The causative agent of tick borne encephalitis is the whole truth about a terrible disease

Tick-borne encephalitis

Tick-borne encephalitis virus (TBEV) of the family Flaviviridae. Three subtypes of the causative agent are known: the European (Western), the Far Eastern (spring-and-summer encephalitis) and the Siberian.

Transmission

TBEV is transmitted by the bite of infected ticks (which often remain firmly attached to the skin for days) or occasionally by ingestion of unpasteurized milk. There is no direct person-to-person transmission.

Nature of the disease

Infection may induce an influenza-like illness followed, in about 30% of cases, by high fever and signs of central nervous involvement. Encephalitis developing during this second phase may result in paralysis, permanent sequelae or death. Severity of illness increases with age of the patient.

Geographical distribution

Tick-borne encephalitis (TBE) tends to occur focally even within endemic areas. Currently, the highest incidences of clinical cases are being reported from foci in the Baltic States, the Russian Federation and Slovenia. High incidencesare also reported from foci in the North-Western Federal Area of the Russian Federation. Other countries that have reported cases within their territories, or that are considered to be at risk because of focally high prevalence of the virus in ticks, include Albania, Austria, Belarus, Bosnia, Bulgaria, China, Croatia, Denmark, Finland, Germany, Greece, Hungary, Italy, Mongolia, Norway, Poland, the Republic of Korea, Romania, Serbia, Slovakia, Slovenia, Sweden, Switzerland, Turkey and Ukraine.

Risk for travellers

Travellers to endemic areas may be at risk during April to November. The risk is highest when hiking or camping in forested areas up to an altitude of about 1500 m.

Precautions

Prevent blood-feeding ticks from becoming attached to the skin by wearing appropriate clothing, including long trousers and closed footwear, when hiking or camping in countries or areas at risk. The whole body should be inspected daily and attached ticks removed as soon as possible. The consumption of unpasteurized dairy products should also be avoided in those areas.

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Feel Bad? It Could Be Lyme Unless Proven Otherwise

Do you have symptoms that come and go? Are you on a medication merry go round? Have you been to 10 or 20 doctors without relief? Maybe you’ve been misdiagnosed.

Lyme disease, caused by Borrelia burgdorferi, is the No. 1 vector borne spreading epidemic worldwide. People often attribute uncomfortable symptoms to aging, stress, or the “aches and pains of daily living,” especially if blood tests and body scans are normal. What if you have Lyme and don’t know it?

It’s not uncommon to get Lyme. If you’ve ever been for a walk in the woods, laid in the grass, live in or visited a Lyme-endemic area, or have a pet cat or dog, you may have exposed yourself to Lyme disease and associated co-infections. There is even the possibility of contracting Lyme if you were born to a mother who has been exposed. Tick born infections can also be transmitted from blood transfusions. This is scary, as Lyme has been found to persist in stored blood, and Ehrlichia and Babesia (two co-infections) have been reported in patients receiving blood transfusions.

Lyme Looks Like Other Diseases

Symptoms of Lyme vary, and you’re more likely to express the disease if your immunity goes down and stress goes up. One clue is that discomfort plagues you! It’s like a spinning dial, changing symptoms every hour, or day. You see, Lyme is a multi-systemic illness, and may affect every part of the body causing fatigue, stiff neck, headaches, light and sound sensitivity, tinnitus (ringing in the ears), anemia, dizziness, joint and muscle pain, brain fog, tingling, numbness and burning sensations of the extremities, memory and concentration problems, difficulties with sleep (both falling asleep and frequent awakening), chest pain and palpitations and/or psychiatric symptoms like depression and anxiety.

I interviewed Dr. Richard Horowitz, a board-certified internist in Hyde Park, N.Y., who has treated more than 12,000 chronically-ill patients with Lyme disease. This expert physician has noticed the trend of varying symptoms. He’s dubbed it “Lyme-MSIDS,” short for Multiple Systemic Infectious Disease Syndrome.

MSIDS is like Pandora’s box. It involves not only the bacterial and parasitic infections mentioned above, but also associated viral and fungal infections, immune issues, inflammation, hormonal disorders, mitochondrial dysfunction (the mitochondria are the part of the cells responsible for energy production), sleep disorders, environmental toxins with heavy metals, and detoxification problems.

Dr. Horowitz’s book, Why Can’t I Get Better? Solving the Mystery of Lyme and Chronic Disease (St. Martin’s Press), presents a comprehensive diagnostic and treatment plan for those suffering from chronic, unrelenting symptoms, for those with Lyme disease, chronic fatigue syndrome, fibromyalgia or any chronic illness. I highly recommend his book, and you can buy it from Amazon.

Dr. Horowitz explained:

The majority of my patients suffer not only from Lyme disease, but a host of associated tick-borne infections, such as Borrelia hermsii (relapsing fever), Babesia, Bartonella, Mycoplasma, Chlamydia, Rocky mountain spotted fever, Q-fever, Ehrlichia or Anaplasma. Rarely, I see a patient presenting with Tularemia and Brucellosis. To see Borrelia burgdorferi by itself is unusual.

This collection of bugs and associated illness explains why the standard treatment protocol (consisting of 30 days antibiotic therapy) doesn’t offer the cure for most sufferers. You can’t just blow up bugs. Detoxification, hormone balancing, heavy metal removal and ramping up immune function are equally important.

Your Symptoms Are Real Even If Your Doctor Can’t See Them

So if ticks are dumping their garbage into our bloodstream, causing various symptoms and organ damage, imagine how difficult it might be to get accurate diagnosis. Go to your physician, and you’ll likely be diagnosed with depression, chronic fatigue syndrome (CFS or Myalgic Encephalomyelitis), fibromyalgia, an autoimmune disease such as rheumatoid arthritis or multiple sclerosis, ALS, Parkinson’s disease or others. Worst of all, you could be told it’s all in your head. In one sense that’s true, Lyme definitely penetrates brain tissue! The consequences of misdiagnosis are lifelong because you will end up buying prescription drugs and supplements for a disease you don’t have, and you’ll probably never find complete relief. My article will inform and stun you all at once, “Long History of Pain? Think Chronic Lyme.”

Conventional blood tests from regular labs are highly unreliable for Lyme. So are blood tests associated with other tick-borne infections such as Bartonella (cat scratch disease) and Babesiosis (a malarial type illness that causes day sweats, night sweats, chills, air hunger and an unexplained cough). How can you figure this out if blood tests are iffy?

To Me, It’s Lyme Until Proven Otherwise

Suspect Lyme disease (and associated co-infections) if you have symptoms that come and go, causing good and bad days; the joint pain and muscle pain often migrates around your body, as does the tingling, numbness and burning sensations (Lyme neuropathy). Women often complain of a worsening of symptoms around their cycle (either right before, during, or after the menstrual cycle, it differs). Symptoms could worsen on antibiotics, if you get a Herxheimer die-off reaction. Sometimes symptoms abate with antibiotic treatment because you’re reducing microbial load.

Lyme is a clinical diagnosis, and confirming the diagnosis of Borrelia burgdorferi (the causative agent of Lyme disease) through a reliable lab is important. I recommend IgeneX laboratory in California, because they specialize in tick-borne testing, and can detect at least two common strains of the organism.

If you insist on using a local laboratory, ask your doctor to order an IgM and IgG Western Blot for Lyme disease. An ELISA or C6 Lyme Elisa peptide can be ordered, but those test(s) may still miss 50 percent or more cases. Don’t completely rely on them.

If you get a positive IgM (with chronic symptoms) you may be told it’s a false positive. I disagree. Doctors and practitioners like myself who belong to the International Lyme and Associated Diseases Society (ILADS) see patients with positive IgM antibodies in chronic Lyme all the time, and the medical literature has confirmed that this is possible. A positive IgM antibody means that you have definitely been exposed and should be treated appropriately, especially if other diagnoses for your symptoms have been ruled out.

How else can you know that you have been exposed to Lyme?

Your Western blot blood test should check for specific bands on the Western Blot (outer surface proteins of the bacteria) that are indicative of exposure to Borrelia. These include the 23 kdA, 31 kdA, 34 kdA, 39 kdA, and the 83/93 kdA bands.

Assuming you have the above classic multi systemic symptoms, and your Western Blot is positive for any of the above bands (without having received LymeriX vaccine), I’d suspect Lyme.

Most physicians agree that tick bites can transmit Lyme but many dismiss you unless a bullseye rash occurs at the site of the bite. But how silly (and potentially deadly) since only 50 percent of people ever get that rash and most people never even see a tick! They are tiny, but their health consequences are massive!

It’s awful that there is such a stealth group of organisms, hard to detect, almost impossible to eradicate, and it mimics hundreds of diseases causing untold suffering every day in countries across the globe. Unreal. If you think you have Lyme disease, please find a doctor well versed in diagnosing and treating tick-borne diseases such as those who belong to ILADS. Get yourself treated properly as fast as you can because the longer you wait, the more symptoms occur. One more thing: Pets have the ability to infect you indirectly, so read “Can Your Pet Cause Illness?”

Fallon, B., et al., Psychiatric manifestations of Lyme borreliosis, Jour of Clin Psychiatry 1993;54(7):263-68.

