do not occur until after 2-4 weeks following the initial tick bite. This is the same time period during which the organisms are being spread throughout the body to other tissues and cells.

Borrelia Slowly Spreads Throughout the Body -- Approximately 4-6 weeks following the tick bite, the first systemic signs of Lyme disease that may or may not occur are in the form of flu-like symptoms or malaise. These symptoms include sore throat, severe headaches and neck aches, severe fatigue, chills and fever, and swollen lymph nodes. Upper respiratory symptoms are usually not present with LD, distinguishing it from other flu-like illnesses. While the LD-flu symptoms can spontaneously resolve themselves, patients can experience relapses.

Soon after the onset of Lyme-flu, arthralgias and/or myalgias (muscle and joint pain) may begin. The arthralgias appear to primarily involve the large joints (i.e. knees, elbows, hips, shoulders), although smaller joints (e.g. wrists, hands, fingers, toes) may be involved. The pains are generally described as severe, jumping from joint to joint, and may be present for only short periods of time. Pain in the teeth and in the temporal-mandibular joints (jaw) is common. Neurological involvement will cause associated paresthesias (muscle twitching, burning sensations, prickling / shooting pains, and numbness). Lyme disease can cause palsy of affected areas, but it’s more likely to cause neurosensory deficits before neuromotor disease.

Facial nerve (Bell's) palsy is another neurological symptom of Lyme disease. Encephalitis or encephalopathy may manifest as cognitive dysfunction, including short-term memory loss, and psychiatric symptoms such as panic, anxiety, or depression. The encephalitis and facial paralysis tend to occur within the first few months following the tick bite, but may also occur as part of a relapse at any time.

Other symptoms in this stage of the disease may include blurred vision, uveitis, ringing in the ear (tinnitus, which was one of my first symtoms) and/or hearing loss, shortness of breath, palpitations or tachycardia (rapid heart rate), chest pains, abdominal pains, diarrhea or irritable bowel, testicular or pelvic pain, urinary incontinence/urgency, dizziness, tremors, dysautonomia, and hepatitis.

Borreliosis: The Clinical Disease

Lingering Lyme: The Chronic Persistent Infection

Some symptoms and signs of Lyme disease may not appear until weeks, months, or years after a tick bite. This stage typically involves intermittent episodes of joint pain or numerous neurological symptoms such as: meningitis, Bell's palsy, dysfunction of cardiac rhythm, and migratory pain to joints, tendons, muscle and bone. Arthritis is most likely to appear as brief bouts of pain and swelling, usually in one or more large joints, especially the knees. In some patients, the first and only sign of Lyme disease is arthritis. In others, nervous system problems are the only evidence of Lyme disease. However, any combination of symptoms can be present.

Primarily unique to humans, neuroborreliosis (the neurological form of Lyme disease) can include numbness, pain, Bell's palsy (paralysis of the facial muscles, usually on one side and more often the left), and meningitis (fever, stiff neck, and severe headache). Dysautonomia (a dysfunctioning autonomic nervous system) and irregularities of the heart rhythm may occur.

In a minority of individuals (11%), development of chronic Lyme arthritis may lead to erosion of cartilage and/or bone. Other clinical manifestations associated with chronic neuroborreliosis include neurologic complications such as disturbances in memory, mood, or sleep patterns, and sensations of numbness and tingling in the hands or feet (parethesia).

The course of the disease can best be described as persistent, with periods of worsening symptoms, often cyclical every few weeks or monthly. Especially disconcerting are persistent symptoms such as pain, headaches and fatigue. Some patients are more symptomatic than are others, which may reflect gender and genetically-determined differences in response to infection. The disease is progressive, destructive, and debilitating, and in severe untreated cases, it can be fatal.

Chronic Borrelia can also cause a degenerative skin disorder now known as acrodermatitis chronica atrophicans (ACA).

Lyme disease causes metabolic/endocrine dysfunctions that lead to weight loss or commonly chronic weight gain.

Generally, women struggle with chronic Lyme disease more severely than men do. It is not known for sure why.

List of Lyme Disease Symptoms

Epidemiol Mikrobiol Imunol. 2001 Feb;50(1):10-6.

Persistence of Borrelia burgdorferi sensu lato in patients with Lyme borreliosis

Honegr K, Hulinska D, Dostal V, Gebousky P, Hankova E, Horacek J, Vyslouzil L, Havlasova J.

Infekcni klinika, Fakultni nemocnice, Hradec Kralove.

