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Tick-Borne Diseases, Lyme
Updated: Aug 26, 2009
Introduction
Background
Lyme disease is a systemic infection caused by the spirochete Borrelia burgdorferi. The bacterium is inoculated into the skin by a tick bite. The tick is almost always of the genus Ixodes.
In general, Ixodes scapularis must be attached for 24-48 hours to transmit the spirochete to the host mammal. Prophylactic antibiotics are more likely to be helpful if feeding is longer. This photo shows 2 I scapularis nymphs. The one on the right is unfed; the other has been feeding for 48 hours. Note its larger size and the fact that the midgut diverticula (delicate brown linear areas on the body) are blurred. Photo by Darlyne Murawski; reproduced with permission.
Although various parts of the syndrome were described in Europe more than 100 years ago, the full spectrum had not begun to be identified until 1975, when a cluster of statistically improbable cases of juvenile arthritis occurred in Connecticut. This outbreak stimulated intensive clinical and epidemiologic research that led to the discovery of the causative agent, the ecology, an expanding list of clinical manifestations, and the geographic range. Furthermore, the initial antibiotic responsiveness of the cutaneous manifestations described in the European literature was confirmed and extended.1
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Pathophysiology
The pathophysiology of Lyme disease is incompletely understood. While active infection by the spirochete causes many manifestations, others may be caused by immunopathogenic mechanisms. Although any body part can be involved, the organism shows a distinct tropism for the skin, CNS, heart, joints, and eyes.
The bacterium is introduced into the skin with a bite from an infected Ixodes tick. In the northeastern and upper midwestern United States, Ixodes scapularis is the vector. In other parts of the country and world, other Ixodes species serve that function. Other ticks (eg, Amblyomma americanum) and insects can carry B burgdorferi, but Ixodes tick bites are thought to cause the vast majority of cases. In the southern and mid-central United States, a Lymelike illness has been reported; the vector appears to be A americanum, and the causative organism or organisms is likely to be a related spirochete.2,3 One such organism, named Borrelia lonestarii, has been cultured in a single case.
Once in the skin, the spirochete can (1) be overwhelmed and eliminated by host defense mechanisms; (2) remain viable and localized in the skin where it produces the pathognomonic skin lesion, or erythema migrans (EM); or (3) disseminate through the lymphatics or blood. Hematogenous dissemination can occur within days to weeks of initial infection; the organism can travel to the skin, heart, joints, CNS, and other parts of the body.
This is the classic target lesion of erythema migrans (EM). Although this morphology has been emphasized in the older literature, in North America, it represents only about 40% of all EM lesions. This morphology is more commonly found in Europe. Photo reproduced with permission; Lyme Disease Foundation, Hartford, CT.
Study findings show that in roughly 10% of patients with isolated EM and no systemic symptoms, B burgdorferi can be cultured or that its DNA can be detected in the bloodstream. Using high volume (9 mL) of plasm for culture, one 2005 study suggests that nearly 44% of patients are spirochetemic, some of them with a single skin lesion and no systemic symptoms.4 Also, early in the course of the disease when EM is still present, the spirochete and its DNA have been isolated from the cerebrospinal fluid (CSF), indicating early CNS penetration. This penetration can occur even in the absence of neurologic symptoms.
Data published in November 2008 show that some genotypes of B burgdorferi are responsible for the large majority of cases of disseminated disease.5 At the present time, this information likely has greater significance for future vaccines or diagnostic tests than it does in routine practice.
The organism can also persist in skin (and possibly in the CNS) for years without causing symptoms. Experimentally, the spirochete can penetrate human fibroblasts and live intracellularly, even when the extracellular medium contains ceftriaxone well above bacteriocidal levels for the spirochete. Clinically, organisms have been cultured from skin many years after primary infection. This mechanism may allow the spirochete to elude the normal host defense mechanisms directed against it.
As with syphilis, the disease classically is divided into stages: early localized, early disseminated, and late. However, distinct cutoff points between the stages are frequently unclear. Early localized Lyme disease refers to isolated EM and patients with an undifferentiated febrile illness. Early disseminated disease refers to the extracutaneous manifestations and secondary skin lesions that occur during the first weeks to months after infection. Late Lyme disease refers to later manifestations (usually in the nervous system and joints) that occur months to years later. Many patients initially have EM; however, in others, neurologic or rheumatologic complaints may be the initial symptoms, either because EM is not present or because it was unrecognized or misdiagnosed.
