Update on Lyme Disease - Diagnosis and Treatment
By Robert Pedowitz, DO, FACOFP
Abstract: Since 1982, Lyme disease has been the most common vector-borne diagnosed illness in the United States. It is caused by the spirochete Borrelia burgdorferi, which is transmitted to humans by Ixodes scapularis or Ixodes pacificus deer ticks. Approximately 20,000 cases of Lyme disease are reported annually.1 Despite the frequency of this condition and that the topic is well researched, much confusion exists today about the diagnosis and management of acute and persistent Lyme disease, and of post-Lyme disease syndrome. This paper will provide an update of recent guidelines and summaries of diagnosis and treatment of Lyme disease.
Background
Lyme disease, or Lyme borreliosis, is a systemic illness, caused by a deer tick [Ixodes scapularis (also known as I. dammini) or Ixodes pacificus] bite that transmits the spirochete Borrelia burgdorferi. The tick must be attached to a human and feeding for 24-48 hours for the bacteria to be transmitted. The disease cannot be transmitted person to person or from pets, food, or breast milk. Untreated Lyme disease acquired during pregnancy may lead to infection of the placenta and possible stillbirth. However no fetal effects have been confirmed if the mother receives appropriate and timely antibiotic treatment. While no cases have been linked to blood transfusion, the bacteria can live in blood stored for donation.2 Therefore, individuals infected with Lyme who have not completed antibiotic treatment should not donate blood.
The infection is most commonly seen in the Northeastern, mid-Atlantic, and north-central United States, and most cases occur in persons aged five to 14 years, and 45-54 years. The peak incidence is during the summer, but infection may occur between May and November (less than 10 percent of cases occur between December and April). The national average of cases is 8.2 per 100,000 persons. The disease is reported to be endemic in 10 states – Connecticut, New Jersey, Delaware, Maryland, Massachusetts, Rhode Island, New York, Pennsylvania, Minnesota and Wisconsin.
A Healthy People 2010 objective is to reduce the annual incidence of Lyme disease from 29.2 cases per 100,000 population to 9.7 cases per 100,000 population in these states.3 In reviewed data3 by the Centers for Disease Control and Prevention (CDC) of 64,382 reported infected patients from 2003-2005, 93 percent were from the above states. Males represented 54 percent of cases, and of 50 percent of cases that specified race, 97 percent were white, 2 percent black, and less than 1 percent as Asian/Pacific Islander or American Indian/Alaska Native.
Clinical Features
Early Disease
The illness can cause symptoms that affect the dermatologic, rheumatologic, neurologic and cardiac systems (see Table 1). Many of the symptoms associated with Lyme disease are non-specific, and a patient with Lyme disease may only show a few of the symptoms listed below. Most commonly, the best clinical marker for the disease is erythema migrans (EM), which is the initial skin lesion that occurs in 60 percent-80 percent of affected patients.4 Reported symptoms in this patient population studied by the CDC included erythema migrans (70 percent), arthritis (30 percent), facial palsy (8 percent), radiculopathy (3 percent), meningitis or encephalitis (2 percent), and heart block (less than 1 percent).3
Primary erythema migrans is referred to as a bulls-eye lesion, based upon its characteristic and distinctively diagnostic appearance as a round or oval, expanding erythematous skin lesion with central clearing as it enlarges. While this is the characteristic appearance of erythema migrans, the rash also may be homogenously erythematous (see Figure 1), or partially purpuric, or even have vesicles or pustules at the center of the primary lesion.6 The lesion is typically ≥5 cm in largest diameter, and may appear seven to 14 days (with a range of 3-30 days) after the tick has detached or been removed. The rash may be warm, but is not usually painful.5 If a rash of smaller diameter appears within 48 hours of tick bite, it is most likely a hypersensitivity reaction, and may appear urticarial and begin to disappear within another 24-48 hours. There may be more than one erythema migrans skin lesion, and the secondary lesions will be ≤ 5 cm, may occur anywhere on the body, and will spread via the hematogenous system.6
There are other common symptoms of early Lyme disease as well, which include flu like symptoms in the first few weeks, consisting of fatigue, muscle and joint aches, fever and chills, headache and swollen lymph nodes. These above symptoms are known as Stage 1 (early localized Lyme disease).