In 18 patients with Lyme borreliosis the authors proved the persistence of Borrelia burgdorferi sensu lato by detection of the causal agent by immune electron microscopy or of its DNA by PCR in plasma or cerebrospinal fluid after an interval of 4-68 months. Clinical manifestations common in Lyme borreliosis were present in only half the patients, in the remainder non-specific symptoms were found. In nine subjects with confirmed Borrelia burgdorferi sensu lato in the cerebrospinal fluid the cytological and biochemical finding was normal. Examination of antibodies by the ELISA method was negative in 7 of 18 patients during the first examination and in 12 of 18 during the second examination. In all negative examinations the specific antibodies were assessed by the Western blot or ELISA method after liberation from the immunocomplexes. In the authors' opinion it is advisable to examine repeatedly plasma and other biological material from potentially affected organs by PCR and subjects with persisting or relapsing complaints after the acute form of Lyme borreliosis as well as to examine cerebrospinal fluid in case on non-specific symptoms and concurrent pathic EEG or MR findings.

The Treatment of Lyme Disease

Our understanding of treating this disease has made a great leap recently with the discovery of Dr. Marshall’s work.

The best approach to therapy is a multifaceted and comprehensive treatment regimen that includes conventional antibiotics, numerous complimentary and alternative therapies, and a nutritional regimen specifically designed to reduce inflammation, aid the liver in detoxifying the BLPs, decrease the risk of yeast infections, repair damage caused by the disease and strengthen the immune system.

The mainstay of treating chronic borreliosis is to follow Dr. Marshall’s protocol for sarcoidosis found here: www.sarcinfo.com. This comprehensive therapeutic approach is much more effective than the conventional treatment that uses only a single therapeutic entity such as antibiotics alone.

Antimicrobial Therapy: The Conventional Treatment -- Antibiotics are the foundation of conventional Lyme disease therapy. We are often told by the medical establishment and the general media that Lyme disease is easily treated with antibiotics. Unfortunately, in most cases, this is not true. If caught early, then yes, Lyme disease can be treated relatively well with only antibiotics. But, as I mentioned earlier, most of the time it’s not caught early and once the borrelia has spread throughout the body and secondary symptoms have occurred, treatment gets much more complicated and less effective.

Oral therapy with doxycycline, minocycline, tetracycline or amoxicillin is appropriate for early cases of Lyme disease. Parenteral therapy, usually intravenous (IV) administration, maybe used for patients with neurologic involvement, severe arthritis, or any life-threatening manifestation of Lyme disease such as complete heart block. However, there’s good evidence to suggest that oral therapy can be just as effective if not more so in most cases.

If you can’t find a LLMD in your area and can’t get in to see one on a timely basis there are places you can order prescription medication without a prescription such as this: http://www.edrugnet.com or www.rxsolutions.com.

The treatment of patients with chronic Lyme disease is very controversial. The more I study the chronic symptoms of Lyme disease, the more I believe that the persistence of the disease is caused by a persistent borrelia infection and the persistent or residual presence of fat-soluble BLPs that can depot in the lipid tissues throughout the body and in many cases lead to immune dysfunction. Permanent damage can also occur throughout different stages of disease and cause chronic symptoms to persist.

Borrelia species are sensitive to several oral antibiotics including: amoxicillin, tetracycline, doxycycline, minocycline, clarithromycin (Biaxin®), metronidazole (Flagyl®), co-trimoxazole sulfamethoxazole/trimethoprim (Bactrim® or Septra®) and azithromycin (Zithromycin®).

Early in Lyme disease at the time of the early skin EM rash, any one of the above antibiotics appears to be effective if given for at least 2 months. Antibiotic treatment of only 2-3 weeks is insufficient and patients often deteriorate with chronic symptoms of borreliosis including; arthralgias, fatigue, and paresthesias. Thus, LLMDs recommend that tetracycline, doxycycline, minocycline or amoxicillin be used for at least 2 months if an EM rash is the first and only symptom of Lyme disease.

If any other symptoms appear after an EM rash, the treatment of LD for only 2-4 weeks frequently fails and relapses occur. LLMDs suggest that several months of doxycycline, minocycline or other appropriate antibiotics have a higher success. In patients with symptoms present for more than six months, the treatment course may need to be more prolonged, or a retreatment course of varying length may be needed. In patients with symptoms for more than a year, several months or years may be needed for complete resolution of symptoms. In general, treatment for chronic LD usually requires a period of time equal to or greater than the time the patient has had the disease. The slow growth rate and the cryptic and stealthy nature of borrelia justify the need for longer antimicrobial treatment periods.

When Some Symptoms are a Diagnostic Sign: The Jarisch-Herxheimer Reaction to Treatment

Once treatment is initiated for patients beyond the EM stage, their symptoms frequently increase during the first several days, or even for the first two weeks of therapy. This reaction is called a Jarisch-Herxheimer reaction (herx) and is the body’s response to the BLPs being released from the dying borrelia. These BLPs stimulate the inflammatory cascade which explains this phenomenon. The herx reaction is a very helpful clinical symptom Lyme clinicians use to support a clinical diagnosis of Lyme disease.