Frequency
United States
The Centers for Disease Control and Prevention (CDC) track cases of Lyme disease by using strict surveillance criteria (not designed for diagnosis of individual cases). The incidence has been increasing over time. This is not simply a result of increased recognition, since in states that perform active surveillance, true incidence and geographic range have increased. The likely causes of this increase are expansion of deer herds and the expanded range of the vector.
During the period between 1992 and 2006, nearly a quarter of a million cases of Lyme disease were reported to the CDC. Over that same period, the number of cases has doubled. In 2001, the CDC reported 17,029 cases and, in 2002, that number rose to 23,763—a 40% increase. Year-to-year variation can be significant. Ninety-three percent of cases come from 10 states: Connecticut, Delaware, Maryland, Massachusetts, Minnesota, New Jersey, New York, Pennsylvania, Rhode Island, and Wisconsin.6 Even within these states, incidence can be quite variable from county to county and even neighborhood to neighborhood.
Overall in the United States, incidence is 6-8.2 cases per 100,000 population (2001 and 2002 data). However, in Connecticut in 2001, the rate was nearly 134 cases per 100,000 population, and, on the island of Nantucket, Massachusetts, the rate has exceeded 1000 cases per 100,000 population.
Epidemiologic data suggest that the actual incidence of Lyme disease could be as much as 10 times higher than the CDC data indicate. This probably is a result of a restrictive case definition from the CDC, inevitable misdiagnosis, and the fact that physicians tend to underreport reportable diseases of all kinds.
International
Lyme disease exists throughout the world, including Scandinavia; central, southern, and western Europe; the former Soviet Union; Japan; and China. While Lyme disease is far more common in the northern hemisphere, occasional cases have been reported in more tropical locales, and it may exist in Australia. Ecology for the disease differs in various parts of the world. Furthermore, different strains of the organism are present in Europe and very likely account for differences in clinical manifestations; these have implications for diagnostic testing and vaccination strategies.
Mortality/Morbidity
Rare fatalities are reported in patients with Lyme disease.
- Some fatal cases occur in patients who were simultaneously co-infected with other tick-borne pathogens. In North America, these other infections are generally babesiosis and ehrlichiosis. In Europe, in addition to these 2 organisms, fatalities have been reported with co-infecting tick-borne encephalitis, a tick-borne flavivirus.
- Patients with neurologic disease that is not promptly diagnosed and treated can have neurologic damage that can be difficult to treat. These fixed neurologic deficits may not respond to antibiotics.
- Similarly, some genetically predisposed patients with arthritis may have ongoing joint inflammation that does not respond to further antibiotic therapy.
Race
No known differential frequency exists in patients of different races; however, EM maybe more difficult to diagnose in dark-skinned individuals.
Sex
Developing Lyme disease is more a function of tick exposure than sex. Likely for this reason, the disease is slightly more common in males than in females.
Age
Lyme disease occurs in patients of all ages. However, a bimodal peak exists: one at age 5-14 years and a second one at 50-59 years.
- About 25% of cases occur in children younger than 14 years.
- The likelihood of contracting Lyme disease is related more to tick exposure than to age, sex, or race per se.
Clinical
History
Because only about 25-30% of patients with Lyme disease recall the bite, history taking must be directed toward determining the epidemiologic probability of a tick bite. Because Lyme disease can affect many body parts, many presenting complaints can exist. Examples may include the following:
- Systemic manifestations
- Fever is generally low grade. A high-grade fever or toxic appearance suggests co-infection, such as ehrlichiosis or babesiosis, or an alternative diagnosis.
- Fatigue is common.
- Myalgias and arthralgias occur early. Frank arthritis (ie, joint swelling, redness, pain) usually is a later manifestation but can occur in the early disseminated phase.
- Flulike illness (undifferentiated febrile illness) may occur. Although the frequency of this is unknown, the phenomenon of Lyme disease with typical flulike symptoms of fevers, chills, myalgias, arthralgias, and malaise (without rash) is well documented. The season of onset, epidemiologic likelihood of a tick bite, paucity of respiratory and GI symptoms, and prompt response to antiborrelial therapy are diagnostic clues.
- Cutaneous symptoms
- The classic rash, erythema migrans (EM), is present in about 75% of patients. Because it is neither pruritic nor painful (although it can be either), some patients may have the rash but not notice it. EM can occur in the same patient more than once.
- About 20% of patients with Lyme disease have multiple lesions (from hematogenous dissemination). The higher figure is from earlier studies; current information suggests that the rate of multiple lesions is closer to 20%.
