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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.
Figure 1: The natural progression of untreated Lyme disease
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.
PART 2: Disseminated infection
and late manifestations of Lyme disease The second phase of untreated Lyme
disease occurs between 1-3 months after the tick bite
and is called early disseminated infection. In some of
these instances the rash of early Lyme disease will
still be present; however, in a significant number of
patients, the early rash cannot be identified (see
figure 1). This second phase of disseminated or distant
Lyme disease occurs because the blood stream is invaded
by the bacteria of Lyme disease. In studies done at
Johns Hopkins Hospital, we showed that many patients
with the early rash of Lyme disease already had bacteria
spread through the blood stream despite the absence of
any symptoms or manifestations. [9] This is consistent with the fact that
untreated patients often go on to develop distant
manifestations of the disease. These typically involve
other areas of the skin, the nervous system, the heart,
or the joints.
When the bacteria of Lyme disease
spread through the blood stream to other areas of skin,
they can cause multiple skin rashes called disseminated
cutaneous Lyme disease (figure 5). Although disseminated
cutaneous Lyme disease may resemble multiple tick bites,
it is actually due to spread of the infection from a
single tick bite through the blood stream. Because of
this, the distant rashes do not have the classic
characteristic appearance of erythema migrans and are
often much more variable in their shape, size, and other
characteristics.
Figure 5: Disseminated cutaneous lesions of Lyme disease
The next manifestation of
disseminated Lyme disease is involvement of the nervous
system, often in the nerves outside of the brain. The
most common manifestation is 7th nerve palsy,
often called Bell’s palsy, in which the nerve is
transiently damaged, producing a droopy face that
resembles a stroke (figure 6). Other nerves throughout
the body can also less commonly be infected, which can
cause pain that mimics other conditions such as
sciatica. Lyme disease can also manifest as a viral-like
meningitis syndrome.
Very rare manifestations of disseminated Lyme
disease include cardiac involvement that may cause
damage to the electrical system of the heart and may
require temporary hospitalization and pacemaker
placement.
Figure
6: VII Nerve Palsy in Lyme Disease
The diagnosis, treatment, and
prognosis of early disseminated infection with Lyme
disease are well known. The diagnosis is based on
finding the characteristic illness in conjunction with
either the rash of early Lyme disease or a positive
serologic blood test for Lyme disease. Serologic blood
tests are based on the finding of the human antibodies
that are made in response to the infection. By the time
of early disseminated infection, these antibodies are
almost always present in the blood stream and can be
identified with simple blood tests. Occasionally,
patients with early disseminated Lyme disease need a
test called a spinal tap to exclude infection of the
nervous system. This is an important finding because
involvement of the nervous system is one of the
indications for treatment with intravenous therapy.
Fortunately,the prognosis for the early disseminated manifestations
of Lyme disease is good. Patients with 7th
nerve palsy almost always recover function of their
nerve, and their facial muscles return to normal.
Permanent cardiac damage is extraordinarily rare, and
the overall outcome from this group of patients is very
good when they are appropriately diagnosed and treated.
The third manifestation of
untreated Lyme disease is late Lyme disease, which
manifests months to years after the initial tick bite
and untreated early infection.
As a result, the rash is never present at the
time that late Lyme disease is diagnosed. Diagnosed
patients have had infection for many months and thus
should universally have a positive IgG western blot for
these Lyme antibodies.
The most common manifestation of late Lyme
disease is swollen joints, especially the knee joint
(figure 7). This was the initial manifestation that led
to the discovery of Lyme disease in Connecticut, when an
observant mother noticed that many children were
developing swollen knees months after they had had a
rash. This connection between a previous rash and a
swollen knee was one of the first clues to the discovery
of Lyme disease in the United States. Patients with
swollen knees often go first to orthopedic surgeons
because of the pain and swelling. Swollen joints
eventually occur in up to 60% of individuals who were
untreated at the time of their initial Lyme infection.
Figure 7: Swollen knee joint in Lyme Disease
You may ask how the patients were
not initially diagnosed and treated, allowing the
infection to go on to develop late complications. This
may occur because initial illness was simply
misdiagnosed or because patients often have no
recollection of their primary infection. In some cases,
patients never notice or even develop a rash, and the
early symptoms alone are not always recognized as being
compatible with Lyme disease. It should be recalled that
without treatment those initial manifestations resolve
on their own and may not recur until the patient notes
the swollen knee months or even years later.