Fallon, B., et al., Late-stage neuropsychiatric Lyme borreliosis. Differential diagnosis and treatment, Psychosomatics 1995;36(3):295-300.

Georglis, K., et al., Fibroblasts protect the Lyme disease spirochete, Borrelia burgdorferi, from ceftriaxone in vitro, Jour of Infectious Diseases 1992;166(2):440-44.

Girschick, H. et al., Intracellular persistance of Borrelia burgdorferi in human synovial cells, Rheumatology International 1996;16(3):125-32.

Halperin, J., et al., Lyme disease cause of a treatable peripheral neuropathy,” Neurology 1987; 37(11):1700-06

Hammond, R., et al., Alzheimer’s disease and spirochetes; a questionable relationship, Neuroreport 1993;4(7):840.

Hess, Al, et al., Borrelia burgdorferi central nervous system infection presenting as an organic schizophrenia-like disorder, Biological Psychiatry 1999;45(6):795.

Horowitz, Richard, Why Can’t I Get Better? Solving the Mystery of Lyme and Chronic Disease, St. Martin’s Press, October 2013.

Kohler, J., Lyme borreliosis in neurology and psychiatry, Fortschrift Med 1990;108(10):191-93, 97.

Legigian, E., Peripheral nervous system Lyme borreliosis, Seminars in Neurology 1997; March, 25-9.

Miklossy, J., Alzheimer’s disease, a spirochetosis?, Neuroreport 1993;4(9):1069.

Pachner, A., et al., The triad of neurologic manifestations of Lyme disease: meningitis, cranial neuritis, and radioculoneuritis, Neurology 1985;35(1):47-53.

Pachner, A., Neurologic manifestations of Lyme disease, the new ‘great imitator,’ Review of Infectious Diseases 1989;11(Suppl 6):S1482-26.

Pachner, A., et al., Central nervous system manifestations of Lyme disease, Archives of Neurology 1989;46(7):790-95.

Pfister, H., et al., Catatonic syndrome in acute severe encephalitis due to Borrelia burgdorferi infection, Neurology 1993;43(2):433-35.

Preac-Mursic, V., et al, Survival of B. burgdorferi antibiotically treated patients with Lyme borreliosis, Infection 1989;17:355.

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Reik, L., et al, Neurologic abnormalities of Lyme disease, Medicine 1979;58:281-94.
Ross, Marty & Brook, Tara., Supplements and Advanced Treatments for Lyme and Associated Diseases. www.TreatLyme.net

Steere, A., et al., Lyme arthritis: A new clinical entity, Hospital Practice 1978;13(4):143-58.

Stein, S., et al., A 25-year-old woman with hallucinations, hypersexuality, nightmares, and a rash, Amer J of Psychiatry, 1996;153(4):545-51.

Waisbren, B., et al., Borrelia burgdorferi antibodies and amyotrophic lateral sclerosis, Lancet 1987;2(8554):332-33.

Zhang, J., et al., Antigenic variation in Lyme disease Borreliae by promiscuous recombination of VMP-like sequence cassettes, Cell 1997;89(2):275-85.

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Lyme Disease

What is Lyme Disease?

Lyme disease (LD) is an infection caused by Borrelia burgdorferi, a type of bacterium called a spirochete (pronounced spy-ro-keet) that is carried by deer ticks( Click here for pictures of deer ticks ). An infected tick can transmit the spirochete to the humans and animals it bites. Untreated, the bacterium travels through the bloodstream, establishes itself in various body tissues, and can cause a number of symptoms, some of which are severe. Often, an erythema migrans (EM) rash appears within 7-14 days at the site of a tick bite (click to see picture of a typical EM rash).

LD manifests itself as a multisystem inflammatory disease that affects the skin in its early, localized stage, and spreads to the joints, nervous system and, to a lesser extent, other organ systems in its later, disseminated stages. If diagnosed and treated early with antibiotics, LD is almost always readily cured. Generally, LD in its later stages can also be treated effectively, but because the rate of disease progression and individual response to treatment varies from one patient to the next, some patients may have symptoms that linger for months or even years following treatment. In rare instances, LD causes permanent damage.

Although LD is now the most common arthropod-borne illness in the U.S. (more than 150,000 cases have been reported to the Centers for Disease Control and Prevention [CDC] since 1982), its diagnosis and treatment can be challenging for clinicians due to its diverse manifestations and the limitations of currently available serological (blood) tests.

The prevalence of LD in the northeast and upper mid-west is due to the presence of large numbers of the deer tick’s preferred hosts – white-footed mice and deer – and their proximity to humans. White-footed mice serve as the principal “reservoirs of infection” on which many larval and nymphal (juvenile) ticks feed and become infected with the LD spirochete. An infected tick can then transmit infection the next time it feeds on another host (e.g., an unsuspecting human).

The LD spirochete, Borrelia burgdorferi, infects other species of ticks but is known to be transmitted to humans and other animals only by the deer tick (also known as the black-legged tick) and the related Western black-legged tick. Studies have shown that an infected tick normally cannot begin transmitting the spirochete until it has been attached to its host about 36-48 hours; the best line of defense against LD, therefore, is to examine yourself at least once daily and remove any ticks before they become engorged (swollen) with blood.

Generally, if you discover a deer tick attached to your skin that has not yet become engorged, it has not been there long enough to transmit the LD spirochete. Nevertheless, it is advisable to be alert in case any symptoms do appear; a red rash (especially surrounding the tick bite), flu-like symptoms, or joint pains in the first month following any deer tick bite could signal the onset of LD.

Manifestations of what we now call Lyme disease were first reported in medical literature in Europe in 1883. Over the years, various clinical signs of this illness have been noted as separate medical conditions: acrodermatitis, chronica atrophicans (ACA), lymphadenosis benigna cutis (LABC), erythema migrans (EM), and lymphocytic meningradiculitis (Bannwarth’s syndrome). However, these diverse manifestations were not recognized as indicators of a single infectious illness until 1975, when LD was described following an outbreak of apparent juvenile arthritis, preceded by a rash, among residents of Lyme, Connecticut.

Where is Lyme Disease Prevalent?

LD is spreading slowly along and inland from the upper east coast, as well as in the upper midwest. The mode of spread is not entirely clear and is probably due to a number of factors such as bird migration, mobility of deer and other large mammals, and infected ticks dropping off of pets as people travel around the country. It is also prevalent in northern California and Oregon coast, but there is little evidence of spread.

In order to assess LD risk you should know whether infected deer ticks are active in your area or in places you may visit. The population density and percentage of infected ticks that may transmit LD vary markedly from one region of the country to another. There is even great variation from county to county within a state and from area to area within a county. For example, less than 5% of adult ticks south of Maryland are infected with B. burgdorferi, while up to 50% are infected in hyperendemic areas (areas with a high tick infection rate) of the northeast. The tick infection rate in Pacific coastal states is between 2% and 4%.

Data on the Number of Reported Cases of Lyme Disease in the U.S., 2005-2014

To view most recent data, click here.

Symptoms of Lyme Disease

The spirochetal agent of Lyme disease, Borrelia burgdoferi, is transmitted to humans through a bite of a nymphal stage deer tick Ixodes scapularis (or Ixodes pacificus on the West Coast). The duration of tick attachment and feeding is a key factor in transmission. Proper identification of tick species and feeding duration aids in determining the probability of infection and the risk of developing Lyme disease.

The early symptoms of LD can be mild and easily overlooked. People who are aware of the risk of LD in their communities and who do not ignore the sometimes subtle early symptoms are most likely to seek medical attention and treatment early enough to be assured of a full recovery.

The first symptom is usually an expanding rash (called erythema migrans, or EM, in medical terms) which is thought to occur in 80% to 90% of all LD cases. An EM rash generally has the following characteristics:

  • Usually (but not always) radiates from the site of the tickbite
  • Appears either as a sol > (range = 2 inches to 2 feet)
  • Persists for about 3 to 5 weeks
  • May or may not be warm to the touch
  • Is usually not painful or itchy

EM rashes appearing on brown-skinned or sun-tanned patients may be more difficult to identify because of decreased contrast between light-skinned tones and the red rash. A dark, bruise-like appearance is more common on dark-skinned patients.

Ticks will attach anywhere on the body, but prefer body creases such as the armpit, groin, back of the knee, and nape of the neck; rashes will therefore often appear in (but are not restricted to) these areas. Please note that multiple rashes may, in some cases, appear elsewhere on the body sometime after the initial rash, or, in a few cases, in the absence of an initial rash.

Around the time the rash appears, other symptoms such as joint pains, chills, fever, and fatigue are common, but they may not seem serious enough to require medical attention. These symptoms may be brief, only to recur as a broader spectrum of symptoms as the disease progresses.

As the LD spirochete continues spreading through the body, a number of other symptoms including severe fatigue, a stiff, aching neck, and peripheral nervous system (PNS) involvement such as tingling or numbness in the extremities or facial palsy (paralysis) can occur.

The more severe, potentially debilitating symptoms of later-stage LD may occur weeks, months, or, in a few cases, years after a tick bite. These can include severe headaches, painful arthritis and swelling of joints, cardiac abnormalities, and central nervous system (CNS) involvement leading to cognitive (mental) disorders.