- Borrelial lymphocytoma, a nodule usually found on the ear lobe or areola of the nipple, develops in some patients early in the course of disease. This is more common in Europe.
- Almost exclusively observed in Europe, acrodermatitis chronicum atrophicans is a rash that patients describe as inflammation or thinning of the skin, usually on the distal legs and hands.7
- Neurologic symptoms
- Headache can occur in early infection as a nonspecific finding and can herald CNS penetration and lymphocytic meningitis. The headache of Lyme disease typically is described as waxing and waning, and the severity varies from mild to severe, even in patients with frank meningitis.
- Patients notice facial weakness, which is similar to a typical Bell palsy and which can be the presenting symptom of Lyme disease. About 25% of patients with borrelial facial palsy have bilateral involvement, which may be sequential and is a point of differential diagnostic significance. Other than Lyme disease and Guillain-Barré syndrome, bilateral seventh nerve palsy is rare.
- In an analysis of 313 children with facial palsy, 34% were due to Lyme disease. Clinical predictors were onset of symptoms between June to October, absence of herpetic lesions, presence of fever, and history of headache.8
- Radicular pain can occur and present as acute disk disease. More common in European patients, radicular pain may be associated with lymphocytic pleocytosis (Bannwarth syndrome).
- Late Lyme disease can cause paresthesias or pain due to peripheral neuropathy and personality, cognitive, and sleep disturbances from chronic encephalopathy. All sorts of neurologic syndromes caused by Lyme disease involving nearly every part of the CNS and peripheral nervous system have been reported in numerous case reports; therefore, Lyme disease may produce numerous symptoms. Although the likelihood that these other symptoms result from Lyme disease in any particular patient may be small, the clinician must remain open minded to this possibility.
- Cardiovascular involvement
- Cardiovascular involvement occurs in fewer than 10% of patients with untreated Lyme disease and is more common in male patients than in female patients.
- Palpitations, lightheadedness, and syncope may be a manifestation of varying degrees of heart block, including complete heart block, which occurs in 50% of patients with cardiac involvement. Lyme disease is an important reversible cause of heart block.9
- Chest pain and dyspnea can occur in the setting of Lyme pericarditis, myocarditis, and myopericarditis. Tamponade has been reported.
- Migratory pains in and around the joints and muscles
- Migratory pain may occur from myositis, tendonitis, and bursitis.
- These symptoms classically wax and wane over hours or days.
- Later, arthritis occurs generally with swelling, redness, and pain in one or a few large joints, typically the knees.
- Synovitis occasionally occurs in the early-disseminated phase of Lyme disease.
- Red, itchy eyes from conjunctivitis
- Red, itchy eyes are the most common ocular symptom.
- Blurred vision and eye pain can occur from keratitis and iritis. Unilateral blindness from panophthalmitis has been reported as well.
- Nausea and vomiting
Physical
The physical examination in patients with Lyme disease can reveal numerous findings, depending on the target organs involved and the phase of the disease at presentation. In addition to fever, findings may include the following:
- Dermatologic findings
- Classic EM is an erythematous papule or macule that occurs at the site of the tick bite (1-33 d later; average, 7-10 d). Often, a central punctum is found at the site. The size varies enormously (as large as 70 cm; average, 16 cm) and depends on disease duration. Central clearing, a phenomenon emphasized in earlier literature, occurs in only a minority of cases in North America (about 40% in one study of culture-proven EM).10 Central clearing is more common in European patients than in North American patients.
- Although lesions are defined, for surveillance purposes, as being greater than 5 cm in size, smaller lesions that are culture positive for B burgdorferi have been reported. EM may not be pathognomonic for Lyme disease; similar lesions are found in patients with a similar tick-borne disease found across the southern United States. In this disease, called southern tick-associated rash illness (STARI), or Master disease, a similar rash is seen. While differences exist between the two rashes as a group, significant overlap exists in individual cases.
- EM usually is flat, round, or oval and monocyclic. Generally, neither itching nor pain is present. The rash enlarges a few centimeters per day and fades, even if untreated, after a few weeks. The rash can be triangular or linear and is sometimes fleeting in duration. Rash location is another important diagnostic clue.2,11
- The clinician must be able to recognize atypical manifestations of EM, such as necrotic and vesicular lesions. The lesion may have central darkening or be uniform in color, and the edges may be raised. Scaling is unusual.
- EM rarely is found on the hands and feet (unlike spider and other arthropod bites). Ticks tend to bite where natural barriers impede their forward motion (eg, axillary or gluteal folds, hairline, areas near elastic bands in bra straps or underwear). In children, the scalp, face, and hairline are more common locations.
