Basic Understandings in Chronic Lyme Disease
The purpose of this paper is to describe the basic biology behind chronic Lyme disease, first discussing major components of the illness and then building up to how the complex factors in chronic Lyme interact, particularly during treatment. I have not tried to be all-inclusive but rather have attempted to draw a picture that can be used as a tool for understanding.
How Lyme Invades
Lyme bacteria invade the human bloodstream after a tick attachment of 4 hours or more (1). In the blood, it is in the spirochete form. This is the “intercellular” form of the infection. It is outside the body cells.
It then leaves the blood and invades other body tissues. When it gets inside a cell, it becomes an “intracellular” infection. It can convert to a form called the “L-form,” which has no cell wall, unlike the spirochete form (1). Studies show it can live inside many cell types (2), but it is especially attracted to joint and nerve tissues (3).
Under stressful conditions the Lyme bacteria also converts to a cyst form. A study has shown that this occurs frequently in the fluid of the spinal cord and brain (4). The pressure of antibiotics is believed to cause Lyme to convert to the cyst form.
From Jemsek Specialty Clinic website:
The emerging research on a cystic form of Bb has changed the long-term treatment picture. In theory, biologic and environmental stress promotes conversion or "morphing" of the spirochetal form to a cystic form, apparently within hours, and this form exhibits different surface antigens and therefore a different presentation to the immune system. The converse is documented, i.e. the cystic form can readily convert back to the spirochetal form (122). It is known that antibiotic pressure, utilizing medications effective against the spirochetal form, accelerates cyst formation (123). In vitro, incubation of Bb with ceftriaxone, for example, leads to Bb cyst formation after just four hours, much faster and more completely than doxycycline exposure (123). As expected, neither of these compounds (or any other commonly used antibiotics in LD) have any effect of the cyst. On the other hand, many studies indicate that metronidazole is effective in killing the cystic form, but not the spirochetal form, of the Bb bacteria (124). For that reason, many Lyme aware physicians have begun to see the value of using combination antibiotic therapy with the addition of the agent metronidazole. In our experience, patients with Bb infection routinely develop a Herxheimer reaction in response to treatment with metronidazole and occasionally these reactions may be severe and limiting. Long term suffering neuroborreliosis patients seem to have the most difficult time with this therapy, suggesting that the cyst load may be higher in this patient group, particularly in the CNS. If this is the case, one might assume that conversion to a cyst form is a natural evolution of the illness for at least some Bb strains. (5)
Treatment implications:
In Lyme disease beyond the earliest stage, more than one antibiotic is required to treat it effectively. Antibiotics are needed for each form of the bacterium (spirochete, L-form and cyst), and must treat both in the bloodstream (intercellular) and inside the cells (intracellular) (1)(5).
Where Symptoms Come From
When the Lyme bacterium has spread through the body and invaded cells, it creates many symptoms. Most of the symptoms are caused by the body’s own immune response to the infection. Wherever an infection is being fought, inflammation occurs. Cleveland Clinic on inflammation:
When inflammation occurs, chemicals from the body’s white blood cells are released into the blood or affected tissues in an attempt to rid the body of foreign substances. This release of chemicals increases the blood flow to the area and may result in redness and warmth. Some of the chemicals cause leakage of fluid into the tissues, resulting in swelling. The inflammatory process may stimulate nerves and cause pain. (6)
Inflammation caused by immune system response can cause fatigue, fever, pain, and cellular dysfunction. Cells can be damaged or die.
Dr. Virginia Sherr describes Bell’s palsy and gastrointestinal symptoms related to the inflammation of nerves in Lyme disease:
Bell's palsy signifies paralysis of facial muscles related to inflammation of the associated seventh Cranial Nerve…. Gastrointestinal Lyme disease may cause gut paralysis and a wide range of diverse GI symptoms…neuropathies can result from the immune (cytokine) system over-activation often seen in chronic Lyme cases. This may lead to prolonged inflammation with resultant damage to the enteric nervous system and/or the autonomic nervous system supplying the gut. In addition, possible spirochetal paralysis of the vagal nerve(s) may cause temporary or long-lasting disruption of normal small intestinal mobility….(7)
In chronic Lyme, the inflammation never goes away, so damage accumulates, and the immune system never rests (8). Chemicals in the body that the immune system needs to function get used up over time (1). Autoimmunity may be triggered (8).
