Lyme disease is due to infection with the spirochete Borrelia burgdorferi and the body’s immune response to the infection. In Europe, the rash (then called erythema chronicum migrans [ECM]) was first described at the beginning of the 20th century. The neurologic manifestations and the association with Ixodes ticks (also known as deer ticks; see Image 1) were recognized by the mid 1930s and were known as tick-borne meningoencephalitis. In the United States, Lyme disease was not recognized until the early 1970s, when an outbreak of pediatric arthritis occurred in the region around Lyme, Connecticut. This was investigated by Allen Steere, MD, and others from Yale. The recognition that the patients in the United States had ECM led to the recognition that Lyme arthritis was one manifestation of the same tick-borne condition known in Europe.
After Willy Burgdorfer, MD, discovered a borrelial organism in Ixodes ticks, it was recovered from patients with clinical Lyme disease, confirming it as the causative agent. This led to the development of antibody tests for the disease. Different strains of Borrelia are recognized, which probably explains why the clinical manifestations of Lyme disease are different in the United States and Europe.
Lyme disease has become common in the United States from Maryland to Maine and in Wisconsin and Minnesota, with a smaller focus in northern California. A great deal of fear and concern exists among residents and visitors to these areas. The development of vaccines against Lyme disease and the subsequent advertising of one of the vaccines have led to further apprehension among the populations of these areas. The emergence of Lyme disease is probably due to the explosion of deer and tick populations with the reforestation of the northeastern United States and the subsequent contact between ticks and humans as people move into deer habitats. B burgdorferi has been found in tick specimens collected in the 1940s on eastern Long Island.
For additional information on Lyme disease, see Medscape’s Lyme Disease Resource Center.
B burgdorferi is a spirochete. It is transmitted from host to host by the Ixodes, or deer tick. The life cycle of the Ixodes tick and B burgdorferi is important, as it relates to the epidemiology of Lyme disease.
The Ixodes tick is born as a larval tick in the summer and feeds only once. Its preferred host is the common field mouse, but other animals apparently suffice. The following spring, it becomes a nymph and again feeds only once, with its preferred host again being the field mouse. In the fall, the nymph becomes an adult and feeds a single time. Its preferred host is the white-tailed deer. Thus, unless the tick feeds on an infected host before feeding on a person, infection cannot result from that tick bite. Even if a tick feeds on an infected animal, it may not acquire the infection. Mice do not appear to develop Lyme disease, but they do carry the bacteria. They may be considered infested rather than infected.
Not all strains of mice continue to carry the bacteria after exposure to B burgdorferi. As mice mature, they may be less able to sustain a B burgdorferi bacteremia. Even when they are exposed to the bacteria, they do not remain carriers for extended periods. Other animals are even poorer hosts for B burgdorferi.
Some studies suggest that uninfected ticks do not become infected unless they feed next to infected ticks that have been feeding on the same animal. This suggests that, although B burgdorferi may disseminate throughout the body of its host, not enough bacteria may be present in the distant sites to pass on the infection.
A tick must be attached to a person for 2-3 days to result in infection. This is due to the life cycle of B burgdorferi in ticks. In previously infected ticks, only small numbers of bacteria are present until the tick feeds. Once feeding begins, the bacteria then multiply in the gut of the tick. The bacteria then migrate to the salivary glands of the tick after 2-3 days. There, they are injected into the animal by the tick as it ends its feeding. Until this multiplication occurs, ticks are rarely able to pass on the infection.
Humans are infected by ticks in the nymph stage 85% of the time (spring to summer) and the adult stage 15% of the time (fall). Thus, for many reasons, only approximately 1% of all tick bites occurring in an endemic area result in Lyme disease.
Once B burgdorferi is injected into the host, 1 of 3 events occurs, as follows:
In the first event, patients may clear the infection without developing any manifestations, as demonstrated by patients who are asymptomatic but seropositive.
In the second event, B burgdorferi spreads throughout the body and produces symptoms by direct invasion, particularly in the early stages of the disease. Because growing B burgdorferi is difficult, confirming that the organism is actually present in a specific organ that may be involved in Lyme disease is also difficult. The inflammatory response to B burgdorferi in the skin is probably the cause of erythema migrans.