This patient's erythema migrans rash demonstrates several key features of the rash, including size, location, and presence of a central punctum, which can be seen right at the lateral margin of the inferior gluteal fold. Note that the color is uniform; this pattern probably is more common than the classic pattern of central clearing.
- Approximately 20% of patients with EM have secondary lesions. These lesions generally are smaller than the primary one, lack the central punctum, and are not necrotic or vesicular.
- Borrelial lymphocytoma most frequently is observed in European patients. This finding can be early or late and can follow or occur concurrently with EM. It is a reddish purple nodule on the ear lobe or the nipple (other locations are possible).7
- Acrodermatitis chronicum atrophicans is nearly exclusively observed in European patients. The two phases are an inflammatory phase with edema and erythema in the distal extremities and a scarring phase with atrophy and skin as thin as cigarette paper. B burgdorferi has been cultured from lesions in which the primary infection occurred over 10 years prior.
- Neurologic signs
- Neck stiffness can occur early, with or without frank meningitis.
- Facial nerve palsy is a lower motor neuron lesion that causes facial weakness of both the lower face and forehead. It can be bilateral. As in idiopathic Bell palsy, sometimes a polycranial neuropathy exists with any nerve involved; this more commonly is reported in the European literature. Nearly every cranial nerve has been reported to be involved, although this is uncommon.
- Weakness and abnormal sensation can occur because of meningoradiculitis and more commonly is reported in European patients. Diminished reflexes can occur with this syndrome. CSF frequently reflects pleocytosis.
- Neuropsychiatric testing and mini-mental status testing may uncover cognitive, memory, and personality changes that occur in late Lyme encephalopathy.
- Peripheral axonal neuropathy can lead to patchy, generally distal abnormalities in sensation. Sensory findings are more pronounced than motor findings.
- Cardiovascular findings
- In patients with complete heart block, Canon A waves may be observed in the neck. A slow or irregular pulse may be palpated.
- A cardiac rub, S3 and/or S4, may be auscultated in patients with myocarditis or pericarditis. Signs of tamponade very rarely can occur. In patients with chronic cardiac involvement with congestive heart failure, typical signs of congestive heart failure may be present.
- Musculoskeletal findings
- Muscle tenderness can result from myositis; tenderness of tendons and periarticular structures may be present.
- Frank arthritis can occur after weeks, months, or years and may lead to erythema, edema, synovial effusion, and tenderness of the affected joints. Usually, this is a monoarthritis or oligoarthritis involving large joints, especially the knee. Swelling often is disproportional to the tenderness.
- Ocular signs
- Conjunctival erythema and injection or retinal hemorrhages and exudates may be present.
- On slit lamp examination, signs of keratitis and cells in the anterior chamber from iritis may be seen.
- In children (especially in North America), papilledema may be present in a pseudotumor cerebri–like syndrome.
- Other signs - Splenomegaly, hepatomegaly, regional lymphadenopathy
Causes
Lyme disease is caused by infection with the spirochete, B burgdorferi, the complete genome of which has been described recently.
- The species Borrelia burgdorferi sensu lato has several well-characterized groups that may lead to different clinical manifestations. These 3 groups are B burgdorferi sensu stricto, Borrelia garinii, and Borrelia afzelii. Other strains, which may be sufficiently different in their genetic structure to be considered separate strains, exist; however, most of these are nonpathogenic to humans. This is an area of active research.
- B burgdorferi sensu stricto is present in most North American isolates.
- B afzelii is common in Europe and is frequently isolated in patients with acrodermatitis chronicum atrophicans.
- B garinii, more common in Europe, is commonly isolated in patients with lymphocytic meningoradiculitis (Bannwarth syndrome) and white matter encephalitis.
- Occupational or recreational activities that place an individual in contact with ticks are the major risk factors.
- Arthritis that is nonresponsive to antibiotics may develop in some genetically predisposed individuals (ie, those who have the HLA-DR4 antigen).
- Some patients will have persistent or recurrent symptoms after what is considered adequate antibiotic therapy for Lyme disease. This phenomenon has been termed chronic Lyme disease, or post-Lyme syndrome. The cause for this is controversial.1,12
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References
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Steere AC, McHugh G, Damle N, Sikand VK. Prospective study of serologic tests for lyme disease. Clin Infect Dis. Jul 15 2008;47(2):188-95. [Medline].
