Essentials of Diagnosis
- Lyme disease should be considered in individuals who have a reasonable risk of exposure to Borrelia burgdorferi-infected ticks and who have the characteristic complex of signs and symptoms.
- Classic clinical features occur in stages:
- Early localized disease (3–30 days after tick bite): a single hallmark skin lesion erythema migrans (EM), occasionally associated with fever, malaise, headache, arthralgias, and myalgias; less commonly, these latter symptoms can occur in the absence of EM.
- Early disseminated disease (weeks to months after tick bite): multiple EM lesions and associated fever, migratory arthralgias, and myalgias; acute pauciarticular arthritis; carditis manifested primarily as atrioventricular (AV) nodal block; neurologic features, including cranial nerve (especially facial nerve) palsies, lymphocytic meningitis, and radiculoneuropathies.
- Late disease (several months to years after tick bite): primarily neurologic features, especially peripheral neuropathies and chronic mild encephalopathy; arthritis, including monoarticular and migratory pauciarticular arthritis.
- Early localized disease (3–30 days after tick bite): a single hallmark skin lesion erythema migrans (EM), occasionally associated with fever, malaise, headache, arthralgias, and myalgias; less commonly, these latter symptoms can occur in the absence of EM.
- Supporting serologic evidence of exposure to B burgdorferi is present in most cases but can be absent in early infection.
General Considerations
Lyme disease is a multisystem disorder caused by infection with spirochetes of the genus Borrelia burgdorferi sensu lato: B burgdorferi sensu stricto, B garinii, and B afzelii. Hard-shelled ticks of the Ixodes family, primarily I scapularis and I pacificus in the United States and I ricinus in Europe, serve as vectors for infection. In the United States, the disease first came to medical attention in 1975 in the region around Lyme, Connecticut, where a clustering of children with presumed juvenile arthritis was observed. Lyme arthritis, as it was initially termed, was soon found to be one manifestation of systemic infection with B burgdorferi. Beginning with a characteristic skin lesion, erythema migrans (EM), early infection was either confined to the skin or disseminated to other sites, with disease most commonly found in the skin, heart, joints, and nervous system. Lyme disease is not a new entity; in Europe, EM had been associated with I ricinus tick bites since the early 20th century, and the skin disease was treated successfully with penicillin after spirochetes were visualized in biopsy specimens in the mid-1900s. Other systemic manifestations were occasionally present, especially neurologic disease (Bannwarth syndrome), but the broad clinical spectrum was not fully appreciated until the late 1970s.
Since its emergence in the United States 40 years ago, Lyme disease has become the most common vector-borne infection in this country. In 2008, 28,921 confirmed and 6277 probable cases of Lyme disease were reported to the Centers for Disease Control and Prevention (CDC) (see http://www.cdc.gov/osels/ph_surveillance/nndss/casedef/lyme_disease_ 2008.htm for the 2008 revised case definition of Lyme disease). More than 86% of confirmed cases originated from only 9 states: New York, Massachusetts, Pennsylvania, New Jersey, Connecticut, Maryland, Wisconsin, New Hampshire, and Minnesota. Delaware, Maine, and Virginia have experienced an increase in case reporting, accounting for an additional 8% of total confirmed cases in 2008. Cases of Lyme disease have been reported from 49 states and the District of Columbia, and also occur in other areas of North America as well as in Europe and Asia. In the latter two continents, other B burgdorferi sensu lato members—B garinii and B afzelii—are the main etiologic pathogens.