Stage 2, the early disseminated stage, can occur within several days to a few weeks after infection, and results from the spirochete spreading hematogenously to different sites in the body. This may result in several symptoms such as malaise, fatigue, regional or generalized lymphadenopathy, increased pain in muscles and joints, meningitis or Bell’s palsy. In addition, Lyme carditis, which may occur in five percent of untreated cases, may present most commonly as conduction abnormalities such as atrioventricular block, and less commonly as pericarditis or myocarditis.7
The AV block may be first-degree, Wenckebach, or complete heart block, with alternating tachycardia and bradycardia and fluctuation between first and third degree heart block can occur within minutes.7 Patients may present with complaints of palpitations, lightheadedness, chest pain, syncope or dyspnea. Left ventricular dysfunction, cardiomegaly, and pancarditis may occur in some individuals. Any cardiac complications from Lyme disease usually last only a few weeks, but may recur.
Late or Persistent Lyme Disease
If Lyme disease persists into Stage 3, several body systems may be affected, and significant manifestations may occur. The most common areas affected are the musculoskeletal system, neurologic system and the skin.
Arthritis will develop in 60 percent of patients in the United States who receive no antibiotic treatment.8, 9 There may be intermittent attacks of arthritis usually affecting large joints, especially the knees, but may affect smaller joints as well. The symptoms may last for weeks to months, and some people may develop chronic symptoms that lead to erosion of the joint(s).
According to one study of 41 patients with antibiotic-refractory arthritis, 23 patients with antibiotic-responsive arthritis, and 10 non-antibiotic-treated controls, joint inflammation may persist in patients with antibiotic-refractory Lyme arthritis after the disease-spreading spirochetes have been killed. In this subgroup of patients, the level of antibody titers to Borrelia burgdorferi increased in the first one to three months of treatment, and patients suffered from persistent joint swelling for a median duration of 10 months. However, by four to six months after initiating antibiotic therapy, antibody titers declined to levels that were similar to the antibody-responsive group, and in contrast to the control group, where antibody titers persisted at high levels throughout a two to five year period of arthritis.9
Chronic neurologic symptoms will develop in as many as five percent of untreated patients within months to years after infection. Such complaints include short term memory loss, problems with concentration, and numbness or tingling in the feet or hands.5 Specific complications may include encephalopathy, radiculoneuritis, and leukoencephalitis. Encephalopathy may affect a patient’s mood, memory, and sleep. A patient may experience radicular pain and paresthesias of one or more extremities. Leukoencephalitis, though more common in Europe than in the United States, is a severe neurologic disorder that produces lesions in the periventricular white matter, and may include spastic paraparesis and upper motor neuron bladder dysfunction.8
An additional complication may be Lyme neuroborreliosis (LNB), which is marked by any combination of lymphocytic meningitis, cranial neuropathy, polyradiculoneuropathy, ataxia or encephalitis.10 Lyme neuroborreliosis is caused when the Borrelia burgdorferi spirochetes penetrate and adhere to endothelial cells and then demonstrate an affinity for astrocytes in nearby brain capillaries, allowing for access to the nervous system through penetration of the blood brain barrier. Followed by the breakdown of the blood brain barrier, focal vasculitis may develop and cause a release of inflammatory mediators that affect the central nervous system.11 Following a period of latent infection, patients with a prolonged course of chronic LNB may exhibit symptoms similar to that of tertiary neurosyphilis, another spirochete-borne illness.