The following is a checklist of common symptoms seen in various stages of LD:

Localized Early (Acute) Stage:

  • Solid red or bull’s-eye rash, usually at site of bite
  • Swelling of lymph glands near tick bite
  • Generalized achiness
  • Headache

Early Disseminated Stage:

  • Two or more rashes not at site of bite
  • Migrating pains in joints/tendons
  • Headache
  • Stiff, aching neck
  • Facial palsy (facial paralysis similar to Bell’s palsy)
  • Tingling or numbness in extremities
  • Multiple enlarged lymph glands
  • Abnormal pulse
  • Sore throat
  • Changes in vision
  • Fever of 100 to 102 F
  • Severe fatigue
  • Arthritis (pain/swelling) of one or two large joints
  • Disabling neurological disorders (disorientation; confusion; dizziness; short-term memory loss; inability to concentrate, finish sentences or follow conversations; mental “fog”)
  • Numbness in arms/hands or legs/feet

Diagnosis of Lyme Disease

If you think you have LD symptoms you should see your physician immediately. The EM rash, which may occur in up to 90% of the reported cases, is a specific feature of LD, and treatment should begin immediately.

Even in the absence of an EM rash, diagnosis of early LD should be made on the basis of symptoms and evidence of a tick bite, not blood tests, which can often give false results if performed in the first month after initial infection (later on, the tests are more reliable). If you live in an endemic area, have symptoms consistent with early LD and suspect recent exposure to a tick, present your suspicion to your doctor so that he or she may make a more informed diagnosis.

If early symptoms are undetected or ignored, you may develop more severe symptoms weeks, months or perhaps years after you were infected. In this case, the CDC recommends using the ELISA and Western-blot blood tests to determine whether you are infected. These tests, as noted above, are considered more reliable and accurate when performed at least a month after initial infection, although no test is 100% accurate.

If you have neurological symptoms or swollen joints your doctor may, in addition, recommend a PCR (Polymerase Chain Reaction) test via a spinal tap or withdrawal of synovial fluid from an affected joint. This test amplifies the DNA of the spirochete and will usually indicate its presence.

Issues and Insights Related to the Diagnosis of Lyme Disease:

Updates and Recent Reports

Announcements from the FDA and CDC on the Diagnosis of Lyme Disease

Treatment Guidelines

Recommended courses and duration of treatment for both early and late Lyme symptoms are shown in our Table of Recommended Antibiotics and Dosages (see also table footnotes).

Early treatment of LD (within the first few weeks after initial infection) is straightforward and almost always results in a full cure. Treatment begun after the first three weeks will also likely provide a cure, but the cure rate decreases the longer treatment is delayed.

Doxycycline, amoxicillin and ceftin are the three oral antibiotics most highly recommended for treatment of all but a few symptoms of LD. A recent study of Lyme arthritis in the New England Journal of Medicine indicates that a four-week course of oral doxycycline is just as effective in treating late LD, and much less expensive, than a similar course of intravenous Ceftriaxone (Rocephin) unless neurological or severe cardiac abnormalities are present. If these symptoms are present, the study recommends immediate intravenous (IV) treatment.

Treatment of late-Lyme patients can be more complicated. Usually LD in its later stages can be treated effectively, but individual variation in the rate of disease progression and response to treatment may, in some cases, render standard antibiotic treatment regimens ineffective. In a small percentage of late-Lyme patients, the disease may persist for many months or even years. These patients will experience slow improvement and resolution of their persisting symptoms following oral or IV treatment that eliminated the infection.

Although treatment approaches for patients with late-stage LD have become a matter of considerable debate, many physicians and the Infectious Disease Society of America recognize that, in some cases, several courses of either oral or IV (depending on the symptoms presented) antibiotic treatment may be indicated. However, long-term IV treatment courses (longer than the recommended 4-6 weeks) are not usually advised due to adverse side effects. While there is some speculation that long-term courses may be more effective than the recommended 4-6 weeks, there is currently no scientific evidence to support this assertion. Click here for an article from the New England Journal of Medicine which presents clinical recommendations in the treatment and prevention of early Lyme disease.

More Information on Treatment Guidelines

Current Clinical Studies

NIAID Clinical Trials

Two Controlled Trials of Antibiotic Treatment in Patients with Persistent Symptoms and a History of Lyme Disease ( The above clinical trials were conducted under the following protocols that were approved by the NIAID Clinical Studies Group, the Institutional Review Board, the NIAID Biostatistics Group, and the Food and Drug Administration (FDA) before the trails were conducted. To ensure complete compliance with the protocols, all procedures associated with the trials were carefully monitored by an independent Data Safety and Monitoring Board (DSMB) that included several distinguished biostatisticians. Note that the protocols stipulated that an interim statistical analysis be performed when 100 subjects have been enrolled.)

Research and Clinical Studies

A Case Revealing the Natural History of Untreated Lyme Disease ( Although the data are not shown in the publication, the author confirms that the IgG Western blot was positive by the CDC criteria and showed the presence of 21,28,30,39,41,45,58,66, and 93 kDa bands. )

How to Evaluate the Claims About Cures and Treatments for Long-term, Chronic Conditions

Studies on Chronic Lyme Disease Syndromes

News Articles and Commentaries

Peer-Reviewed Scientific Publications

Clinical Trials on the Efficacy of Extended Antibiotic Therapy

Two Controlled Trials of Antibiotic Treatment in Patients with Persistent Symptoms
and a History of Lyme Disease ( The above clinical trials were conducted under the following protocols that were approved by the NIAID Clinical Studies Group, the Institutional Review Board, the NIAID Biostatistics Group, and the Food and Drug Administration (FDA) before the trails were conducted. To ensure complete compliance with the protocols, all procedures associated with the trials were carefully monitored by an independent Data Safety and Monitoring Board (DSMB) that included several distinguished biostatisticians. Note that the protocols stipulated that an interim statistical analysis be performed when 100 subjects have been enrolled.)

Lyme Disease and Co-Infections

Antibiotics

Commentaries and Reviews on Lyme Disease

From the Desk of the Executive Director

Misinformation on Lyme Disease

Bacteria produce only two types of toxins: endotoxins, which are non-secreted lipopolysaccharides (LPSs) that make up a large part of the cell wall of gram-negative bacteria; and, exotoxins that are secreted by some gram-positive bacteria and a few strains of gram-negative bacteria.

At one time, Borrelia burgdorferi, was thought to possess an endotoxin since a product isolated from B. burgdorferi was reported to be pyrogenic for rabbits, mitogenic for human mononuclear cells and mouse spleen cells, capable of clotting limulus lysate (a diagnostic test for LPS), and cytotoxic for mouse macrophages; these are properties generally ascribed to bacterial LPS (1). However, subsequent studies revealed the absence of lipid A and other chemical structures characteristic of classic gram-negative endotoxins (2). Although B. burgdorferi does not produce an endotoxin, it does possess lipoproteins that interact with Toll-like receptors (TLRs) on the surface of mammalian cells that comprise the innate immune system, to cause them to release inflammatory products that result in tissue damage and some of the clinical manifestations of Lyme disease (3-9).

There is abundant evidence to show that treatment with a short course of oral antibiotics is likely to cure active infection by B. burgdorferi (10); however, it is possible that some biologically active lipoproteins from dead bacterial cells persist in host tissues for periods of time after the initial infection has been cured.

Although some claim that B. burgdorferi produces a potent neurotoxin, there is no published, peer-reviewed evidence indicating that B. burgdorferi is an exotoxin-producing bacterium. In fact, the genomic sequence data do not reveal the presence of genes that encode for either key structural elements of any known bacterial exotoxin, or components of a secretory apparatus required for the export and delivery of an exotoxin (11).

In view of these considerations, treatment regimens for Lyme disease based on the neutralization — or removal by chelation– of a yet-to-be-identified neurotoxin should be viewed with much skepticism; such quackery is not only likely to be a waste of time and money, but also has the potential to cause great harm. There is no clinical evidence to indicate that such treatments are safe or effective.

1. Beck, G., G.S. Habicht, J.L. Benach, and J.L. Coleman. 1985. Chemical and biological characterization of a lipopolysaccharide extracted from the Lyme disease spirochete, (Borrelia burgdorferi). J. Infect. Dis. 152: 108-117.

2. Takayama, K., R.J. Rothenberg, and A.G. Barbour. 1987. Absence of lipopolysaccharide in the Lyme disease spirochete, Borrelia burgdorferi. Infect. Immun. 55: 2311-2313.

3.Wooten, R.M. and J.J. Weis. 2001. Host-pathogen interactions promoting inflammatory Lyme arthritis: use of mouse models for dissection of disease processes. Current Opinion in Microbiol. 4: 274-279.

4. Aliprantis, A.O., R.B. Yang, M.R. Mark, et al. 1999. Cell activation and apoptosis by bacterial lipoproteins through Toll- like receptor-2. Science 285: 736-739.

5. Brightbill, H.D., D.H. Libraty. S.R. Krutzik, et al. Host defense mechanisms triggered by microbial lipoproteins through Toll-like receptors. Science 285: 732-736.