Lyme disease begins when humans serve as incidental bloodmeal hosts for B burgdorferi-infected ticks. Although all three forms of ticks—larvae, nymphs, and adults—can harbor B burgdorferi, nymphs are more likely to transmit infection to humans because of their promiscuous feeding patterns and small size (see CDC website for description of vector life cycle and image of ticks). Ixodes ticks feed only once per developmental stage, so that the incidence of Lyme disease follows the seasonal feeding patterns of nymphs (late spring, summer, and early fall). Larvae are rarely, if ever, vectors for the disease because they must first acquire infection by feeding on a reservoir host. Nymphs feed for 3–8 days, during which time spirochetes migrate from the tick midgut to the salivary gland and egress into the host through salivary secretions. Transmission of infection generally requires 24–48 hours of tick feeding, so that tick surveillance and early removal of embedded ticks is a primary preventive strategy in areas endemic for Lyme disease. Spirochetes first establish infection in the skin, where local immune responses give rise to EM, a hallmark of early, localized infection. This rash is present in up to 80% of cases and typically appears within the first month after tick bite. Thereafter, spirochetes can disseminate hematogenously to all areas of the body, but disease primarily manifests in other areas of the skin, the heart, the joints, and the nervous system.
The diagnosis of Lyme disease relies on a characteristic clinical presentation and can be supported by serologic tests showing the presence of antibodies to B burgdorferi. Patients may have negative test results early in the course of their treatment or, rarely, when they have been treated early with antibiotics. Most patients with Lyme disease can be treated successfully with antibiotics, with few long-term sequelae. Misdiagnosis of other conditions as Lyme disease remains the most common reason that patients do not respond to conventional therapy. Oral antibiotics for 2–4 weeks are appropriate initial therapy for all patients except those with severe cardiac or neurologic involvement, who should receive intravenous therapy. One exception may be patients with isolated Bell palsy because they respond equally well to oral antibiotics. Patients with chronic residual signs and symptoms after treatment for Lyme disease may have irreversible tissue damage, a post-Lyme fibromyalgia syndrome, or possibly infection-induced autoimmunity. Extended courses of oral or intravenous antibiotics have not been shown to provide benefit over placebo for this patient population and should be avoided unless clear objective evidence of active infection is present.
Pathogenesis
B burgdorferi survive in nature through alternating infection with ticks and reservoir hosts, including mammals and birds. Ticks feed only once per developmental stage and can lay dormant for years. Thus, spirochetes require that their vertebrate hosts survive in order to increase the probability of transmission back to ticks. In mammals, spirochetes cause disease as they initially infect and disseminate within the host, but inflammation generally resolves even if the organism is not cleared. In humans, B burgdorferi is difficult to culture from infected tissues except for EM lesions, but rare positive cultures have been reported at all stages of the disease, including from blood, cerebrospinal fluid (CSF), heart biopsies, and joint fluid. Recently, improved detection of B burgdorferi infection by large volume culture of human plasma has been reported but only in individuals with early signs of Lyme disease, such as EM, suggesting that the bloodborne phase of B burgdorferi infection is likely brief. In animal models, few spirochetes can be seen in infected tissues, yet an exuberant inflammatory response arises and then resolves, with spirochetes persisting in tissues. Despite transient sightings of spirochetes within cells, no intracellular phase of B burgdorferi infection has been documented. B burgdorferi uses several immune evasion mechanisms that are common to extracellular pathogens. Spirochete lipoproteins, which are expressed on internal and surface-exposed pathogen membranes, incite acute inflammation by activating innate immune cells through Toll-like receptor pattern recognition receptors. Downregulation of lipoprotein expression as spirochetes adapt to persist in the host may impede their clearance by innate immune cells and by borrelicidal antibodies targeting specific lipoproteins. Antigenic variation, particularly of the VlsE lipoprotein, has been demonstrated, providing another mechanism whereby the spirochete can evade protective antibodies. B burgdorferi also possesses a family of lipoproteins that bind host Factor H to impede lysis by complement. Antibiotic therapy may release internally sequestered lipoproteins from dead spirochetes and contribute to the Jarisch-Herxheimer reaction, a febrile response and transient exacerbation of symptoms noted by up to 15% of patients with Lyme disease at the start of therapy. Delayed clearance of spirochete inflammatory products may also contribute to lingering symptoms after antibiotic treatment for Lyme disease.