Cutaneous symptoms of chronic disease may include lymphocytoma cutis and acrodermatitis chronica atrophicans. Lymphocytoma cutis presents often as a solitary, reddish-purple nodule, most likely to be seen on the earlobe. The lesion may also be grouped or occur as a plaque, and may range in color from translucent to red to brown to purple, and may appear on other areas of the head, areola, scrotum and extremities. The lesions are usually asymptomatic and are 3-5 cm in diameter. Acrodermatitis chronica atrophicans, most often occurring on the acral areas or extensor surface of an arm or leg, presents as a localized or diffuse reddish-violaceous discoloration that may be accompanied by mild or prominent edema. It then becomes sclerotic or atrophic over several months to years. The veins and subcutaneous tissue may become prominent, and easily lifted or pushed into folds. There may also be localized plaques and fibromas seen as subcutaneous periarticular nodules. A band of fibrotic nodules along the ulna is pathognomonic for this condition.12
Post-Lyme Disease Syndrome
Post-Lyme disease syndrome occurs in patients who have had Lyme disease, but, after a course of appropriate antibiotic treatment, continue to have various symptoms such as musculoskeletal pain, fatigue, and neuro-psychiatric symptoms. The neurologic aspects may be sleep disturbance, cognitive difficulty, headache and paresthesias.14 Patients with these complaints usually would have been diagnosed with and treated for Lyme disease within the last six months and have had symptoms for at least six months.
Most people who are treated with antibiotics will not develop chronic or recurrent Lyme disease. However, much controversy exists regarding whether some people who were appropriately treated and demonstrated objective response with antibiotics can continue for months to years to have subjective symptoms. The recently published guidelines from the Infectious Diseases Society of America state that “there is no convincing biologic evidence for the existence of symptomatic chronic B. burgdorferi infection among patients after receipt of recommended treatment regimens for Lyme disease.”6 However, in one study, 91 percent of 47 symptomatic patients who had experienced relapse after receiving oral and intravenous antibiotic therapy were confirmed, via the use of fluorescent antibody immunoelectron microscopy, to still have Borrelia burgdorferi bacteremia.13
Though the symptoms above may be seen in patients with Lyme disease, there is much documented discussion and research about whether post-Lyme disease syndrome can explain the above symptoms, or if there is cause to consider other illnesses that may present similarly, such as chronic fatigue syndrome, depression, or fibromyalgia. Therefore, understanding the presentation of Lyme disease throughout all of its potential stages, and how to appropriately diagnose and treat the patient are crucial in helping the patient to recover without experiencing complications or related ailments.
Diagnosis
The diagnosis (see Figure 2) of Lyme disease is made by both clinical and serologic evaluation. Objective physical findings and symptoms, as mentioned above, along with history of possible exposure to infected ticks are used to make the diagnosis. Erythema migrans, pathognomonic for Lyme disease, can stand alone in diagnosis, and patients in endemic areas do not need any further testing to make the diagnosis. If a patient brings in the tick that was on him or her, it is not necessary to identify or test the tick to see if antibiotics or further evaluation or treatment are needed if the patient presents with clinical and/or serological findings. The local health department can be contacted, however, if it is felt that the tick should be identified or tested.
In cases where there is no characteristic rash, or if the disease is in later stages, or the patient is in a non-endemic area, laboratory testing for Lyme disease is recommended for confirmation. Currently, the CDC recommends using a 2-test approach to make the serodiagnosis of Lyme disease. Serologic testing should also be correlated with the patient’s clinical presentation, especially considering that the antibody response to B. burgdorferi develops slowly, and may only be positive in approximately one half of patients with early-stage Lyme disease.15
The ELISA, the first test, will show the antibody titer to B. burgdorferi. If it is negative, it is highly unlikely a patient has Lyme disease, and no further testing would be recommended.16 If the ELISA is positive, the second test, the western blot, is performed. This test is for either IgM or IgG antibodies in the patient’s blood that react to a specific B. burgdorferi protein. If the western blot is negative, then the ELISA is a false positive test. The IgM assay is most accurate when used during the first month (antibodies appear 2-4 weeks after onset of symptoms) of the illness.
After this period of time, the IgG assay (antibodies appear 4-6 weeks after onset of symptoms) is more accurate, but it will not distinguish between active and past infection.15, 17 If a person is still sick after one month, and is positive only by IgM and not IgG, the test should be repeated. If the patient is still positive only by IgM, this may be a false positive.16
After 4-6 months of illness, the IgM should decline to very low levels, but the IgG may remain at low levels for several more months to years, even after successful antibiotic treatment.15 The IgM blot is positive when at least 2 of 3 bands are present – 23, 39, or 41 kDa. The IgG blot is positive when at least 5 of 10 bands are present – 18, 23, 28, 30, 39, 41, 45, 58, 66, or 93 kDa. A positive or indeterminate ELISA and a positive Western blot are necessary to consider a patient positive for Lyme disease.17
When a patient presents with a rash that is not clearly erythema migrans on appearance or presents with other symptoms suggestive of Lyme disease, and especially if the patient lives in a non-endemic area, a couple of alternative diagnostic tests may be used. One test is a skin biopsy utilizing a quantitative Polymerase Chain Reaction (PCR) technique. When used early in the course of the rash, this test may be more sensitive than the two-step serologic test.