6. Hirschfield, M., C.J. Kirschning, R. Schwandner. et al., 1999. Inflammatory signaling by Borrelia burgdorferi lipoproteins is mediated by Toll-like receptor-2. J. Immunol. 163: 2382-2386.

7. Lien, E., T.J. Sellati, A. Yoshimura, et al. 1999. Toll-like receptor- 2 functions as a pattern recognition receptor for diverse bacterial products. Chemistry 274: 33419-33425.

8. Ozinsky, A., D.M. Underhill, J.D. Fontenot, et al. 2000. The repertoire for pattern recognition of pathogens by the innate immune system is defined by cooperation between Toll-like receptors. Proc. Nat. Acad. Sci. 97: 13766-13771.

9. Alexopoulou, L., V. Thomas, M. Schnare, et al. Hyporesponsiveness to vaccination with Borrelia burgdorferi Osp A in humans and in TLR-1 and TLR-2 deficient mice. Nature Medicine 8: 878-884.

10. Wormser, G.P., R.J. Dattwyler, E.D. Shapiro, et al. 2006. The clinical assessment, treatment, and prevention of Lyme disease, human granulocytic anaplasmosis, and babesiosis: clinical practice guidelines by the Infectious Disease Society of America. Clin. Infect. Dis. 43: 1089-1134.

11. Fraser, C., S. Casjens, W.M. Huang, et al. (1997). Genomic sequence of a Lyme disease spirochete, Borrelia burgdorferi. Nature 390: 580-586.

The Plum Island Animal Disease Center (PIADC), that is now managed by the U.S. Department of Agriculture, is dedicated to research on plant and large animal diseases likely to have a significant economic impact on the livestock and agricultural industries. Because of its isolation from the main land mass and stringent containment facilities, it is ideally suited for such work. In 1952, it was managed by the U.S. Army Chemical Corps as a component of its biological warfare program. However, when that program was abolished by a Presidential directive in 1969, it was transferred to the U.S. Department of Agriculture for its present use.

Some claim that Lyme disease was introduced into the northeastern region of the U.S. by a man-made strain of Borrelia burgdorferi that escaped from a high containment biological warfare laboratory on Plum Island. However, there is ample evidence to indicate that both Ixodes ticks and B. burgdorferi were present in the U.S. well beforethe Plum Island facility was ever established. An examination of museum specimens ofIxodes ticks showed that the presence of Lyme disease spirochetes in suitable arthropod vectors preceded — by at least a generation — the year (1982) when Lyme disease was first recognized as a distinct clinical entity in the U.S. (1, 2). More recent studies revealed that Ixodes ticks and B. burgdorferi were present in the northeastern and Midwestern regions of the U.S. in pre-colonial times and many thousands of years before European settlements were established in the U.S. (3). Lyme disease certainly existed in the U.S. long before anyone knew how to diagnose and treat it.

Although the per capita incidence of Lyme disease in the Northeastern United States is more than twice that in the Midwestern United States, the prevalence of B. burgdorferiin the tick vector is nearly identical in both regions. The disparity in the incidence of disease did not appear to be due to a disparity in human invasiveness since a genetic analysis revealed that B. burgdorferi population in the Northeast and Midwest shard a recent common ancestor. This suggests that substantial evolutionary divergence in human invasiveness has not occurred and that the disparity in the incidence of disease between the two regions may be due to animal ecology or human behavior (4).

Finally, the prehistoric remains of “The Ice Man”–more than 5,000 years old– provide positive evidence of infection by Borrelia burgdorferi(http://ngm.nationalgeographic.com/2007/07/iceman/hall-text) .

1. Persing, DH, Telford, SR III, Rys, PN, Dodge, DE, White, TJ, Malawista, SE and Spielman, A. Detection of Borrelia burgdorferi DNA in museum specimens of Ixodes damimini ticks. Science 249: 1420-1423, 1990.

2. Burgdorfer, W, Barbour, AG, Hayes, SF, Benach, JL, Grunwaldt, E, and Davis, J.P. Lyme disease: a tick-borne spirochetosis? Science 216: 1317-1319,1982.

3. Hoen, AG, Margos, G, Bent, S.J. Duik-Wasser, MA, Barbour, A, Kurtenbach, K, and Fish, D. Phylogeography of Borrelia burgdorferi in the eastern United States reflects multiple independent Lyme disease emergence events. Proc. Natl. Acad. Sci. 106: 15013-15018, 2009.

4. Brisson, D., Vandermause, M.F., Meece, J.K., Reed, K.D. and Dykhuizen. Evolution of Northeastern and Midwestern Borrelia burgdorferi in the United States. Emerg. Infect. Dis. 16: 911-917, 2010.

This photo has been reproduced from the more detailed version of the Tick Map found on the Home Page of the ALDF website. It summarizes current information, from 2006 – 2008) on the incidence of infected Ixodes ticks, as well as reported cases of Lyme disease in the continental United States.

Note that no Ixodes scapularis or I. pacificus ticks are found in some States, and that there are several States in which I. scapularis or I. pacificus have been reported, but host-seeking nymphs — the major transmitters of Lyme disease — are extremely low as well as the prevalence of infection. Since Lyme disease is not a sexually transmitted disease and is transmitted to humans only by infected Ixodes ticks (see preceding articles in this section), it is not surprising that most (>95%) reported cases of Lyme disease occur in those States (the Northeastern and Upper Mid-Central States) where host-seeking nymphal I. scapularis ticks are abundant.

Ixodes ticks are not found in the Arizona, Colorado, Idaho, Montana, Nevada, North Dakota, Utah, and Wyoming. Consequently, it is reasonable for residents of those States with non-specific symptoms often associated with Lyme disease in the absence of positive serological tests conducted by validated standard procedures and possible exposure to Ixodes ticks from visits to endemic areasto consider other possibilities to explain their symptoms.

Although Amblyoma americanum ticks sometimes carry a strain of Borrelia called Borrelia lonestarii, there is no evidence to indicate that B. lonestarii produces disease in humans (1). Furthermore, A. americanum has not been shown to be a competent vector for B. burgdorferi, the spirochete that causes Lyme disease (2,3).

1. Wormser, G.P., Masters, E., Livedris, D. et al. “Microbiologic evaluation of patients from Missouri with erythema migrans.” Clin, Infect. Dis. 40: 423-428, 2005.

2. Ledia, K.E., N.S. Zeidner, J.M. Riberio, et al. “Borreliacidal activity of saliva from the tick Amblyomma americanum. Med.Vet. Entomol. 19: 90-95, 2005.

3. Piesman, J., and C.M. Kapp. “Ability of the Lyme disease spirochete Borrelia burgdorferi to infect rodents and three species of human-biting ticks (blacklegged tick, American dog tick, lone star tick). J. Med. Entomol. 34: 451-456, 1997.

Some Lyme disease patient advocates claim that there is a causal relationship between amyotrophic lateral sclerosis (ALS) and Lyme disease, simply because some patients with ALS appear to test positive in serological tests for Lyme disease. However, the results of recent clinical studies negate the validity of such a relationship. An examination of 414 patients with ALS who also underwent validated serological tests for Lyme disease, showed that only 24 (5.8%) were seropositive for Lyme disease; furthermore, the medical record of only 4 of these seropositive patients (0.97%) confirmed previous infection by Borrelia burgdorferi(1). In another larger study conducted in the U.S., more that 4,000 patients with ALS also were tested for Lyme disease; only 30 ( Does Lyme disease induce autism in children?

The view that Lyme disease induces autism in children has been advanced by the Lyme-Induced Autism Foundation (LIAF) which claims that up to 90% of autistic children are infected with Borrelia (1). There are no published data to substantiate such a claim. Having a positive ELISA or Western Blot test is not proof of active infection; it might indicate the presence of antibodies that are the result of past infection with Borrelia burgdorferi, the causative agent of Lyme disease. Such antibodies may persist at low levels, months to years after the active infection has been cured by appropriate antibiotic therapy. In some persons, a positive ELISA or Western blot is due to a non-specific cross-reaction (i.e., a false positive test).

There are serious problems with the quality of the laboratory tests used to support the claim that a large percentage of autistic children are seropositive for Lyme disease. First, the actual data upon which the claim is based have never been published in a peer reviewed scientific journal; this casts doubts on their accuracy. Second, there has been no independent confirmation to establish that the results are valid and reproducible. Third, in many cases, it appears that non-standard criteria were used to interpret the Western blots that were used to support an association between Lyme disease and autism. Such criteria are at variance with those recommended by the CDC, thereby resulting in a significant number of false positive tests. Consequently, the unpublished results of the serological tests reported by the LIAF must be viewed with grave skepticism.

The results of two recent carefully conducted controlled studies completely refute the erroneous claim of the LIAF, namely, that Lyme disease induces autism in children (2,3).