Prevention
The best way to prevent Lyme disease is to reduce the risk of human exposure to B burgdorferi-infected ticks through personal preventive behavior and environmental controls. Avoiding physical contact with common tick habitats, such as wooded areas, stone fences, woodpiles, tall grass and brush, helps limit exposure risk of individuals in areas endemic for Lyme disease. Environmental controls such as the removal of tall grass and brush, clearance of woodpiles and the application of area insecticides, can reduce the risk of human contact with infected ticks. If entry into tick habitats is anticipated, wearing protective, light-colored clothing such as long-sleeved shirts and long pants tucked into socks allows for ticks to be readily seen and reduces their access to exposed skin. Insect repellants containing diethyltoluamide (DEET) applied to the clothing and exposed skin surfaces provide added protection. Permethrin can also be sprayed on clothing and kills ticks directly.
Daily tick checks are essential for persons with exposure risk to ticks. Prompt removal of ticks embedded in the skin can effectively reduce the incidence of Lyme disease in endemic communities. Attached ticks should be removed by grasping the mouthparts with tweezers and pulling steadily up. Use of alcohol, heat, or vaso-occlusive substances will not promote tick detachment. A single 200 mg dose of doxycycline administered within 72 hours of tick bite has been shown to prevent Lyme disease. However, the risk of infection after tick-bite is low (˜1.4% even in endemic areas), making the routine use of prophylactic antibiotics in individuals bitten by ticks unwarranted. Such persons should be observed for 30 days for the development of a rash at the site of tick bite or for unexplained fever, which may be indicative not only of Lyme disease but of other tick-borne infections as well.
One effective method for prevention of Lyme disease is vaccination. Two vaccines using the spirochete lipoprotein Osp A were developed and tested in humans for safety and efficacy. Although immune responses to Osp A that arise after natural infection have been associated with chronic arthritis (see below), the incidence of arthritis in patients undergoing Osp A vaccination did not differ from those receiving placebo. One of the two Osp A vaccines, LYMErix, was approved by the Food and Drug Administration; 76% of adults (aged 18–75) who received three doses of LYMErix were protected from symptomatic Lyme disease. However, limited demand for the vaccine and public concern over potential vaccine-related sequelae led to its discontinuation by the manufacturer.
Clinical Findings
Lyme disease typically occurs in stages that reflect the in vivo biology of the spirochete. After establishing infection in the skin at the site of tick feeding, spirochetes that escape initial immune destruction disseminate through the skin, the blood, and the lymphatics to infect virtually any organ system. The clinical manifestations of Lyme disease thus depend on the stage of the illness at which the patient presents—early localized infection, early disseminated disease, or late disease.
The most common early manifestation of Lyme disease is the skin rash EM, present in up to 80% of patients. EM appears within a month after exposure to B burgdorferi, with a median of 7–10 days, and first appears at the site of tick bite. Ticks may initially bind to clothing or exposed skin, but typically choose skin folds or creases and areas where clothes are particularly confining (eg, near elastic bands). In adults, the most common sites for EM are the popliteal fossa, gluteal fold, trunk, and axilla; in children, EM often arises near the hairline.
The most characteristic feature of EM is its morphology: a flat, macular erythematous lesion that expands rapidly, 2–3 cm/d, and which can enlarge to more than 70 cm in diameter. The lesion should be >5 cm in diameter to fulfill diagnostic criteria. Although central clearing to produce a target or bull’s-eye rash can occur in up to 40% of cases, especially when the lesion is large, more often it presents with uniform erythema. Occasionally, the center can be intensely erythematous, vesicular, or even necrotic. Despite its appearance, EM itself rarely produces much in the way of local symptoms other than tingling. Rarely, the lesion is intensely pruritic or painful. Systemic “flu-like” symptoms may be present, including low-grade fever, malaise, neck pain or stiffness, arthralgias, and myalgias; these are particularly severe in individuals with coinfection with another tick-borne pathogen, such as Babesia microti or Anaplasma phagocytophilum, the pathogen of human granulocytic ehrlichiosis. In about 18% of cases, Lyme disease can also manifest with a summer flu-like syndrome, without respiratory or gastrointestinal involvement, in the absence of EM.