In one study18, the quantitative PCR of a skin biopsy was 81 percent sensitive vs. 64 percent sensitive for the two-step serologic test for Lyme disease. PCR has also been used to test for B. burgdorferi DNA in synovial fluid8, which would strengthen the diagnosis of Lyme arthritis if there is a positive 2-tier test. A second test is focus floating microscopy (FFM), which is a modified immunohistochemical technique that combines several strategies to detect microorganisms in tissue sections. In a different study19, FFM proved to be 96 percent sensitive vs. 45.2 percent sensitive with PCR and quantitative PCR, and almost as specific (99.4 percent vs. 100 percent) to PCR and quantitative PCR. It is important to note, however, that if a patient presents in an endemic area or there is no question of the appearance of erythema migrans or of other characteristic symptoms in a patient, then skin biopsy and quantitative PCR testing or focus floating microscopy is not necessary or indicated.
If a patient presents with neurologic symptoms consistent with meningitis or radiculopathy, and Lyme disease is suspected, a lumbar puncture to assess the cerebrospinal fluid (CSF) may be performed. This may show a lymphocytic pleocytosis, an elevated protein level and a normal or slightly low glucose level.8
Treatment
Preventive measures are recommended to avoid infection with Lyme disease. First, avoidance of ticks and the use of tick repellents such as DEET (N, N-diethyl-m-toluamide) on one’s skin or clothing may prevent Lyme disease. If a tick is attached to one’s body, prompt removal is strongly recommended, as longer attachment correlates with higher rates of transmission of B. burgdorferi. Currently, there is no vaccine available to prevent Lyme disease in humans. There was a vaccine, released in 1999, made from a recombinant outer surface protein of B. burgdorferi, which was effective by causing spirochetes in the gut of an engorged tick to be destroyed before the bacteria could be transmitted to humans. The three dose injectable vaccine was 76 percent effective in preventing symptomatic disease and 100 percent effective in preventing asymptomatic disease.20 However, it was discontinued in 2002 due to reported poor sales.3
The pharmacologic treatment of Lyme disease involves the early use of antibiotics directed at the pathogen (see Table 2). If a patient presents within 72 hours of removing a tick, he or she may be given a single 200-mg dose of doxycycline, and this medicine may be up to 87 percent effective in preventing erythema migrans.21 This is most efficacious when the patient is in an endemic area and fairly certain that the tick is of the Ixodes species.
When a patient presents in the early stages, doxycycline is the drug of choice, and is to be used for 21 days. Amoxicillin and cefuroxime are also indicated for acute of early infection. Azithromycin and other macrolides are much less effective, but if used, patients should be closely observed to make sure their clinical symptoms have resolved. Fluoroquinolones are ineffective against B. burgdorferi. If a patient advances to later stages of the disease, doxycycline or amoxicillin may be used, but if complications of the neurologic, cardiac or musculoskeletal system develop, IV ceftriaxone or cefotaxime may be used for 14-28 days.14, 22
Patients having persistent or recurrent joint swelling several months after initial infection, and after a recommended course of oral antibiotics, may be treated with another four week course of oral antibiotics or with parenteral medications as above. In any stage of or condition related to Lyme disease, other symptomatic treatments may be used, such as NSAIDS for pain relief or the use of a temporary pacemaker in patients with heart block. Also, treatment regimens and duration of therapy may not always be sufficient for a complete response, and pending patient symptoms after treatment, a second course of antibiotics may be needed.