It should also be noted that data on the prevalence of autism and Lyme disease (number of reported cases per 100,000 residents) for nine States (Al, AR, CO, GA, MD, MO, NC, PA, SC, and WI) for the years 2004 and 2006, provide no indication of an association between Lyme disease and autism (4,5). An analysis by Spearman’s rank correlation test yields r values of 0.234 and 0.317 for the years 2004 and 2006, respectively. In this particular method of statistical analysis, r values must be at or very close to 1.0 to affirm a close association between Lyme disease and autism. Furthermore, the average age at which the first signs/symptoms of autism occur in children is lower than that of Lyme disease, and there is no evidence that autistic children are exposed to ticks at a greater frequency than normal children.

Since families with autistic children already suffer enormous financial and emotional burdens, they should not have their hopes needlessly raised by unproven speculations that are not supported by scientific evidence. It would be irresponsible and even harmful to treat autistic children with extended antibiotic therapy, as some physicians are already recommending and doing, in the absence of indisputable evidence of a persistent infection. Neither the National Institutes of Health nor the Autism Science Foundation, which fund almost all of the research on autism and have developed many promising and successful approaches for treating autism, have any evidence to support a link between Lyme disease and autism.

2. “Serologic markers of Lyme disease in children with autism”.
Ajamtan, M., Kosofsky, B.E., Wormser, G.P., Rajadhyalsha, A., and Alaedini, A.
JAMA 309: 1771-1772, 2013.

3. “Lack of serum antibodies against Borrelia burgdorferi in children with autism”
Burbelo, P.D., Swedo, S.E., Thurm, A., Bayal, A., Levin, A.E., Marques, A.,
and Iadorola, M.J.
Clinical Vaccine Immunology, May 2013, on-line ahead of print publication.

4. Autism and Developmental Disabilities Monitoring Network Report of 2009(http://www.cdc.gov/ncbddd/autism/states/ADDMCommunityReport2009.pdf).

Although the report by M.J. Middelveen et al. (1), suggests that Lyme disease may be a sexually transmitted infection, it relies solely on the detection ofBorrelia in the semen and vaginal secretionsof a small number of people; there is no evidence to date indicating that borreliosis can be transmitted in this manner. Based on little more than these preliminary and unconfirmed observations, Stricker and Middleveen (2), nevertheless, have proposed that their results “might create a paradigm shift that would transform Lyme disease from a tick-borne illness into a sexually transmitted infection”. This is nonsense to say the least

Because Borreliaburgdorferihas been reported to elicit a generalized disseminated infection in several well-characterized animal models of borreliosis, it is not surprising that sprirochetes have been isolated from the spleen, eyes, kidneys, liver, tested and the brain of infected animals, several days after infection (3, 4). However, the concept that borreliosis can be transmitted by direct contact or sexually of was refuted several years ago by the well-designed, peer-reviewed published studies of Moody and Barthold (5), as well as Woodrum and Oliver (6), internationally known experts on Lyme disease.These investigatorsused well-characterized animal models of borreliosis in which infection is much more disseminated and profound than it is in humans. It should be noted that, in the United States, Lyme borreliosis has historically been defined as atick borne infection caused by Borreliaburgdorferisensulato(7).

To determine if borreliosis can be transmittedby direct contact, Moody and Barthold (5) housed three-day-old (or three-week-old) Lewis rats, deliberately infected with B.burgdorferi, with normal, uninfected ratsfor 30 days. As expected, all deliberatelyinfected rats continued to be actively infected, 30 days later; however, none of the uninfected rats acquired infection after 30 days of intimate direct contact withtheir infected cage mates.

In other experiments, Moodyand Barthold (5) were unable to demonstrate venereal transmission of borreliosisfrom seven infected females-or sixinfected males -to uninfected rats of the oppositesex. In the work of Woodrum and Oliver (6), six female Syrianhamsters infected with B.burgdorferiwere mated with six uninfected males; conversely, three infected males were mated with six uninfected females. None of the uninfected hamsters became infected after matingwith an infected partnerof the opposite sex, indicatingthat borreliosisis not sexually transmitted.Obviously, the mere presence of borrelia in genital tissues does not mean that infection can be transmitted sexually. It should be noted that epidemiological data do not support the view that Lyme disease is sexually transmitted. Extensive data collected by the CDC indicate that 96% of all reported cases of Lyme disease occur in 14 States (http://www.cdc.gov/lyme/stats/index.html ), a pattern that is strikingly different from that for sexually transmitted diseases. Woodrum and Oliver (6) likewisefailed to demonstratecontact transmission of B. burgdorferibetween infected female-or male-hamsters and uninfected hamsters of the opposite sex. Itwas not possible to transmit borreliosisto uninfected hamsters with urine or feces from infected hamsters.

Sadly, the observations of Middleveen et al.(1) have already generated an inordinate amount of fear and anxiety within the lay community due to sensationalized reports of their unconfirmed findings by an uncritical -and often naïve -press. This has already caused much harm, as evidenced by the fact that I have received numerous inquiries from distraught individuals, wondering if they now should even consider marrying their previously diagnosed and treated spouse-to-be for fear of getting Lyme disease and/orrisking the possibility of giving birth to an infected or congenitally deformed child.

To examine the issue of in uterotransmission of boreliosis, Moody and Barthold (5) inoculated pregnant female Lewis rats with viable B. burgdorferi, at four days of gestation. All of the inoculated pregnant females became seropositive as expected, and B. burgdorfericould be cultured from their spleens at 20 days of gestation; however, their placentas and fetuses were culture negative, indicting the lack of
in uterotransmission. Moody and Barthold (5)used two different experimental protocols to determine if transplacental transmission of B. burgdorferioccurs. One protocol involved six non-pregnant infected females that were subsequently mated and became pregnant. Three of the females were allowed to carry to full term, whereas the remaining three were sacrificed just prior to parturition. All offspring
and offspring-to-be were found to be culture negative for B. burgdorferi, as well as seronegative for antibody specific for B. burgdorferi, indicating that transplacental transmission of infection does not occur. In the second protocol, six females were infected viatick bite after becoming pregnant, and were allowed to carry their fetuses to birth; all were negative for infection. The resultsof these studies likewise failed to provide evidence for the transplacental transmission of naturally acquired borreliosis.

Other investigators examined the possibility of congenital birth defects in humanswith Lyme diseaseby doing a rather large comparative study involving 5,000 infants, half from an area in which Lyme disease was endemic and half as controls froman area without Lyme disease (8). They found no significant differences in the overall incidence of congenital malformations between the two groups.

In another study, involving 1,500 subjects including controls,no increased risk of giving birth to a child with a congenital heart defect wasnotedin women who had either been bitten by a tick or had been treated for Lyme disease during or before pregnancy (9).Finally, an extensive analysisof the world literature revealed“that an adverse outcome due to maternal infection with B. burgdorferiat any point during pregnancy in humans is at most extremely rare” (10).

Phillip J. Baker, Ph.D.
Executive Director
American Lyme Disease Foundation
P.O. Box 466
Lyme, CT 06371
[email protected]

1. Middleveen, MJ, Burke, J, Mayne, PJ, and Stricker, RB. F1000Research 27 Apr 2015,(doi 10.126881/f1000research.5778.33:309

2. Stricker, RB, and Middleveen, 1MJ. Sexual transmission of Lyme disease: challenging the tickborne disease paradigm. Expert. Rev. Anti. Infect. Ther. 2015; 11:1303-1306.

3. Johnson,RC, Marek, N, and Kodner, C. Infection of Syrian hamsters with Lyme disease spirochetes. J. Clin. Microbiol. 1984; 20:1099-1101.

4. Barthold, SW, Persing, DH, Armstrong, AL, and Peeples, RA. Kinetics of Boreliaburgdorferidissemination and evaluation of disease after intradermal inoculation of mice. Amer. J. Pathol 1991; 139:263-273.

5. Moody, KD and Barthold, SW. Relative infectivity of Borreliaburgdorferiin Lewis rats by various routes of inoculation. Amer. J. Trop. Med. Hyg. 1991;44:135-139.

6. Woodrum, JE and Oliver, JH Jr. Investigation of venereal, transplacental, and contact transmission of the Lyme disease spirochete, Borreliaburgdorferi,in Syrian hamsters. J. Parasitol. 1999;85:426-430.

7. Wormser, GP and O’Connell, S. Treatment of infection caused by Borreliaburgdorferisensulato. Expert. Rev. Anti. Infect. Ther 2011;9:245-260.

8. Williams, CL, Strobino, B, Weinstein, A,etal Maternal Lyme disease; congenital malformations and a cord blood serosurvey in endemic and control areas. Paediatr. Perinat. Epidemiol. 1995;9:320-330.

9. Strobino, B, Abid, S, and Gewitz, M. Maternal Lyme disease and congenital heart disease: a case control study in an endemic area. Amer. J. Obstet. Gynecol 1999;180:711-716.

10. Elliot, DJ, Eppes, SC, and Klein, JD. Teratology Update: Lyme disease. Teratology 2001;64:276-286.

Lyme disease affects the nervous system. This statement is both accurate and terrifying since, for many of us, damage to the brain is the most feared consequence of disease. However, when it comes to Lyme disease, much of this fear is misplaced. Lyme disease can affect the lining of the brain, a disorder known as meningitis. Other than causing fever and bad headaches, this form of meningitis is remarkably benign; nobody has ever died of it, and it has rarely — if ever — caused significant damage to any patient’s brain. On extremely rare occasions, the infection can involve the brain or spinal cord, disorders that are now extraordinarily rare. Other patients can develop inflammation of various nerves, e.g., the nerves that control the muscles on one side of the face (Bell’s palsy); this might occur in about 5% of untreated individuals. Other nerves can be affected, but even less frequently.

