Lyme disease is a tick-borne illness caused by three pathogenic species of the spirochete Borrelia burgdorferi, the sole cause of the disease in the United States. Lyme disease has a broad spectrum of clinical manifestations, and it also varies in severity due, in part, to differences in the infecting species. Lyme disease was first described in 1977 as "Lyme arthritis" in studies of a cluster in Connecticut of children who were thought to have juvenile rheumatoid arthritis.
The clinical manifestations of Lyme disease can generally be divided into three phases: early localized, early disseminated, and late disease. Early localized disease is characterized by the appearance of the characteristic skin lesion named “erythema migrans” with or without constitutional symptoms like fever and chills. Early disseminated disease is characterized by multiple “erythema migrans” lesions and/or neurologic and/or cardiac findings. Some of these patients have no history of antecedent early localized Lyme disease. Late Lyme disease is associated with intermittent or persistent arthritis involving one or a few large joints, especially the knees, sometimes preceded by migratory arthralgias, and/or certain rare neurologic problems, primarily a subtle encephalopathy or polyneuropathy. Late Lyme disease may develop months to a few years after the initial infection. Arthritis may be the only presenting manifestation of the disease.
Early localized disease includes erythema migrans occuring in approximately 80 percent of patients usually within one month following the tick bite. Approximately 25 percent of patients with early, localized Lyme disease recall a tick bite. Skin lesions typically expand slowly over the course of days or weeks, often with central clearing, and may reach a diameter of more than 20 cm. During the first days, the lesions may be uniformly red. As they expand, some central clearing often develops, and they may have a more complex target or bull's eye appearance. During the first days or weeks of infection, patients with early, localized, or disseminated Lyme disease often also have nonspecific signs and symptoms resembling a viral syndrome: Fatigue - 54 percent, Anorexia - 26 percent, Headache - 42 percent, Neck stiffness - 35 percent, Myalgias - 44 percent, Arthralgias - 44 percent, Regional lymphadenopathy - 23 percent, Fever - 16 percent.
Early disseminated Lyme disease with acute neurologic or cardiac involvement usually occurs weeks to several months after the tick bite and may be the first manifestation of Lyme disease. Neurologic features of early disseminated Lyme disease may include: Lymphocytic meningitis, Unilateral or bilateral cranial nerve palsies (especially of the facial nerve: Bell’’s palisy), Radiculopathy, Peripheral neuropathy, Mononeuropathy multiplex, Cerebellar ataxia (rarely), Encephalomyelitis (rarely) The classic triad of acute neurologic abnormalities is meningitis, cranial neuropathy, and motor or sensory radiculoneuropathy, although each of these findings may occur alone. Although the facial nerve (No.7) is the most commonly affected cranial nerve, other nerves such as the abducens nerve (No.6) may be involved. Lyme disease is one of the few causes of bilateral cranial nerve palsies. Other causes include tuberculosis, sarcoidosis, and trauma. Cardiac manifestations of Lyme disease include fluctuating degrees of atrioventricular heart block, sometimes with myopericarditis, which is usually mild when it occurs.
A variety of ocular manifestations have been associated with Lyme disease, including conjunctivitis, keratitis, iridocyclitis, retinal vasculitis, choroiditis, optic neuropathy, and uveitis. Except for conjunctivitis, which occurs in about 10 percent of patients early in the infection, all of the other manifestations are rare. Cutaneous findings present as a single bluish-red swelling with a diameter of up to several centimeters, which usually occurs later and lasts longer than erythema migrans, but resolves spontaneously. It is most commonly located on the earlobe in children and near the nipple in adults, and often occurs near a previous or concurrent skin lesion. Pathology reveals a dense lymphocytic infiltration of the cutis and subcutis layers of the skin.