In the third event, B burgdorferi induces an immune response that may lead to symptoms in various organs, with little evidence of bacterial invasion. Studies of Lyme arthritis have shown that the arthritis is associated with certain immunological factors, including the production of proinflammatory cytokines and the formation of immune complexes, and also genetic factors, such as human leukocyte antigen (HLA)–DR4 and HLA-DR2.
The manifestations of Lyme disease are related to the particular strain of Borrelia involved. In the United States, isolates from the East Coast are known as B burgdorferi sensu stricto. In Europe, B burgdorferi garinii is associated with neurologic disease, while B burgdorferi afzelii is associated with a dermatologic manifestation known as acrodermatitis chronica atrophicans.
At best, frequency data for Lyme disease are approximations, for the following reasons:
Separating false-positive antibody tests from asymptomatic infection is impossible. Approximately 5-10% of patients in endemic areas have positive antibody results without a history of symptoms.
Although Lyme disease is a reportable disease, not all cases are reported or discovered through laboratory records because early disease should be treated without antibody testing.
In 1999, state health departments reported 13,306 cases of Lyme disease. This was 3500 cases fewer than in 1998. Approximately 90.5% of cases were reported from the states between Maryland and Maine, 2.8% from Wisconsin and Minnesota, and 1.1% from California and Oregon. Wisconsin had an 82% drop in reported cases between 1998 and 1999.
In 1997, Connecticut had the highest reported rate of Lyme disease in the United States at 69.9 cases per 100,000 persons, with a 16.6-fold difference among the 8 counties in Connecticut. Maryland had only 9.6 cases per 100,000 persons but a 180-fold difference in rates by county. In both states, the lowest rates were reported from the most urban areas.
Actual rates of Lyme disease may be 5 times higher than state health department rates.
Rates of Lyme disease in Europe may be similar to those in the United States. A rate of 69 cases per 100,000 persons was reported in southern Sweden, with peaks at ages 5-9 years and 60-69 years.
Lyme disease is reported primarily in whites. In the United States in 1998, 76% of reported cases involved whites, followed by other ethnic groups at 21%.
Reports from Europe indicate that, among children, the rate of Lyme disease is slightly higher in boys than in girls, but, in the older age peak, the disease is more common in women than in men.
The incidence of Lyme disease has two age-based peaks: at age 5-9 years and another at age 50-54 years. The incidence of Lyme disease is lowest in individuals aged 20-24 years.
The manifestations of Lyme disease have been divided into 3 stages: localized, disseminated, and persistent. The first 2 stages are part of the early infection, while persistent disease is considered late infection. Unlike syphilis, stage 3 disease may occur within 1 year of infection, not many years later. Certain manifestations of Lyme disease are more common in the United States, while others are more common in Europe.
The primary symptoms of stage 1 are erythema migrans and some associated symptoms. The primary symptoms of stage 2 include intermittent arthritis, cranial nerve palsies and radicular symptoms, atrioventricular (AV) nodal block, and severe malaise and fatigue. The primary symptoms of stage 3 include prolonged arthritis; chronic encephalitis, myelitis, and parapareses; and symptoms consistent with fibromyalgia.
The natural history of Lyme disease is as follows:
The Ixodes tick is small, and the bite is often innocuous enough that 30% of patients in the United States do not remember being bitten.
In Europe, 64% do not remember being bitten.
Erythema migrans (see Image 2) is an erythematous lesion that grows (hence the name) over several days. It may be asymptomatic or it may itch or burn. It often occurs at or near the site of the tick bite, which may be an area not normally visualized by individuals, such as the axilla, groin, or popliteal areas. The rash may not be observed until it is already full size.
Untreated, the rash persists for 2-3 weeks. Eighty percent of patients with Lyme disease have only one episode of erythema migrans, while 20% may have recurrent episodes. Multiple lesions may occur in 40% of patients with Lyme disease and are not the result of multiple tick bites. The rash may be associated with lymphadenopathy and symptoms such as fever and myalgias, which may be described by the patient as flulike in nature.
Malaise and fatigue are the most common findings after the skin lesion in early disease. They affect as many as 80% of patients with Lyme disease in the United States but less than 35% in Europe.