Occasionally, other joints besides the knee, such as
smaller joints of the hands or feet, can be involved
with late Lyme arthritis.
The neurologic system may again be
involved in the late phases of Lyme disease. Rarely, the
central nervous system is infected with syndromes that
mimic strokes or multiple sclerosis. More commonly, the
peripheral nervous system is involved with damage to the
nerves resulting in pain, numbness, and abnormal
sensations in the skin.
The diagnosis of late
manifestations of Lyme disease is based on the objective
findings of the damage done by the disease process. By
objective findings, we mean abnormalities that can be
seen by an experienced physician on the physical
examination of the patient. In the instance of
arthritis, this would mean that the joints are visibly
swollen and inflamed. In the manifestations of
neurologic involvement, this would mean that there are
visible findings of nerve damage that can be objectively
quantified by a physician. All patients with late Lyme
disease who have not previously been treated should have
positive blood tests for the antibodies to Lyme disease.
In the case of joint involvement, fluid may be obtained
from the joint by an orthopedic surgeon. If this is
done, there are characteristic findings of the cells
that are removed, allowing the opportunity to verify the
diagnosis with what is called a PCR test on the joint
fluid.
In the case of neurologic
involvement, the diagnosis is confirmed with imaging
tests such as MRIs that would show damage to the nervous
system. Spinal tap or lumbar puncture is also an
important test in neurologic disease to confirm that
there is, in fact, evidence of inflammation in the
cerebrospinal fluid which would be expected with active
infection. An additional test that is used in patients
with nerve damage in the extremities is called a nerve
conduction study where a series of needle tests is used
to demonstrate that there is damage to the functioning
of the nerves in the extremities or face.
The prognosis of patients with late
Lyme disease after appropriate treatment is a mixed
picture. This is a theme in Lyme disease that is
important to understand. It was known very early on that
some patients with late Lyme arthritis did not always
recover completely after appropriate treatment. Even
patients who received intravenous therapy occasionally
had persistent evidence of joint inflammation. Dr. Alan
Steere at Yale University has spent his career studying
patients with persistent joint disease after treatment
for Lyme disease. Approximately 10% of patients who are
treated have persistent symptoms, and these patients are
called antibiotic refractory late Lyme arthritis
patients. Of note, persistent infection cannot be
demonstrated in patients after treatment. When fluid
from their joints is examined, bacteria are not able to
be recovered, raising questions about why patients
continue to have ongoing symptoms.
Some patients with late neurologic
disease may not recover completely after treatment. This
may be due to the fact that the neurologic system does
not heal easily after it has been damaged for a long
period of time. We
are all well aware that other neurologic diseases such
as stroke may result in permanent damage that is not
able to be repaired by the body. This is the case in
Lyme disease as well and accounts for the fact that
recovery from neurologic symptoms may be partial or very
slow and may not occur for a period of months or even
years after treatment.
Patients with late Lyme disease who
are treated may also have persistent subjective symptoms
after treatment. The term “subjective symptoms”
refers to symptoms that are readily apparent to the
patient but do not result in quantifiable or visible
damage to the patients body that can be seen and
objectively described by the physician. An example of
this would be a painful joint that is disabling to the
patient but does not exhibit any signs of inflammation
or infection to the examining physician. Other
subjective symptoms would be symptoms such as fatigue or
memory problems that again cannot be quantified in a
typical clinical examination but can be completely
disabling to the patient. What is apparent in Lyme
disease is that subjective symptoms after treatment are
common. In late Lyme disease after treatment, anywhere
from 13% to 30% of patients have persistent post
treatment symptoms such as joint achiness, weariness,
and memory problems.
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.
- Coulter P, Lema C, Flayhart D, Linhardt AS, Aucott JN, Auwaeter PG &
Dumler JS.
Two-year evaluation of Borrelia burgdorferi culture and
supplemental tests for definitive diagnosis of Lyme disease:
J of Clin Micro 2005;43(10: 5080-5084.
PART 3: Late manifestations -- Coming Soon
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