Co-Infections
It is well known that ticks transmit other pathogens. We most commonly think of Ehrlichia, Babesia, and Bartonella. When present, these additional microbes become a major issue as the immune system becomes suppressed in chronic Lyme (1)(5)(9).
Also, pathogens that already live in small numbers inside of us, and which are usually kept in check by a healthy immune system, become problems when the immune system becomes weakened by Lyme (9).
Lyme Grows Slowly
Lyme and some of the associated co-infections are REALLY slow growing (3)(5)(9). This fact has implications for how LLMDs (Lyme Literate Medical Doctors, i.e. physicians who have experience in treating tick-borne diseases) treat it.
First, Lyme must be treated for a long duration. From “Complexities of Lyme Disease” by Tom Grier:
Since most antibiotics can only kill bacteria when they are dividing, a slow doubling time means less lethal exposure to antibiotics. Most bacteria are killed in 10-14 days of antibiotic. To get the same amount of lethal exposure during new cell wall formation of a Lyme spirochete, the antibiotic would have to be present 24 hours a day for 1 year and six months! (3)
On the bright side, slow growth opens an option in treatment called “pulsing,” in which antibiotics can be given on a schedule that skips days and uses higher dosages for better effectiveness with less side effects (9). Dr. Joseph Burrascano mentions this “advanced treatment” option for chronic Lyme in his guidelines (1).
The long duration needed to treat Lyme is also influenced by other biological defenses such as the presence of protective biofilms (10) and the influence of an “efflux pump” mechanism that Lyme uses to keep antibiotics from reaching killing concentrations within the microbe (11). Efflux pump inhibitors are a type of antibiotics being investigated for use against Lyme. (Example: Tigecycline) (11)(12)
Lyme Evades, Invades, and Suppresses the Immune System
A 2008 study from the University of Toledo states:
Upon introduction into the host dermis by an infected tick, the spirochetal bacteria must quickly adapt to their vertebrate host, disseminate from the skin to various host tissues, and evade the developing immune responses. This evasion must continue until the bacteria receive appropriate signals that lead to reemergence from their immunoprivileged niche and subsequent migration to and infection of a feeding tick. Although this extended persistence within an immunocompetent host is essential for the existence of the bacteria, the mechanisms that they utilize to escape immune clearance are largely unknown (13).
The Lyme bacterium has evolved to avoid being destroyed by our immune systems. How it does this is poorly understood, but we know, for example, that it hides in tissues, particularly collagen (fibroblasts) and avoids immune detection (3)(5), it changes its surface antigens, it invades immune system cells such as macrophages and lymphocytes (3)(5), it suppresses the production of substances necessary for immune response (13), and it suppresses natural killer (NK) cells such as the CD57 (1). On top of all that, the constant work by the immune system uses up necessary chemicals, resulting in things such as adrenal fatigue and vitamin deficiencies, which further harm the ability of the immune system to function (1).
An Inconvenient Truth: The Herxheimer Reaction
The Herxheimer reaction is a phenomenon where the die-off of bacteria makes symptoms worse before they get better (1)(5)(14). The Lyme bacterium is especially obnoxious in how bad it makes a patient feel when antibiotics are doing their job! Toxins are produced by the immune system in response to the Lyme die-off and increase inflammation wherever the Lyme is hiding, and also create fatigue, headache, fever, etc. as the toxins get dumped into the bloodstream (5)(14). Whatever symptoms exist often worsen, new symptoms appear, and the increased fatigue can be crushing. Even psychiatric or emotional symptoms such as depression or irritability worsen.
Helping the patient tolerate the die-off reaction or “herx” is important. LLMDs recommend a variety of methods for “detoxing” to help lessen the herx effects (1)(5)(8)(9). Drinking a lot of fluids is at the top of everyone’s list. Some herbals and other detox supplements work by binding with the toxins in the gut so that they can pass out of the body.