Within weeks to months of initial infection, spirochetes can disseminate widely throughout the host. At this stage, infection can be present in multiple tissues but disease most commonly arises in four organ systems: the skin, the heart, the musculoskeletal system, and the nervous system. Patients are generally ill-appearing and complain of debilitating fatigue and malaise. While specific localizing signs and symptoms may be intermittent, persistent fatigue is a hallmark of untreated disseminated Lyme disease.
Multiple EM lesions are a sign of dissemination and arise in about 50% of patients with untreated early, localized infection. Secondary lesions have a random distribution, are smaller than the primary lesion, and less often necrotic or vesicular, although they may exhibit central clearing.
A variety of musculoskeletal signs and symptoms may be present in disseminated Lyme disease. Migratory pains in muscles, joints, and periarticular structures (especially tendons and ligaments) that last only hours to days are seen in early localized infection as well as in acute disseminated disease. True inflammatory arthritis usually involves a single joint, particularly the knee, and presents with a large effusion (>50–100 mL) accompanied by stiffness and only mild pain. Other joints involved in order of frequency include the shoulder, ankle, elbow, temporomandibular joint, and wrist. It is rare for Lyme arthritis to involve more than five joints at any time. Acute Lyme arthritis is usually episodic, with attacks of monoarticular or oligoarticular arthritis lasting only weeks and decreasing in frequency with time. In most patients, the arthritis resolves completely within 5 years, even without antibiotic therapy. In a minority of patients arthritis can become chronic (see below).
Central or peripheral nervous system disease (or both) occurs in about 15% of patients with early, disseminated Lyme disease. The classic triad consists of aseptic meningitis with cranial neuropathy, especially involving the VIIth nerve, and painful peripheral radiculoneuropathy. Central nervous system (CNS) involvement most commonly presents as aseptic meningitis, although meningoencephalitis with subtle cognitive deficits can occur. In comparison to other forms of meningitis, headache may be waxing and waning and neck stiffness is generally mild, so that a high index of suspicion may be required to make the diagnosis. Cranial neuropathy occurs in about 50% of patients with early neuroborreliosis and most often affects the facial nerve. CSF abnormalities may be present in cases of facial palsy and reflect asymptomatic CNS involvement. Although usually unilateral, bilateral facial nerve palsies occur in nearly 30% of patients with VIIth nerve involvement. Peripheral radiculoneuropathy is a mixed motor and sensory neuropathy that presents with sharp, lancinating pain in the distribution of the affected nerves and, later, hyporeflexia. Often, multiple nerves and nerve roots are involved in an asymmetric fashion. Acute radiculoneuritis is rarely seen in the United States but is common in Europe where it is also known as Bannwarth syndrome. In untreated patients, neurologic signs and symptoms can have a relapsing, remitting course over many months. Rarely, Lyme disease can be a cause of transverse myelitis.
Lyme carditis is relatively rare, occurring in <10% of patients with disseminated Lyme disease. Conduction system abnormalities with varying degrees of AV block are the most common cardiac manifestation, with symptomatic third-degree AV block occurring in about 50% of such patients. Occasionally, myocarditis with heart muscle dysfunction and pericarditis can also occur, but valvular disease is not found. Because Lyme carditis is usually self-limited, cardiac involvement in disseminated Lyme disease may be overlooked, especially if it remains clinically asymptomatic in comparison to other features.
A variety of other organs can exhibit pathology with disseminated B burgdorferi infection. These include the eye (keratitis), the ear (sensorineural hearing loss), the liver (hepatitis), the spleen (necrosis), skeletal muscle (myositis), and subcutaneous tissue (panniculitis). In general, other more classic manifestations of Lyme disease are present concurrently or have been present in the recent past to suggest the diagnosis.
Less than 10% of patients with acute Lyme disease develop chronic manifestations of the disorder, most often in the skin, joints and nervous system. In Europe, infection with B afzelii is associated with the late skin lesion acrodermatitis chronica atrophicans.
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