For patients with preexisting symptoms of more than a few months, relief of any of their symptoms may not occur until after 4-6 weeks of therapy. Typically, there are short periods of relief, followed by relapsing or migrating symptoms. With continued therapy, there are longer symptom-free periods. Some arthralgias may require several months of therapy to resolve, and fatigue and dizziness may be the last symptom to resolve.

The preference for a variety of antibioitics by some LLMDs is based on a large number of failures that were noted in patients who had been on only amoxicillin, or doxycycline. It seemed that patients generally have some initial relief, but then plateau. It’s not clear if tetracycline is as effective as doxycycline; some claim it is not while others say it is better. There are some physicians who use doxycycline at high doses of 600mg daily to achieve a more successful result. It’s my opinion that low to moderate doses of antibiotics is more appropriate. See the work of Dr. Brown: www.roadback.org.

Metronidazole (Flagyl) is a very effective antimicrobial for treating chronic Lyme disease. It distributes well throughout the body and is able to penetrate tissue and cells. This ability allows metronidazole to reach the cryptic borrelia throughout the body and kill it. Metronidazole is also effective at attacking the cyst form of borrelia. This may be the single most effective antimicrobial pharmaceutical for treating Lyme disease. The disadvantage of metronidazole is it’s toxicity to the liver and neurological system. It can raise liver enzymes and cause peripheral neuropathies similar to LD itself. These side-effects must be prudently monitored.

Of the beta lactams used for the treatment of Lyme disease, the most effective appears to be ceftriaxone (Rocephin). In limited comparitive trials, cefotaxime appears to be equally effective, and high-dose IV penicillin is too. In early stages of LD, oral amoxicillin is as effective as doxycycline. In later stages, however, many failures are noted, despite the use of up to 3 grams of amoxicillin daily.

The newer macrolides such as azithromycin, roxithromyin and clarithromycin are effective. LLMDs often use clarithromycin and azithromycin in higher dosages for longer periods of time than regularly recommended for these antibiotics.

In evaluating all of the possible factors, it would appear that antibiotics that can inhibit the bacteria’s ability to synthesize toxic bacterial lipoproteins and achieve intracellular concentrations are the most efficacious drugs. The results fit with clinical experience that the tetracyclines, (minocycline, doxycycline), sulfamethoxazole/trimethprim, lincosamides (clindamycin) and the macrolides (clarithromycin and azithromycin) achieve the greatest success.

Fortunately, there have been no reports showing any change in antibiotic resistance patterns regarding antibiotic susceptibility of the specific borrelial organisms in a given case.

Again, my personal preference is use of low-dose antibiotics such as doxycycline or minocycline.

Combinations of Antibiotics

Antibiotics that inhibit protein synthesis

Antibiotics that inhibit protein synthesis will also inhibit the production of BLPs by borrelia. This can be a useful tool for reducing the load of BLPs the body must deal with. Since the BLPs trigger the disease and the symptoms of borreliosis, reducing their production would be of significant benefit.

The tetracyclines including: tetracycline, doxycycline, minocycline; inhibit protein synthesis in bacteria. They do this by binding to the 30S unit of the bacterial ribosome. This binding blocks the bacteria’s ability to synthesize proteins. Unfortunately, this binding is reversible. So, they must continued to be used until the bacteria die or are cleared from the body.

Macrolides and Lincosamides

The most widely used macrolides for LD are azithromycin and clarithromycin. These are relatively non-toxic antibiotics. Macrolides binds to the 50S ribosomal subunit and inhibits either peptidyl transferase activity or translocation of the growing peptide.

Clindamycin which is a lincosamide, has a similar mode of action as the macrolides.

Adjunct Anti-Microbial Therapies

http://health.groups.yahoo.com/group/Magpulser/?yguid=159339971

http://www.magnetcure.com/reports.html

Rife Machine -- Rife machines are electronic devices that produce varying frequencies of energy (similar to a microwave, but at frequencies not harmful to the body). This energy penetrate the tissues of the body and cause the spiral-shaped Borrelia to resonate so much that the integrity of the bacteria is disrupted; weakening and even killing them. This is an effective means for killing borrelia and is supported by the production of herx reactions in Lyme patients after Rife treatments, while non-infected individuals don’t experience the herx reactions when exposed to rife treatment. Rife machines are not approved by the FDA and are relatively expensive. A reasonable price for a good machine is about $1,000. Homemade ones can be much less expensive and just as effective. Here is a message board that I follow and participate in where the members discuss numerous alternative therapies including rifing: http://health.groups.yahoo.com/group/Lyme-and-rife/

Beck Electrification -- Low-voltage electrification is also useful for disrupting the integrity of microbes including borrelia. It may also enhance the ability of antibiotics to penetrate the cells of the body so they can reach the hidden intracellular borrelia. Herx reactions after treatment also substantiate the effect of this therapy.