When considering these disorders, it is essential to recognize some key facts. First, the infection is highly responsive to antibiotics. Second, if the facial nerve has been severely damaged, there may be some residual weakness after treatment. However it is extraordinarily rare for there to be any permanent damage to the brain itself.

More importantly, there are many symptoms that occur in patients with Lyme disease and most other infections that may make one think there is a problem with the brain; however, that is not the case. Headaches, which are remarkably common in individuals with fever of any cause, are rarely due to a brain infection. Slowed thinking, with difficulty in concentrating, remembering or mentally focusing occurs to a greater or lesser extent in virtually everyone with an active inflammatory condition; however, it is almost never due to the disease affecting the brain itself. Rather, these are the effects of chemicals produced by the body in response to an infection or inflammation. These effects disappear as soon as the infection or inflammation resolves.

Since some patients with Lyme disease develop fatigue and thinking difficulties, some have suggested that these symptoms in isolation– are strongly suggestive of this infection. However, this is misguided thinking. Studies have shown that symptoms such as these, which are severe enough to affect day-to-day functioning but are never due to nervous system disease, occur in over 2% of the population at large at any given time. In the U.S., this amounts to 6,000,000 people! Since there only about 30,000 cases of Lyme disease are reported each year, patients with Lyme disease obviously represent only a very tiny fraction of the total number of individuals with these symptoms.

There is a great deal of misunderstanding, among patients and doctors, about what laboratory test for the diagnosis of Lyme disease actually measure and what constitutes a positive test result.

The most common, widely used tests simply measure antibodies against the Lyme disease bacterium, Borrelia burgdorferi. Since antibodies are produced by the body’s immune system to fight infection, detecting the presence of antibodies against bacteria or a virus is a good way to determine if someone has — or had– an infection. Some of the confusion about Lyme disease testing is due to the fact that different types of antibodies are produced at various stages of the infection. The type of antibody produced changes as the immune response to infection matures. Immunoglobulin M (IgM) develops first, during the first 7 to 10 days of infection; it is followed by the development of Immunoglobulin G (IgG), one to two weeks later. IgM is a less specific antibody that is quite a bit stickier than IgG. The stickiness of IgM makes tests that measure IgM less reliable and more likely to be falsely positive.

Why do we use IgM assays at all? It is because IgM is produced first. IgM can be found in people very early during infection, well before IgG antibody is produced. Within 1-2 weeks following the onset of infection, IgM antibodies to B. burgdorferi can be detected in the vast majority of infected individuals. However, after one month, IgG antibody responses predominate and there is no longer a need to depend on an unreliable assay based on the detection of IgM antibody. Thus, because of the limitations of IgM assays and the high rate of false positives, their use should be limited to the first month of infection; however, that frequently is not the case. A positive IgM test along with a negative IgG test after the first month of infection almost always results in a false positive test.

There are a number of different ways to measure antibodies against B. burgdorferi. The two most common procedures are by ELISA and Western blot. An ELISA is carried out on a plastic plate and measures the amount of antibody that binds to one or more B. burgdorferi proteins (antigens). A Western blot is like a bar code. Different kinds of B. burgdorferi proteins are separated by size on a strip of special paper and the antibodies in the patient’s blood bind specifically to the proteins on the paper. The binding antibodies are then colored and the bar code is read. People who have been infected with B. burgdorferi have antibodies against certain specific proteins, thereby resulting in a positive bar code. What constitutes a positive pattern was established by the CDC in collaboration with many experienced physician scientists from major research centers based on thousands of comparative tests as well as an extensive analysis of antibodies known to be both specific and characteristic of various stages of B. burgdorferi infection.

There are some who claim that several important proteins (e.g., OspA, OspB, and other B. burgdorferi proteins or antigens) were not included in the positive pattern established by the CDC; however, these proteins were initially considered for inclusion, but were rejected because they did not contribute significantly to diagnosis. Although it is true that OspA and OspB antigens are indeed specific for B. burgdoreferi, these antigens are produced only when the bacterium is grown on artificial laboratory media or in the midgut of Ixodes ticks. Since these antigens are not — or are only minimally produced — during the course of a human infection, they are of little or no diagnostic value for human disease; the presence of other antibodies recommended in the CDC standard criteria predominate and thus are of greater relevance, as demonstrated by the results of thousands of comparative laboratory tests.

In sharp contrast to the CDC standard criteria, some doctors and commercial laboratories (e.g., IGeneX) use or advocate non-standard criteria that have not been validated by rigorous comparative studies by the CDC and or FDA (http://igenex.com/Website) . Consequently, the results of their tests fall outside the range of standard practice and have a much greater rate of false positives than one would get using the CDC criteria.

The CDC is responsible for guiding physicians in the appropriate use of laboratory tests for the diagnosis of Lyme disease and other infectious diseases. The CDC has warned about nonstandard testing and the interpretation of laboratory test results using unvalidated criteria. This carries great weight among mainstream physicians, as well as scientists working at State public health laboratories. Thus, the CDC criteria remain the standard and other criteria are considered to be unvalidated and unacceptable.

As is the case for most serologic assays, Lyme disease serologic assays are not by themselves diagnostic. A diagnosis of Lyme disease can only be made in the presence of well defined objective clinical abnormalities associated with Lyme disease. Because the presence of fatigue or vague aches and pains are too nonspecific, a positive serology in such individuals would have a very low positive predictive value. Simply demonstrating that someone has an immune response against B. burgdorefri does not mean that person is actively infected, or that any general symptoms have anything to do with B. burgdorferi infection. It also is important to realize that the immune system has memory. That means that an individual who makes a mature antibody response against any infecting bacterium or virus continues to have detectable antibodies in their blood. This is true for all infections, including Lyme disease. Thus, a positive test after someone has been treated is in fact normal and does not indicate on going infection.

There is no indeterminate designation in the CDC criteria. Also there is no separate CDC surveillance criteria for serologic assays. The lack of a positive serology in a patient without the clear objective abnormalities known to be associated with Lyme disease has a very high negative predictive value, indicating that patient does not have Lyme disease.

The CDC has issued the following statement which summarizes its views on the diagnosis of Lyme disease (LD):

A two-test approach for active disease and for previous infection using a sensitive enzyme immunoassay (EIA) or immunofluorescent assay (IFA) followed by a Western immunoblot is the algorithm of choice. All specimens positive or equivocal by a sensitive EIA or IFA should be tested by a standardized Western immunoblot. Specimens negative by a sensitive EIA or IFA need not be tested further. When Western immunoblot is used during the first 4 weeks of disease onset (early LD), both immunoglobulin M (IgM) and immunoglobulin G (IgG) procedures should be performed. A positive IgM test result alone is not recommended for use in determining active disease in persons with illness greater than 1 month’s duration because the likelihood of a false-positive test result for a current infection is high for these persons. If a patient with suspected early LD has a negative serology, serologic evidence of infection is best obtained by the testing of paired acute- and convalescent-phase serum samples. Serum samples from persons with disseminated or late-stage LD almost always have a strong IgG response to Borrelia burgdorferi antigens.

Although Borrelia burgdorferi-like organisms have been observed in mosquitoes, horse flies, and deer flies in areas where Lyme disease is endemic, these organisms have not been cultured to verify their identity. Experiments attempting to transmit B. burgdorferi from infected to uninfected laboratory animals by mosquitoes have not been successful (1). Furthermore, epidemiological studies have shown that the date of onset for Lyme disease occurs in June, coincident with the peak abundance of nymphal Ixodes scapularis ticks, and not during August when mosquitoes and other biting files are at peak abundance (2). Despite findings of B. burgdorferi in other tick species such as the American dog tick (Dermacentor variabilis) and the lone star tick (Amblyomma americanum) in the field, laboratory transmission studies have confirmed that these tick species cannot transmit the infection to laboratory animals; thus, they are not competent vectors for Lyme disease (3). Both experimental and epidemiological studies have shown that Ixodes scapularis and Ixodes pacificus are the only tick species in North America that are capable of transmitting B. burgdorferi, the spirochete that causes Lyme disease, to humans. Please consult the Lyme Disease Risk Assessment Map on the home page of the ALDF website (www.aldf.com) for specific information on the incidence of Ixodes ticks as well as the numbers of reported cases of Lyme disease for individual States.

1. Magnarelli, LA, and Anderson, JF. J. Clin. Microbiol. 26: 1482-1486, 1988.

2. Falco, R.C., D.F. McKenna, T.J. Daniels, R.B. Nadelman, J. Nowakowski, D. Fish, and G.P. Wormser. Am. J. Epidemiol: 149: 771 -776, 1999.

3. Piesman, J. and Happ, CM. J. Med. Entomol. 34: 451-156, 1997.

Do Borrelia form “cysts”?