In Dr. Joe Jemsek’s words:
The ‘toxins’ to which I refer are termed pro-inflammatory cytokines and are produced by T lymphocytes and which include IL-2, TNF, and IL-6 primarily…these pro-inflammatory cytokines tend to leach into fat and probably vascular tissues and circulate in blood where they pass thru the liver and are passed into the hepatobiliary enterohepatic circulation cycle, i.e. collected in bile and resorbed by the gut…the idea is for the resin to bind them in the gut and then pass out thru the gut…I am not a huge fan of this but will support it in pts who note benefit, so long as I am certain they are not binding meds in the gut…(15)
The severity of the herx during treatment tends to be proportional to the bacterial load in the body (1). As the bacterial load lowers, so does the herx (5). If the herx is too severe, the doctor may reduce the dose of medication for a while, and then try to go back up. Treatment then takes longer, and too low a dose may be ineffective, so a balance must be found between the herx being tolerable and treatment being adequately effective.
It is a job of the LLMD to help the patient distinguish between a herx and other possible side effects of the medications or allergic reactions.
The build-up of toxins from the herx response over long periods can become a stressor on the immune system and counter-productive to getting well. Some LLMDs recommend “wash out” periods or treatment “holidays” to allow for effective detoxification (5)(9).
In effective treatment, the die-off reaction is the worst when starting treatment, and also when starting a new antibiotic, and then lessens over time (5). Lyme symptoms should start to improve as the herxing lessens (5).
Chemical Bridges
The symptoms from chronic Lyme will only be resolved by killing the bacteria, but there are times in treatment when symptoms can be treated temporarily with medications and other therapies that reduce the symptoms to allow the patient to get through Lyme treatment tolerably (9). An important example of this is in the case of severe neurological symptoms such as seizures, or depression, rage, OCD, etc… The treatment of pain is also important. Since symptoms will initially worsen on antibiotic treatment (5), pre-medicating difficult symptoms creates a “chemical bridge” to allow the patient to pass more safely and tolerably through treatment to the other side where the infection is reduced and symptoms truly resolve.
Complicated Treatment for a Complex Disease
The biology of chronic Lyme creates a system in which Lyme in its three different forms plus other microbes wear down the immune system and at the same time compete with each other. Effective treatment, therefore, must address ALL of this complexity (1), and it must do so in the face of the challenge of the Herxheimer response with its associated discomfort and toxicity.
What is the goal of treatment in chronic Lyme disease? We know from the 2008 UC Davis study (16) that after Lyme has found its way out of the blood stream and into tissues, it can hide from antibiotics, even a LOT of antibiotics for a long time, so we can have no realistic expectation of a 100% cure. Rather, the goal of treatment must be remission (8); a state where the number of bacteria left after treatment can be kept in check by the recovering immune system (8)(9), leaving the patient free of symptoms. Some irreparable damage may be done by the infection (5). How much damage is hard to determine since cellular healing and rebuilding, especially in nerves, can take a long time.
Patient outcomes cited by Dr. Sam Shor:
100 patients with chronic Lyme disease that I aggressively treat with formal antimicrobials, at least 80-85% improve. Of the 100, at least 50% go back to normal. There are some residual symptoms in a subset even once you get off antibiotics. Of the 100, there are 10-15% of people that I throw the kitchen sink at and they just don't seem to improve. I refer them to other ILADS doctors such as Joseph Jemsek, MD. (8)
The Balancing Act of Treatment
Factors in treatment that must be balanced:
Examples of the balancing act:
Preventing Relapse
If chronic Lyme disease can’t be cured, then will I have to stay on antibiotics the rest of my life? Good question.
The official position of ILADS is to treat as long as symptoms reflect ongoing infection (17). Dr. Joseph Burrascano also recommends a normal CD57 count before stopping (1)(8). No guarantee is made that one will not relapse, and retreatment is recommended when relapse does occur (1)(8)(17).
One approach being used by some LLMDs is that of a “maintenance” protocol consisting of either herbal antimicrobials (8) such as samento and cumanda or short periodic dosages of antibiotics that keep the infection in remission and give early warning of relapse by return of the herx (18). Maintenance protocols do not guarantee one will not relapse (1)(8), but they help avoid the extremes of relapse commonly experienced by Lyme patients in the past.
About the Author:
Kathy Meyer received her B.S. degree in biology from the College of William and Mary in 1976. She is a teacher and has two young adult children with Lyme disease and also raised a son with profound multiple disabilities and cerebral palsy until his death at age 15. Kathy receives her best encouragement and support for the Lyme journey in a growing group of very special mothers in Northern Virginia! This paper is with love to them.