Approximately one third of all patients with erythema migrans develop no further manifestations of Lyme disease, while two thirds of patients develop further symptoms listed below.
Intermittent inflammatory arthritis
This often begins as a migratory polyarticular process involving bursae, tendons, and joints, which evolves over 1-2 days into a monoarticular process involving the knee, ankle, and wrist, in decreasing frequency. When asked about their symptoms after they have resolved, patients with Lyme disease are less likely to remember those symptoms that occurred prior to the monoarthritis. Polyarticular episodes may also occur.
In two thirds of patients, the first episode occurs within 6 months of the erythema migrans lesion. Untreated, the episodes last approximately a week. Two thirds of patients have 3 recurrences approximately 2.5 months apart. The recurrences are more likely to involve more than one joint than the initial event. With time, these episodes become less frequent and severe and involve fewer joints. Even without treatment, the recurrent episodes usually resolve over a 10-year period.
Some patients may present with intermittent joint pain without inflammatory findings. This is more common in Europe, where arthritis was not recognized as a manifestation of Lyme disease until the early reports from the United States.
Cranial nerve palsies
This is the most common neurologic manifestation of Lyme disease in the United States and is probably the most common in Europe, particularly in children. More than half of children with neurologic symptoms have a facial palsy. It may be bilateral.
The palsy lasts less than 2 months and may begin to resolve even in the first several days.
Meningoradiculoneuritis (Bannwarth syndrome)
This occurs much more frequently in Europe than in the United States.
It is characterized by severe radicular pain (due to neuritis), with a prominent nocturnal component. The meningitis may be relatively mild.
This usually manifests as fever and syncope due to AV block.
The level of AV block varies and fluctuates so that the symptoms may be intermittent. The block rarely lasts longer than a week; a temporary pacemaker is rarely required.
This may occur along with other neurologic manifestations or by itself.
Severity ranges from mild to severe and usually presents as headache, photophobia, and/or a stiff neck. The severity of the meningitis is less than that observed in patients with more typical bacterial meningitis.
Approximately 10% of patients with intermittent arthritis develop a chronic arthritis that typically involves the knee.
While it may last several years, it rarely develops into a destructive arthritis.
Chronic paresthesias and, less frequently, radicular pain without sensory or motor deficits may occur.
This is usually not associated with other chronic neurologic symptoms.
This appears to be more common in Europe than in the United States.
Abnormalities in mood, memory, and sleep may develop.
Symptoms may vary from mild to severe. More severe symptoms of ataxia, spastic paresis, and cognitive dysfunction may develop, possibly more often in patients who have had CNS involvement. Children who have had Lyme disease seem to be at low risk for the development of such findings.
Fibromyalgia and chronic fatigue
Symptoms consistent with fibromyalgia and chronic fatigue syndrome develop in patients who have had clear-cut Lyme disease, even after adequate treatment.
A biological relationship does not seem to exist between these symptoms and Lyme disease, and it does not appear to be due to active infection.
A bluish-red nodular lymphocytic infiltrate known as a lymphocytoma, typically appearing on the earlobe or nipple, occurs in Europe but not the United States. It is usually found as part of stage 2 disease.
Atrophic areas can develop over the extensor surfaces of the extremities during late disease and are known as acrodermatitis chronica atrophicans. This has not been reported in the United States.
Erythema migrans is an erythematous lesion. The entire lesion may be uniform in color or central clearing may be present (one third of US cases and two thirds of European cases). More proximal to the clearing may be additional erythema leading to a so-called “bull’s eye” appearance. The center may be scaly or discolored. Single lesions average 16 cm in diameter.
Lyme arthritis presents with the usual findings of an acute arthritis. These include warmth, erythema, and swelling and pain upon motion of the joints, but usually not as severe as in a septic joint. Effusions may be large and generally recur following aspiration, as is often seen in spondyloarthropathies.
Lyme meningitis does not manifest as the usual signs of bacterial meningitis (boardlike rigidity, Kernig and Brudzinski signs).
Chronic radicular paresthesias are usually not associated with motor or sensory deficits, and the physical examination results are normal.