Some investigators mistakenly use the term “cyst” to describe what are properly termed L-forms or “cell-wall deficient” variants of bacteria. Such variants are present in senescent cultures as amounts of essential nutrients become limiting, and most often appear after exposure to antibiotics that influence cell wall formation and/or protein synthesis (1). There are of two types that differ mainly in the amount of residual cell wall material they possess: spheroplasts, which contain some remnants of the original cell wall material; and, protoplasts that lack residual cell wall material (2).

Saunder’s “Dictionary and Encyclopdeia of Laboratory Medicine and Technology”, lists two definitions for the term “cyst”. The first is used to describe any closed cavity or sac — both normal and abnormal — that is lined by epithelial cells; in some locations, this cavity may be lined by connective tissue or bone. The second definition is used to describe a stage in the life cycle of certain parasites (e.g., Echinococcus granulosus) during which they are enclosed within a protective sac called a hydatid cyst. Neither definition applies to Borrrelia since they do not form such structures. Two genera of soil dwelling bacteria (Azotobacter and Myxobacteria) form a distinctive outer cyst-like structure called an “exine”, surrounding the “intine” or vegetative cell (3). Although both of these structures have been isolated and characterized for Azotobacter, neither is formed by Borrelia. Some bacteria (Bacillus and Clostridia species) form protective heat-resistant structures called spores; however, Borrelia burgdorferi does not make spores. In view of these considerations, use of the term “cyst” with reference to B. burgdorferi is incorrect. In most cases, the term is used to convey the false impression that, by forming “cysts”, Borrelia are somehow able to evade destruction by recommended antibiotic therapy and host immune defense mechanisms, thereby enabling them to establish a long-term, antibiotic-refractory, persistent infection that some associate with the poorly defined phenomenon of “chronic Lyme disease”. Some even advocate additional treatment with metronidazole and other compounds called “cyst busters” to eliminate these variant forms (4); however, this is likely to be a fruitless effort since there is no evidence to confirm that that these morphologic variants are present, let alone cause disease.

Protoplasts and spheroplasts may be stable or unstable, respectively, depending on their capacity to revert to the original parental cell type when placed in an antibiotic- free environment that then permits normal metabolism and/or protein synthesis. If reversion does occur, it happens relatively early after antibiotic treatment, i.e., when the levels of antibiotic first begin to decline (2). Since neither spheroplasts nor protoplasts are surrounded by a “cyst-like” protective structure, there is no reason to believe that they are any less permeable or susceptible to antibiotics than the original parental cell type. In the cases of B. burgdorferi, these variants have not been fully characterized and then only with regard to their general morphology. More important, no well-controlled functional or physiological studies have been conducted to demonstrate that they indeed are relevant to human disease. Two studies show that such residual structures may exist in mice after treatment for B. burgdorferi infection; however, they were found to be not cultivable, not virulent, and eventually eliminated by host defense mechanisms without causing disease (5, 6, and 7).

A systematic review was made as to determine whether B. burgdorferi morphologic variants play a role in “chronic Lyme disease” (7). In the context of the broader medical literature, it is not possible to ascribe a pathogenic role to any morphologic variants of B. burgdorferi in either typical manifestations of Lyme disease or in other disease states, such as “chronic Lyme disease”. There is no clinical literature to justify specific treatment to eliminate B. burgdorferi morphologic variants (7).

1. Brorson, O, and Brorson, SH. An in vitro study of the susceptibility of mobile cystic forms of Borreli burgdorferi to metronidazole. APMIS 107: 566-576, 1999.

2. Allan, EJ, Hoischen, D, and Gumpert, Bacterial L-forms. J. Advan. Applied Microbiol. 68: 2-39, 2009.

3. Wyss, O, Neuman, MG, and Socolofsky, MD. Development and germination of the Azotobacter cyst. J. Biophys. Biochem. Cytology 10: 555-565, 1961,

4. Hodzic, E, Feng, S, Holden, K, et al. Persistence of Borrelia burgdorferi following antibiotic treatment in mice. Antimicrob. Agents Chemother. 52: 1728-1736, 2008.

5. Bockenstedt, LK, Mao, J, Hodzic, E, et al. Detection of attenuated. Non-infectious spirochetes in Borrelia-burgdorferi- infected mice after antibiotic treatment. J. Infect. Dis. 186: 1430-1437, 2002.

6. Wormser, GP, and Schwartz, I. Antibiotic treatment of animals infected with Borrelia burgdorferi. Clin. Microbiol. Rev. 22: 387-395, 2009.

7. Lantos, PM, Auwaerter, PG, and Wormser, GP. A systematic review of Borrelia burgdorferi morphologic variants does not support a role in chronic Lyme disease. Clin. Infect. Dis. 58: 663-671, 2014.

Is it Possible to Make a Valid Diagnosis of Lyme Disease Based on Symptoms Alone?

Lyme disease has been defined historically in the United States as a tick-borne infectious disease caused by a bacterial spirochete, Borrelia burgdorferi sensu stricto (1). It was named for the town of Old Lyme, Connecticut, near where it was discovered in the U.S. in the mid-1970s. It also has been called “the great imitator” because its symptoms are said to resemble those associated with several unrelated medical conditions. However, the fact that there are more than 350 medical conditions with symptoms very similar to those often attributed to Lyme disease (2), renders it extremely difficult — if not impossible— to make a valid diagnosis of Lyme disease based on symptoms alone, even in situations where the diagnosis of Lyme disease might seem to be most likely. For example, individuals living in endemic areas and exposed to ticks may develop a “bulls-eye” or erythema migrans (EM) rash that may be sufficiently pathognomonic for Lyme disease to justify antibiotic therapy with no additional testing; however, such a rash is present in 70-80% — not 100%– of those who acquire Lyme disease, and is sometimes mistaken for other types of skin reactions (3, 4). Although some consider the appearance of facial palsy a hallmark feature of Lyme disease, it is sometimes expressed in patients with other medical conditions, including several common viral infections (5). Even in regions where Lyme disease is endemic, 3 of 4 facial palsies are unrelated to Lyme disease (6).

The Centers for Disease Control and Prevention (CDC) conducts annual surveys of undiagnosed symptoms that commonly occur in the general population of the U.S. They report that about 15% of women and 10% of men in the general population of the United States felt exhausted or extremely tired (fatigued) either every day or most days of the preceding 3 months (7), and that about 16% of men and 22% of women experienced pain in the past 3 months (8). It is estimated that nonspecific irritable bowel symptoms affect about 11% of the general population (9). Subjective cognitive decline (SCD) is a form of impairment in which more frequent or worsening confusion or memory loss can affect the ability to care for oneself. Among adults aged > 45 years, 11.2% reported SCD, including 10.4% of adults aged 45-54 years (10). In a 2016 study, the CDC noted that about 20% of U.S. adults (approximately 20 million) had high-impact chronic pain linked to restrictions in mobility and daily activities, dependence on opioids, anxiety and depression, and poorly perceived health or reduced quality of life (11). The Institute of Medicine (IOM) reports that nonspecific chronic pain affects 100 million Americans, about 30% of the general population; such individuals go from one physician to another, unable to find anyone who can identify the cause of their pain or suggest a remedy (12). Individuals who believe that they have “chronic Lyme disease”, a poorly defined condition that occurs in about 10-15% of patients previously treated for Lyme disease, might well be included in the above noted study groups, simply based on the presence of symptoms that are widely prevalent in the general population and occur with about the same frequency.

Although the diagnosis of Lyme disease is sometimes described as a “clinical judgement”, this can mean different things to different people. The term generally implies a clinical judgement based on the results of a large body of evidence derived from peer-reviewed research, i.e., evidence that is generally accepted by well-informed physicians in the medical community at large. To date, a PubMed search of the scientific literature reveals more than 12,000 publications dealing with practically every aspect of Lyme disease.

Since its discovery in the United States in the mid-1970s, we have learned much about the cause, diagnosis, and treatment of Lyme disease. It is not the strange and mysterious disease that uninformed individuals imagine it to be, nor is it “a disease without a cure” as some have proclaimed falsely. A physician who is board certified in the specialty of infectious diseases surely is “Lyme literate” and should know how to diagnose and treat Lyme disease; the same is true for general practitioners in endemic areas with much experience treating patients with Lyme disease. Lyme disease conforms to the same fundamental rules and principles that apply to other infectious diseases. This likewise applies to the host immune response to B. burgdorferi and/or its various cell surface antigens. There are no “special rules” that apply only to Lyme disease, and one does not need to acquire “special training” or insights in medical school — or anywhere else for that matter — just to learn how to diagnose and treat Lyme disease. Although there is abundant knowledge upon which to base a rational clinical judgement, the results of an approved and correctly performed objective laboratory test certainly are invaluable in making a valid diagnosis of Lyme disease.