Kathy Meyer
klizm@aol.com
9/09/2009
References
(1) Burrascano JJ. Advanced Topics in Lyme Disease: Diagnostic Hints and Treatment Guidelines for Lyme and Other Tick-borne Illnesses, 16th Ed. October, 2008. http://www.ilads.org/lyme_disease/B_guidelines_12_17_08.pdf
(2)
Livengood JA,
Gilmore RD Jr. Invasion of human neuronal and glial cells by an infectious
strain of Borrelia burgdorferi. Microbes Infect 2006, 8:2832-2840.
http://www.ncbi.nlm.nih.gov/pubmed/17045505?dopt=Abstract&holding=f1000,f1000m,isrctn
(3) Grier TM. The Complexities of Lyme Disease. http://www.canlyme.com/tom.html
(4)
Miklossy J, Kasas S, Zurn A, McCall S, Yu S, McGeer PL. Persisting
Atypical and Cystic Forms of Borrelia burgdorferi and Local Inflammation
in Lyme Neuroborreliosis. Journal of Neuroinflammation 2008, 5:40.
http://www.jneuroinflammation.com/content/5/1/40
(5) Jemsek, JG. Lyme Disease—Detailed Overview (2002). Jemsek Specialty Clinic Website. http://www.jemsekspecialty.com/lyme_detail.php
(6) http://my.clevelandclinic.org/symptoms/Inflammation/hic_Inflammation_What_You_Need_To_Know.aspx
(7) Sherr VT. Bell’s Palsy of the Gut and Other GI Manifestations of Lyme and Associated Diseases. Practical Gastroenterology, April 2006. http://www.lymenet.de/literatur/vtsherr_gut.htm
(8) Forsgren S. From IDSA to ILADS, A Journey Toward Reconciliation. Public Health Alert, May 2009. (Interview with Dr. Samuel Shor.) www.intmednova.com
(9) Garcia T. The Power of Truth Spoken by Joseph G. Jemsek, MD. Public Health Alert, 2009. http://publichealthalert.org/Articles/tinagarcia/Jemsek%20Part%201.htm
(10) MacDonald A. Interview transcript in Lyme Disease Research Database, April, 2008. http://www.lyme-disease-research-database.com/alan-macdonald-transcription.html
(11) Weintraub P. What We Don’t Know About Lyme. Experience Life, June 2009. http://www.experiencelifemag.com/issues/june-2009/health-wellness/what-we-dont-know-about-lyme.html
(12) Yang X, Nguyen A, Qiu D, Luft BJ. In vitro activity of tigecycline against multiple strains of Borrelia burgdorferi. The Journal of Antimicrobial Chemotherapy, January 31, 2009. http://jac.oxfordjournals.org/cgi/content/abstract/dkn551v1
(13) Lazarus JJ, Kay MA, McCarter AL, Wooten RM. Viable Borrelia burgdorferi Enhances Interleukin-10 Production and Suppresses Activation of Murine Macrophages. Infection and Immunity, March 2008. http://iai.asm.org/cgi/content/full/76/3/1153
(14) http://en.wikipedia.org/wiki/Herxheimer_reaction (Good history, description and documentation of the Herxheimer reaction.)
(15) Jemsek JG. Personal correspondence with the author, 2009.
(16) E Hodzic, S Feng, K Holden, KJ Freet, SW Barthold. Persistence of Borrelia burgdorferi Following Antibiotic Treatment in Mice. Antimicrobial Agents and Chemotherapy, March 2008. http://aac.asm.org/cgi/reprint/AAC.01050-07v1
(17) Cameron DJ, Gaito A, Harris N, Bach G, Bellovin S, Bock K, Bock S, Burrascano J, Dickey C, Horowitz R, Phillips S, Meer-Sheerer L, Raxlen B, Sherr V, Smith H, Smith P, Stricker R. ILADS Lyme Disease Treatment Guidelines. http://www.ilads.org/lyme_disease/treatment_guidelines_summary.html (Full text can be downloaded.)
(18) Jemsek JG. Excerpts from Lyme Borreliosis Complex: Evaluation and Preparation, Treatment and Recovery. Presentation at University of South Florida, January 19, 2008.