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Lyme disease can be confusing and difficult to understand. The infection is more complicated than most bacterial infections because it has both an early and a late phase of disease. The early phase of the illness may remain localized to the immediate area surrounding the infecting tick bite or may result in signs of “disseminated” or blood-borne infection. Disseminated infection results when the bacteria enter the blood stream and infect other organs systems such as the joints, heart, and the nervous system. Late manifestations of infection may occur months to years after untreated early Lyme disease. Late Lyme disease results from bacteria that spread during the initial dissemination phase, only to result in symptoms months or even years later.
Perhaps the most difficult aspect of Lyme disease for both patients and physicians is recognizing and understanding the symptoms of Lyme disease that persist after standard courses of antibiotic therapy. This post treatment Lyme syndrome is a controversial topic where diverse opinions are the rule. Patients are often overwhelmed by the different sources of information that are found on the internet regarding Lyme disease because of this complexity. Post treatment Lyme Syndrome is often called chronic Lyme disease by the public. The name post Lyme disease syndrome is used in the recent Infectious Disease Society Guidelines (1) Much of the confusion may be clarified by understanding that many of the patients suffering from persistent symptoms of Lyme disease probably have post-treatment Lyme syndrome. Until we understand the origin and effective treatment of post treatment Lyme syndrome, the controversy and confusion will likely continue.
One paradigm of thinking about patients with Lyme disease separates the manifestation of untreated Lyme disease from symptoms that persist after treatment (whether intentional treatment for Lyme disease, or unintentional antibiotic treatment administered for an incorrect diagnosis). This way of thinking about pre and post treatment Lyme disease may help you to understand the various manifestations of Lyme disease including the newly defined syndrome of post treatment Lyme Syndrome. The following educational material and links will attempt to captures the complexity of Lyme disease and identifies those areas that a well understood while identifying those areas of uncertainty and confusion.
PART 1: Early Lyme Disease
In order to understand Lyme disease, it is very important to understand that the disease is a complicated illness that is manifested differently at different stages of the illness. This may be a new concept to many people who are used to the idea of simple infections like urinary tract infections or bronchitis that have a single phase and are treated and then go away. Unfortunately, Lyme disease is not like that. Lyme disease has three phases of illness that occur in a predictable order when a patient is not treated. The first early phase of Lyme disease is when the infection is localized to a single skin lesion. The second phase of Lyme disease occurs after the bacteria from the initial skin lesion spread in the blood stream throughout the system and are manifested in distant sites. Common sites of involvement include the joints, other areas of the skin, the nervous system and rarely the heart. The third phase is the late phase of Lyme disease that can occur months or even years after the initial infection. Late Lyme disease is manifested when the infection recurs at distant sites such as the joints or nervous system.
These three phases of Lyme disease follow in a natural progression which I will call the natural history of untreated Lyme disease. In order to understand the controversy of Lyme disease, however, it is also important to understand what happens to patients with Lyme disease after they are treated. Unlike many simple infections, many patients with Lyme disease have symptoms that persist even after what should be effective therapy. This concept may be familiar to people who know about the idea of fatigue that persists for many weeks or months after infectious mononucleosis. The same type of situation occurs after treatment of Lyme disease, although in this case symptoms can last for much longer periods of months or even years.
Only by understanding the progression and outcome of both untreated and treated Lyme disease will we be able to understand the controversies currently surrounding Lyme disease. As I will discuss later, this controversy really centers on understanding and explaining why patients who have been treated for Lyme disease often manifest persistent and often disabling symptoms.
The natural progression of untreated Lyme disease unfolds over a period of months to years (figure 1).
As this figure shows, Lyme disease has 3 distinct phases including an early skin lesion called erythema migrans, a second phase in the following 1-3 months which includes early involvement of the neurologic and other distant symptoms, and finally a third phase that is manifested months to years later involving the musculoskeletal and neurologic systems. There is a characteristic response of the human immune system manifested as antibody production that has a consistent relationship to this progression of Lyme disease. The figure shows that there are 2 types of antibodies, IgM and IgG antibodies, which form in a predictable time sequence in response to infection in Lyme disease.
The bacterial agent of Lyme disease is an unusual type of bacteria called a spirochete. The name of this spirochete bacterium is Borrelia burgdorferi, and as is shown in this figure the spirochete is found in the blood steam transiently in many patients early on in their infection. This accounts for the phenomenon of distant disease that spreads through the blood stream and appears at later periods of time in untreated patients.
Figure 1 shows the first phase of Lyme disease which is best known by the lesion or skin rash called erythema migrans (which may or may not be a classic bull’s eye rash, see below). The incubation period for early Lyme disease is anywhere between 3 and 30 days after the bite of the infected tick. There are three possible ways that infection with Lyme disease can manifest itself in this early phase. The first is asymptomatic infection where there actually is no evidence of infection in the person who was bitten. You may ask how we know the patient was infected if there are no symptoms, and the answer to that is that they develop antibodies that are characteristic and specific to exposure and infection with the bacteria. That is called asymptomatic seroconversion, and it occurs in about 11% of patients.
The second and most common way that a patient manifests infection is with the characteristic skin lesion called erythema migrans. Typically, this is seen about 7-10 days after the tick bite at a time in which the tick is no longer present. In addition, the majority of patients do not even recall a tick bite because of their small size and painless bite. Patients with the skin lesion may or may not be sick. Some of the patients have a flu-like illness and some do not. This flu-like illness can be present as the only manifestation of Lyme disease in approximately 16% of patients. The flu-like symptoms would include fever, achiness of the joints and muscles, headache, and tiredness. Patients may be mildly ill or may be sick enough that they are in bed and miss several days or even a week or two of work.