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[Guideline] Halperin JJ, Shapiro ED, Logigian E, Belman AL, Dotevall L, Wormser GP, et al. Practice parameter: treatment of nervous system Lyme disease (an evidence-based review): report of the Quality Standards Subcommittee of the American Academy of Neurology. Neurology. Jul 3 2007;69(1):91-102. [Medline].
[Guideline] Wormser GP, Dattwyler RJ, Shapiro ED, Halperin JJ, Steere AC, Klempner MS, et al. The clinical assessment, treatment, and prevention of lyme disease, human granulocytic anaplasmosis, and babesiosis: clinical practice guidelines by the Infectious Diseases Society of America. Clin Infect Dis. Nov 1 2006;43(9):1089-134. [Medline].
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Nadelman RB, Nowakowski J, Fish D. Prophylaxis with single-dose doxycycline for the prevention of Lyme disease after an Ixodes scapularis tick bite. N Engl J Med. Jul 12 2001;345(2):79-84. [Medline].
Dattwyler RJ, Luft BJ, Kunkel MJ, et al. Ceftriaxone compared with doxycycline for the treatment of acute disseminated Lyme disease. N Engl J Med. Jul 31 1997;337(5):289-94. [Medline].
Wormser GP, Ramanathan R, Nowakowski J, et al. Duration of antibiotic therapy for early Lyme disease. A randomized, double-blind, placebo-controlled trial. Ann Intern Med. May 6 2003;138(9):697-704. [Medline].
Oksi J, Nikoskelainen J, Hiekkanen H, et al. Duration of antibiotic treatment in disseminated Lyme borreliosis: a double-blind, randomized, placebo-controlled, multicenter clinical study. Eur J Clin Microbiol Infect Dis. Aug 2007;26(8):571-81. [Medline].
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Halperin JJ. Nervous system Lyme disease. Infect Dis Clin North Am. Jun 2008;22(2):261-74, vi. [Medline].
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Further Reading
Clinical Guidelines
Practice parameter: treatment of nervous system Lyme disease (an evidence-based review). Report of the Quality Standards Subcommittee of the American Academy of Neurology. American Academy of Neurology - Medical Specialty Society. 2007 Jul. 12 pages. NGC:005671
Evidence-based guidelines for the management of Lyme disease. International Lyme and Associated Diseases Society - Disease Specific Society. 2004. 13 pages. NGC:003481
Infectious Diseases Society of America practice guidelines for clinical assessment, treatment and prevention of Lyme disease, human granulocytic anaplasmosis, and babesiosis. Infectious Diseases Society of America - Medical Specialty Society. 2000 Jul (revised 2006 Jun). 150 pages. NGC:005085
Clinical Trials
Evaluation of Lyme Disease: Clinical, Microbiological, and Immunological Characteristics
Evaluation, Treatment, and Follow-up of Patients with Lyme Disease
Study and Treatment of Post Lyme Disease (STOP-LD)
A Randomized, Double-Blind, Placebo-Controlled, Multicenter Trial of the Safety and Efficacy of Ceftriaxone and Doxycycline in the Treatment of Patients With Seronegative Chronic Lyme Disease
A Randomized, Double-Blind, Placebo-Controlled, Multicenter Trial of the Safety and Efficacy of Ceftriaxone and Doxycycline in the Treatment of Patients With Seropositive Chronic Lyme Disease
Analysis of Lyme Disease Lesions
Keywords
tick-borne disease, Lyme disease, tick bite, Borrelia burgdorferi, Ixodes, vector-borne disease, juvenile arthritis, B burgdorferi, spirochete, tick-borne pathogens, myalgias, arthralgias, flulike illness, borrelial lymphocytoma
acrodermatitis chronicum atrophicans, lymphocytic meningitis, facial weakness, Bell palsy, borrelial facial palsy, lymphocytic pleocytosis, Bannwarth syndrome, chronic encephalopathy, syncope, heart block, complete heart block, lyme pericarditis, lyme myocarditis, lyme myopericarditis, myositis, tendonitis, bursitis, synovitis, conjunctivitis, keratitis, iritis, erythematous papule, erythematous macule, polycranial neuropathy
meningoradiculitis, lyme encephalopathy, peripheral axonal neuropathy, tamponade, congestive heart failure, monoarthritis, oligoarthritis, retinal hemorrhages, retinal exudates, papilledema, pseudotumor cerebral-like syndrome, splenomegaly, hepatomegaly, regional lymphadenopathy, , white matterencephalitis, HLA-DR4 antigen