Lauricidin -- The monoglyceride of lauric acid is called monolaurin. The concentrated form of monolaurin has potent antibacterial properties. While nontoxic and approved as a direct food additive by the FDA, monolaurin adversely affects bacteria, yeast, fungi, and enveloped viruses.  It damages the cell membrane of pathogenic bacteria.

www.lauricidin.com

Colloidal Silver -- Colloidal silver therapy for Lyme disease appears to be significantly effective with many individuals that have used it. There is much controversy regarding this therapy. Argyria, is the name of the condition in which the skin turns bluish-gray from silver. This is very rare and is linked to the use of silver salts and not pure colloidal silver. It appears to be important to use pure colloidal silver. The size of the colloidal particles is also important. The smaller the particles size of CS the better the bioavailability, the stronger the anti-microbial effect and the safer to use.

Cat’s Claw / Samento / Saventero – A Peruvian herb (Uncaria tomentosa) is quickly becoming a rising star within the LD community. It appears to have both anti-microbial and anti-inflammatory properties both of which are significantly effective. Tolerance is a question for some. It can cause anxiety, insomnia, and irritability in certain individuals. Adjusting the dose appropriately can control this side-effect. Even at very low doses it seems to be beneficial.

Artemisinin – Is the active constituent of the herb (Artemesia annua). Tea made from this herb has been used in Asia to successfully treat malaria. Artemisinin (pronounced art-ee-MISS-in-in) is the preferred antimalarial therapy. It is also being used to treat cancer in veterinary medicine and is an effective anti-parasite and anti-microbial treatment.

Artemisinin also seems effective in treating LD. There are many testimonials from users claiming significant benefits.

Goldenseal root – The best brand out there is may be Eclectic Institute's freeze-dried goldenseal root.

Teasel – Another effective herbal therapy.

Olive Leaf Extract – (Oleuropein) Must be taken at high doses though. Take 1500 – 2000 mg three times per day.

Garlic – Antimicrobial and helps reduce blood clotting. Use fresh garlic or freeze-dried supplements.

European (or Hungarian) Mistletoe – There is a little information that this may be beneficial for LD as an antimicrobial.

Peroxide – Is a potent antiseptic but I’m concerned about the safety of oral and IV administration.

Ozone – Similar concern as with peroxide.

Controlling Inflammation and the Immune Dysfunction

Protecting the Nervous System from Neurotoxins

Detoxifying and Excreting the Toxins of Borrelia

NAC (N-acetyl-cysteine): The best supplement that increases the production of glutathione, which is used in detoxification.

Taurine: An amino acid that aids in detoxification by providing a good source of sulfur.

Immune Modulation

Tick Protection and Prevention

If an attached tick is found on your body, remove it carefully with fine tweezers. Grab the tick as closely to the skin as possible. Do not squeeze the body; do not apply Vaseline; do not touch the tick with a burnt match; and do not clean it with alcohol while the tick is attached. Any of these actions could cause transmission of Lyme disease by causing the tick to regurgitate the borrelia bacteria that live in their gut into the skin where it is attached. Ticks can be identified and tested for the bacteria. However, Borrelia frequently cannot be grown in the laboratory due to its fastidious nature and so nothing shows up. It’s still important to save the tick for identification as a possible vector. Place the tick in a glass or plastic vial with a few blades of moist grass or a moistened cotton ball. A clean pill vile is good. If none is available, use a Ziploc storage bag as a temporary container.

Stop It Before It Starts

Vaccine

Animals

What Can You Do?

First of all, prevention is the best cure. If you have to be outside, use insect repellent with deet. Take a hot shower as soon as you can and check, in your hair especially, for any ticks. Since it is believed that a tick needs to be on your skin for at least 24 hours before spreading the disease, this prevention could save you in the long run. Strongly consider prophylactic antibiotics when bitten by a tick.

If you are suffering with a number of different symptoms and you aren’t quite sure what you have, don’t rule out Lyme disease. This disease is called "the great imitator" and you don’t need a rash on your body to have it. If these symptoms have been going on for a while and you think there is a chance, I would strongly recommend contacting a Lyme disease specialist. One specialist that I know is Dr. Charles Crist in Springfield, MO (417) 886-8389. Here’s his website: www.drcharlescrist.com. For more information about doctors that have worked with LD patients in the state of Iowa, you can contact Judy Weeg who is with the Central Iowa Lyme Disesase Association at (515) 388-1401.

You can find great support at thes websites: www.MarshallProtocol.com and www.lymenet.org