The classic skin lesion of Lyme disease is shown in figure 2.
Figure 2: “Classic” Lyme EM rashes: bulls eye and uniform lesion
People are usually aware that the classic skin lesion can have a “bull’s eye” appearance. What they are unaware of is that as many as 80% of skin lesions of Lyme disease are not bull’s eye in appearance but are uniformly red throughout(2). What is always characteristic, however, is that skin lesions of Lyme disease are round or oval and sharply demarcated. They are often warm, but they rarely are severely painful or itchy. The skin lesions last for weeks and expand at the rate of 1 or 2 cm a day reaching an average size of 15 cm, although they can be considerably larger. The skin lesion of Lyme disease may be missed or not diagnosed correctly. A patient may not see a skin lesion that is in an unapparent location because, again, they are often not painful. Sometimes, patients see skin lesions and misconstrue their cause and attribute them to spider bites or other types of injuries(3).
Occasionally, the skin lesions of Lyme disease have different appearances that can be confusing to both patients and physicians. One or two percent of skin lesions have fluid-filled blisters or pustules at the center of the skin lesion (4). Occasionally, the skin lesion has more of a bluish appearance and is misconstrued as a bruise. Examples of variations in the appearance of the skin lesion are shown in figure 3.
Figure 3: Lyme EM Rashes can be mistaken for spider bites or other skin infections
It is important to understand that only a minority of tick bites actually transmit Lyme disease. On average, approximately 2% of tick bites result in Lyme disease. Tick bites that do not cause Lyme disease still may leave a small dime-sized or less lesion where the tick was attached to the skin. These small tick bite skin lesions can last for weeks but do not expand and enlarge the way the Lyme disease skin lesion does.
Figure 4: Tick bite reaction without rash of Lyme disease
The diagnosis of early Lyme disease is what is called in the medical field a “clinical diagnosis.” This means that the diagnosis of early Lyme disease is based on the physician’s recognition of the characteristic erythema migrans skin lesion. Blood tests should not be counted on for diagnosis of early Lyme disease and, in fact, can be quite misleading. Blood tests are misleading in early Lyme disease because there are a high percentage of falsely negative Lyme blood tests in the first 2-4 weeks of infection(5). If the characteristic skin lesion of Lyme disease is not present in the early illness the diagnosis is much more difficult to make. The most appropriate course of action may be to draw blood tests, realizing that they may be negative, and observe the patient without beginning antibiotic treatment. The test can then be repeated in 2-4 weeks’ time. After this 2-4 week time period, the human immune system should have had time to make the characteristic antibodies and the follow-up blood test should be positive. There may be cases where the clinical situation calls for antibiotic treatment in the absence of a skin lesion, however in this situation, the treatment must be an individual decision made by the physician and patient without the benefit of a definitive diagnosis.
The treatment of early Lyme disease with a skin lesion and no other manifestations of spread of infection is with oral antibiotics (6). In adults, oral doxycycline is the treatment of choice. In children under the age of 12, amoxicillin is the preferred antibiotic because of the side effects of doxycycline. An important point to make, however, is that many commonly used antibiotics for other infections such as quinolone antibiotics (the most well known being ciprofloxacin), as well as other commonly used antibiotics such as a Z-Pak or antibiotics called first generation cephalosporins do not effectively treat Lyme disease(7,8). As we all know, these other antibiotics are used for other types of infections such as sinusitis and urinary tract infections commonly treated in primary care medicine. Because these antibiotics are not effective against Lyme disease, it is very important that physicians be certain of the diagnosis and that they are aware that they should not prescribe antibiotics without activity against Lyme disease in situations where the diagnosis of Lyme disease is a possibility.
Reference:
- Wormser GP, Dattwyler RJ, Shapiro ED, Halperin JJ, Steere AC, Klempner MS, Krause PJ, Bakken JS, Strle F, Stanek G, Bockenstedt L, Fish D, Dumler S & Nadelman RB. The clinical assessment, treatment and prevention of Lyme disease, Human Granulocytic Analplasmosis and Babesiosis: Clinical Practice Guidelines by the Infections Diseases Society of America. Clin Infec Dis 2006;43: 1089-1134Early Lyme Wormser
- Tibbles CD & Edlow JA. Does this patient have erythema migrans? JAMA 2007;23:2617-2627.
- Osterhoudt KC, Zaoutis T, Zorc JJ. Lyme Disease Masquerading as Brown Recluse Spider Bite. Annals of Emerg Med 2002;39(5):558-61.spider bite reference
- Goldberg NS, Forseter G, Nadelman RB, et al. Vesicular erythema migrans. Arch Dermatol 1992 Nov;128(11):1495-8.
- Wormser GP. Early Lyme disease. N Engl J Med 2006; 354:2794-2801
- Treatment of Lyme Disease. The Medical letter on Drugs and Theraputics. 2007; v49 (issue 1263) 49-51
- Failure of treatment with cephalexin for Lyme disease. Arch Fam Med 2000; 9:563–7
- Luft BJ, Dattwyler RJ, Johnson RC, et al. Azithromycin compared with amoxicillin in the treatment of erythema migrans: a double blind, randomized, controlled trial. Ann Intern Med 1996; 124:785–91.
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