Late Lyme disease occurs months to a few years after the onset of infection and may not be preceded by a history of early localized or disseminated Lyme disease. In the United States, arthritis in one or a few joints is the most common feature of patients with late Lyme disease, but neurologic manifestations, such as a subtle encephalopathy or polyneuropathy can also occur. Lyme arthritis is characterized by intermittent or persistent arthritis in a few large joints, especially the knees. Months after the onset of infection, about 60 percent of patients developed joint swelling and pain. A few small joints or periarticular sites (tendons or bursae) were also affected, primarily in early attacks. The number of patients who continued to have recurrent attacks decreased each year. However, in a small percentage of cases, involvement in large joints (usually one or both knees) became chronic and sometimes led to erosions of cartilage and bone. Fibromyalgia can occur in the aftermath of Lyme disease, perhaps triggered by infection with B. burgdorferi, but fibromyalgia is not a feature of Lyme disease itself. The neurologic manifestations of late Lyme disease are different from those in early disseminated disease. In the United States, a mild neurologic syndrome, called Lyme encephalopathy, has been reported, manifested primarily by subtle cognitive disturbances.
POST-LYME DISEASE SYNDROME AND CHRONIC LYME DISEASE
Several distinct syndromes have been described after recommended antibiotic therapy for Lyme disease. The term "post-Lyme disease syndrome" is often used to describe the nonspecific symptoms (such as headache, fatigue, and arthralgias) that may persist for months after treatment of Lyme disease. For the majority of patients, these symptoms improve gradually over six months to one year. The proportion of patients who develop post-Lyme disease syndrome is relatively small. Of the three major randomized trials of patients with post-Lyme disease syndrome, all had substantial difficulty in identifying subjects who met the entry criteria and therefore enrolled only a minority of those who were screened. The majority of the other patients typically have no evidence of having had Lyme disease, although many have been given a diagnosis of "chronic Lyme disease."
Chronic Lyme disease is a term that is used by some practitioners and patient advocacy groups. In its typical usage, it includes the post-Lyme disease syndrome described above, as well as illnesses and symptom complexes for which there is no convincing scientific evidence of any relationship to B. burgdorferi infection. Many of these patients have other recognizable syndromes or diagnoses. Among patients with nonspecific symptoms of fatigue and myalgias, these subjective symptoms are sometimes accompanied by tender points of fibromyalgia. Since fibromyalgia is common in the general population, the association of Lyme disease and fibromyalgia may sometimes be by chance alone. In patients with late stage disease who develop arthritis, a small percentage have persistent arthritis after the completion of two to three months of oral and intravenous therapy. Antibiotic-treated patients with persistence of arthritis after clearance of B. burgdorferi DNA from the synovial fluid (as determined by PCR) do not respond to additional courses of antibiotics. The mechanism for persistence of arthritis is unclear; however, these patients may respond to antiinflammatory therapy. It has been hypothesized that infection of the joints may have triggered autoimmunity in the joints of these patients. In the absence of antiinflammatory therapy, "antibiotic-refractory arthritis" may persist for months to several years, but will eventually resolve spontaneously. Almost no patients have persistent symptoms extending past five years.
— Reinfection with B. burgdorferi is possible following the successful treatment of early Lyme disease. Reinfection typically presents as erythema migrans at a different location on the skin. Reinfected patients may have a marked anamnestic immune response with rapid IgG isotype switching. However, in patients who are treated during the early stages of disease, this immune response is typically directed against antigens for which antibodies do not protect against reinfection or in which variations in proteins expressed by different strains of B. burgdorferi can thwart protection from these previously developed immune responses. In contrast, patients who have had late stage manifestations of Lyme disease often have an expanded antibody response to many additional antigens that protects against reinfection.