Two-tier testing has long been accepted as the standard procedure for the laboratory diagnosis of Lyme disease (13, 14). Unfortunately, there is much false and misleading information about its accuracy and reliability. For example, it is often stated that the criteria used for the interpretation of Western blots used in the second step of the two-step procedure were selected arbitrarily. Instead, they were based on the results of a rigorous statistical analysis of Western blots for hundreds of patient and control specimens that revealed 8 IgM bands associated with early infection, and 10 IgG bands detected 4-6 weeks after infection (15). When receiver operating characteristic (ROC) curves, which are plots of sensitivity vs specificity, were constructed for the most common IgM bands detected in early infection, as well as for the most common IgG bands detected after several weeks of infection, the area under each optimal ROC curve indicated that the minimum number of bands required to obtain 99% specificity, was at least 2 for IgM bands, and at least 5 for IgG bands; this gave the greatest incidence of unequivocal positive values in combination with the lowest incidence of false positive values (15). These objective findings provide the foundation for the criteria recommended by the CDC for Western blots now being used in two-tier testing for Lyme disease (14). Note that recombinant proteins now have replaced undefined whole-cell sonicates as ligands in Western blots; this has not only increased sensitivity and precision, but also has considerably reduced intra-laboratory variation in the results obtained.

Comparisons were made between the results obtained using the standard two-tiered test procedure vs those obtained using ELISA tests performed with whole-cell sonicates (WCS) or different well-defined and highly specific peptides (C6 or VlsE) as ligands (16). They showed that, in assays of specimen samples collected 4-6 weeks or longer after infection, there was complete agreement in all cases, thereby confirming the reliability of standard two-tier testing done late after infection (16). However, for comparisons made using specimens from patients with acute EM and during early infection, greater sensitivity (25-50%) was noted for ELISAs using the defined ligands than for ELISAs using whole-cell sonicates (16-38%). Since Borrelia replicate (divide) at a slow rate (once every 12 hours), it may not be possible to realize much greater gains in sensitivity and the earlier detection of antibody; it simply takes time for enough antibodies to be generated by the host immune system in response to Borrelia antigens, even when these extremely sensitive methods are used for their detection (13). The results of other comparative studies also suggest that the use of two ELISAs conducted with defined ligands (C6 and VlsE) give results comparable to those obtained using the conventional two-tier procedure.

Although this suggests that the use of two ELISAs using defined ligands might obviate the need for doing Western blots (16), additional studies are needed to establish that point.

A major disadvantage of using Western blots is that the results obtained are qualitative, rather than quantitative in nature. The use of quantitative ELISAs and specific peptides as ligands should enable one to distinguish between high levels of serum antibody characteristic of active infection from the low levels of background antibodies often detected in patients cured of infection. Since low levels of background antibody often persist for several years after an infection has been cured by antibiotic therapy, this makes it difficult to distinguish between active infection and past exposure by means of Western blots (13). The use of quantitative ELISAs should be more fully evaluated for routine use, since ELISA plate readers with relevant software have been commercially available for many years at low cost.

A second misconception about two-tier testing is the notion that its reliability is no better than that of “a coin toss” (17). This false claim is due to misinterpretation of the results obtained early after infection — at the time an EM is present – and when sensitivity is known to be at or less than 50%; in contrast, the situation is quite different 4-6 weeks after infection by which time the full array of Borrelia specific antigens is expressed and antibodies specific for most — if not all — of these antigens can be detected in blood. There is ample evidence to indicate that individuals infected for 4 or more weeks in duration — unless immunocompromised — are seropositive by the CDC IgG Western blot criteria (13). Therefore, one must seriously question whether individuals who claim that they have suffered from Lyme disease for long periods of time or years and are seronegative by two-tier testing, really have Lyme disease. Even the most specific and sensitive diagnostic test for Lyme disease that one can imagine will not give a positive result for an individual who does not have Lyme disease.

A third major misconception is the view that the post treatment symptoms that some patients experience after receiving recommended treatment for Lyme disease (PTLDS), are due to a persistent infection termed “chronic Lyme disease” that requires longer antibiotic therapy with other kinds of antibiotics — given singly or in combination– to cure. It should be noted that the results of five placebo-controlled clinical trials on the efficacy of extended antibiotic therapy for the treatment of PTLDS, provided no evidence of a persistent infection in such patients by culture and/or other laboratory tests; the results of all of these clinical studies showed no significant lessening of symptoms which one would expect to occur if such symptoms were due to a persistent infection (18-21). Furthermore, most seronegative individuals who believe that they have “chronic Lyme disease” seldom — if ever — have evidence of a persistent infection by culture or any other laboratory test.

Some believe that reports indicating the ability of Borrelia survive antibiotic treatment in vitro mimic what occurs in vivo during “chronic Lyme disease” and suggests the likelihood of a persistent infection in patients previously treated with antibiotics. However, such in vitro studies fail to compensate for the protective effects attributed to the host immune system in vivo. More important, there is no evidence that such in vitro findings have any clinical relevance (22). The presence of antibiotic resistant “persisters” may very well be an in vitro laboratory artifact that can be explained by basic biochemical kinetics since the ability to detect “persisters” in vitro is influenced greatly by both the numbers of Borrelia and concentration of antibiotics used (23).

What are the implications for those who believe that they have Lyme disease based on symptoms alone, but are seronegative by two-tier testing? There are several that could have serious consequences:

First, the inability to make a valid diagnosis of Lyme disease based on symptoms alone, means that the decision to treat with antibiotics for prolonged periods of time until symptoms disappear — in the absence of any evidence of active infection — is unwise to say the least. Since some antibiotics (e.g., tetracyclines) are known to have anti-inflammatory properties, they may provide temporary relief against chronic pain, thus creating the false impression that this is the result of eliminating a persistent infection. However, when symptoms return after antibiotic therapy is discontinued, as often occurs when most pain relievers are discontinued, this is interpreted to be a “relapse” of infection, thereby requiring longer antibiotic therapy — sometimes for years — perhaps using different antibiotic given singly or in combination. The situation resembles what occurs when one is taking non-steroidal anti-inflammatory agents for chronic pain such as that caused by osteoarthritis. There is relief while one is taking such medication; unfortunately, the pain returns after the medication is discontinued and once the effects of the medication subside. With respect to the conditions ascribed to “chronic Lyme disease”, subsequent rounds of antibiotic are no more effective than the first. Thus, there is no true and lasting benefit attributable to extended antibiotic therapy, simply because there is no persistent infection to begin with.

Second, being dissatisfied with the failed results of extended antibiotic therapy, some pursue various unorthodox remedies that falsely claim to cure the Lyme disease that they do not have. Many of these unproven approaches not only have no demonstrable benefit but also may even be harmful (24). Often, this is done at great personal expense — sometimes for as much as $70K-$80K per year — since health insurance companies will pay only for remedies known to be beneficial and safe for the treatment of correctly diagnosed illnesses. In contrast, the cost of a recommended course of treatment for Lyme disease with an oral, generic antibiotic (doxycycline) is about $40. Obviously, it would not be in the best interest of the public health to pass legislation requiring health insurance companies to pay for unorthodox remedies of no proven benefit. That would increase the costs of medical care for all, making it even more difficult for those who can least afford it to obtain the medical care they need. Here, the solution is to demand to see published, peer-reviewed evidence showing that such unorthodox treatments are indeed beneficial and safe. Testimonials are no substitute for such rigorous proof, since for every patient claiming to have benefited from such therapy, there may be many, many more who derived no benefit whatsoever and perhaps have experienced adverse consequences.

Third, the fixation on Lyme disease — and only on Lyme disease — as the sole cause of their symptoms prevents one from seeking medical advice to consider other possible causes for their symptoms. When correctly diagnosed and treated, such symptoms may be resolved promptly, with an almost miraculous return to normal good health. In such cases, health insurance companies will cover the costs involved.

Fourth, the dissatisfaction resulting from the failure of various unproven and unorthodox remedies, as well as the dissemination of false and misleading information about Lyme disease on the internet and in the media, have generated much dissatisfaction and distrust. Unfortunately, many competent scientists and physicians, who have just the expertise needed to address key issues related to Lyme disease have become the targets of such negativity and distrust (25). To make matters worse, a concerted effort is being made to discredit the recommendations made by the Infectious Diseases Society of America (IDSA) in its guidelines for the treatment of Lyme disease (3). These guidelines are universally accepted by experts on Lyme disease throughout the world, and the treatment recommended has been demonstrated to be both beneficial and safe (25). No other set of guidelines has been subjected to such independent and intense scrutiny and critical review — and survived the process intact with no revisions recommended (26).

If we chose to abandon the rational and disciplined approaches historically associated with evidence-based science and the practice of medicine, then all we are left with is magic, superstition, and quackery. Obviously, the solution is to seek information, not from blogs and the social media, but from only reliable sources such as websites managed by the CDC (www.cdc.gov), the National Institute of Allergy and Infectious Diseases (https://www.niaid.nih.gov/ ), the IDSA (http://www.idsociety.org/Index.aspx) and the American Lyme Disease Foundation (www.aldf.com). One will find that the information derived from these sources is consistent as would be expected for information that is factually correct. Only a fool would consider that to be evidence of a conspiracy.

Finally, the IOM published a comprehensive report advocating a multidisciplinary rational approach for dealing with chronic pain and other nonspecific symptoms that occur in the general population and that often are incorrectly attributed to Lyme disease (12). Here, the goal is to identify specific biomarkers so that individuals with chronic pain can be assigned to appropriate treatment groups where they are most likely to derive tangible benefit. Its recommendations make good sense and deserve to be given serious consideration and implemented.

www.aldf.com

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