For patients presenting with post-Lyme disease syndrome, antibiotics are NOT indicated for nonspecific symptoms, such as fatigue or cognitive dysfunction. While a few studies have shown that fatigue, but not cognitive dysfunction, has improved somewhat in antibiotic treated patients, the risk of side effects has outweighed the benefits.14, 23 Therefore, it is recommended to treat for the relief of the symptoms and not to treat with a prolonged course of antibiotic therapy.
Discussion
Though patients with Lyme disease may be adequately treated (per guidelines), they may often request repeat blood work to see if there was a response (immunologic) to therapy because patients may like to see objective proof of disease improvement, and feel that a lab may provide such proof. Furthermore, physicians may wonder how long a patient may exhibit an immune response to Borrelia burgdorferi, especially when considering whether any new patient complaints involving the musculoskeletal or neurologic systems may be related to old Lyme disease, reinfection, or some other unrelated ailment.
In one study, ten to twenty years after having active infection, two-thirds of patients with Lyme arthritis and one-third of those with early Lyme disease had positive IgM or IgG responses to B. burgdorferi. This correlated with the fact that 10-20 years later, those patients who were initially treated with antibiotics earlier in the disease had a lower antibody response than those patients treated with antibiotics later in the disease who had a higher antibody response.17
In another study24, 113 patients with erythema migrans were followed up for at least a mean of one year after receiving standard antibiotics, and it was determined that patients who had either larger-diameter EM lesions, or the rash for a longer duration prior to treatment, likely had more persistently positive IgG titers.
If a patient clinically responds to treatment and exhibits no signs or symptoms of Lyme disease, there is no need to repeat serologic testing. However, if symptoms do not resolve, or if new ones (related to Lyme disease) develop within 6-12 months, there may be some benefit to determining if there has been a decline or change in antibody response by repeating the two step testing. Nevertheless, short of reinfection, it is not recommended to issue a second course of antibiotics if nonspecific symptoms, such as fatigue or musculoskeletal pain, persist or recur, mostly because of lack of evidence that there would be a benefit to the patient.
In addition, there would be an increase risk of side effects by overuse of antibiotics. Patients that “just want to know” their titers after receiving treatment should be reassured that the antibodies can persist for months to years and that there is no benefit to repeat testing. If anything, a new false positive result or a persistent high titer, despite adequate clinical response to antibiotics, might cause some patients to insist on repeat antibiotics, which would only increase risk of adverse events (from medication), and not provide any clinical benefit. Perhaps it would be beneficial, if, in the future, a more definitive serologic marker would be developed to see if a person has fully responded to treatment or is free of any Lyme disease related sequelae.
With so many patients infected with Lyme disease per year, the cost of medical care (which includes evaluation, diagnostic studies, and treatment) rising, and with the potential risk of complications for those patients not treated or inadequately treated, it may be worth looking at the development of a new vaccine to prevent disease transmission. Such a vaccine could be an improvement on its predecessor, with a longer duration of effectiveness and hopefully, at a more reasonable cost that would be covered by insurance.
While the vaccine would be most utilized and needed for those living in endemic regions, it may also prove beneficial for those individuals traveling to these locations, or for those who spend a lot of time outdoors in areas more likely to be populated by deer ticks. Although emphasizing prevention and increased surveillance techniques may help in lowering infection rates, it may take the use of a vaccine to help the CDC achieve its Healthy People 2010 objective to reduce the number of annual infections to 9.7 per 100,000 persons in endemic areas.
Conclusions
Lyme disease, though an illness that can lead to cutaneous, musculoskeletal, neurologic, and cardiac complications, is highly treatable and quite preventable. If Lyme disease is suspected in any patient presenting with signs or symptoms consistent with infection, especially if living in an endemic area, it is important to make an accurate diagnosis and use the correct antibiotic to treat the illness. Also, given that this is the most common vector-borne diagnosed illness in the United States, it is important that we, as physicians, properly educate our patients about the infection, so that they also have a correct understanding of the nature of the illness, from prevention to symptoms they may experience (if infected) to treatment and to how long they can expect to show evidence of antibodies to the spirochete.
Dr. Pedowitz is board certified in osteopathic family medicine and osteopathic manipulative medicine. He is the Medical Director of Bordentown Family Medical Center, located in Bordentown, New Jersey.
References