— Because Borrelia species are spirochetes, there has been concern about the possibility of congenital Lyme disease given the serious congenital disease that can result from maternal syphilis, another spirochetal disease. Current evidence suggests that there is no definable congenital Lyme disease syndrome. If adequately treated, Lyme disease occurring during pregnancy does not predispose to congenital anomalies or fetal demise. A woman who has a history of Lyme disease diagnosed and treated before the pregnancy has no reason for concern. Diagnosis and treatment for Lyme disease during pregnancy is the same as in the nongravid patient, except that doxycycline and tetracycline are not used. Several early case reports and small studies suggested a link between maternal Lyme disease and congenital malformations or fetal demise. However, more recent studies have not supported an association between Lyme disease in pregnancy and adverse fetal outcomes, congenital malformations, or cardiac malformations.
COINFECTION WITH OTHER TICK-BORNE PATHOGENS — Patients with Lyme disease in endemic areas may be coinfected with the other infections transmitted by Ixodes ticks: Anaplasma phagocytophilum, which causes human granulocytic anaplasmosis (HGA; previously called human granulocytic ehrlichiosis), and Babesia microti in the United States; and tick-borne encephalitis virus in Europe. Reported rates of coinfection with babesiosis or HGA have ranged from 4 to 28 percent in endemic regions of the United States.
The oral doxycycline, amoxicillin, and cefuroxime axetil have equivalent efficacy for the treatment of early Lyme disease. We recommend treatment with one of these drugs in patients with erythema migrans. Doxycycline is often used because it is effective in treating a potential coinfecting agent, Anaplasma phagocytophilum. Of the oral agents commonly used to treat Lyme disease, doxycycline has the best penetration into the central nervous system. Doxycycline is not recommended for children under the age of eight years or for pregnant or lactating women. However, a single treatment course of doxycycline may be given to children younger than eight years in whom the alternate agents are contraindicated. In the United States, macrolides (eg, azithromycin, clarithromycin, erythromycin) are NOT recommended as first-line therapy for erythema migrans because they are less effective than amoxicillin and presumably the other first-line drugs. Some strains of B. burgdorferi exhibit resistance to macrolides. Macrolides should be reserved for the minority of patients who are intolerant of amoxicillin, doxycycline, and cefuroxime. First-generation cephalosporins (eg, cephalexin) are NOT effective for Lyme disease and should not be used. In some cases, erythema migrans may be confused with cellulitis. When this occurs in a Lyme-endemic area, it is appropriate to treat a skin rash with an antibiotic that will treat both cellulitis pathogens and Lyme disease (eg, amoxicillin-clavulanate or cefuroxime).
Dosing — Dosing of antibiotics for early Lyme disease is as follows:
- Doxycycline 100 mg orally twice daily for adults; 2 mg/kg twice daily (maximum 100 mg dose) for children ≥8 years of age for 30 days
- Amoxicillin 500 mg three times daily for adults; 50 mg/kg per day in three divided doses (maximum 500 mg per dose) for children for 30 days
- Cefuroxime axetil 500 mg twice daily for adults; 30 mg/kg per day in two divided doses (maximum 500 mg per dose) for children for 30 days.
Response to therapy — The majority of patients with early Lyme disease who receive appropriate antibiotic therapy have complete resolution of the signs and symptoms of infection within 20 days and, in one trial, erythema migrans and its associated symptoms resolved in a mean of five to six days. Patients who are more systemically ill at the beginning of treatment may take longer to recover. In addition, appropriate dosing and duration of therapy early in the course (ie, within weeks of the onset of infection) prevents progression to late Lyme disease. Some patients have mild subjective symptoms, such as headache, musculoskeletal pain, arthralgia, or fatigue, that persist for weeks to months after treatment. These subjective findings often resolve spontaneously, usually within six months, without further antibiotic therapy and they are not due to ongoing active Lyme disease. More prolonged subjective symptoms after appropriate antibiotic therapy has been called the post-Lyme disease syndrome. Patients with persistent objective findings, particularly high fever, may be coinfected with the other tick-borne infections transmitted by Ixodes ticks. Investigation for coinfection with these agents is warranted if the initial antimicrobial does not have activity against these pathogens. Almost all patients who have a satisfactory response to antibiotic therapy do well over the long term.