Lyme Disease Clinical Presentation
- Author: John O Meyerhoff, MD; Chief Editor: Herbert S Diamond, MD more...
Because only approximately 25-30% of United States patients with early Lyme disease recall the tick bite, the clinician must direct the history toward the possibility of a tick bite. (In Europe, 64% do not remember being bitten.) Patients are generally unaware of a tick bite because these ticks are extremely small (nymphal Ixodes ticks are approximately the size of a poppy seed) and their bites are often painless.
Epidemiologic context is extremely important. The clinician should determine where the patient lives, works, and vacations, and should ask about specific activities in which the patient participates at those locales. The probability of a tick bite—and thus, the likelihood of contracting Lyme disease—is highest in persons who spend time outdoors (particularly in wooded, brushy, or grassy habitats) in a geographically endemic area.
Endemic areas can be defined as those with established populations of Ixodes scapularis or other vector ticks and evidence of enzootic transmission of Borrelia burgdorferi between the tick and the resident animal population. (See Epidemiology.)
The season is important, especially in patients with early disease. Most cases of erythema migrans occur from late spring through early fall, because that is when ticks in the nymphal stage are seeking a blood meal, and nymphs account for 90% of Lyme disease cases. For patients presenting with later cutaneous manifestations, especially acrodermatitis chronica atrophicans, questions must be directed at assessing the risk of tick bite (or previous manifestations of Lyme disease) from many years in the past.
Because people who engage in activities that put them in risk for tick bites tend to continue those activities, reinfection is not uncommon. Patients who have previously had erythema migrans can be reinfected (meaning that the first infection has been successfully treated, and they have a new infection with B burgdorferi). This has been clearly demonstrated in reinfected patients who were culture positive and had different serotypes isolated in the first and second infections.
Reinfections manifest in much the same ways as first infections, although a tendency towards less hematogenous spread is noted. In contrast, relapse (as opposed to reinfection) is very unusual in patients who have been treated with appropriate antimicrobials.
Certain 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, and infection with this organism has a particular predilection to affect joints, whereas other strains are more common in Europe, such as B burgdorferi afzelii, which is associated with acrodermatitis chronica atrophicans.
Similar to syphilis, the manifestations of Lyme disease have been divided into three stages: localized, disseminated, and persistent. However, in individual patients, no rigid cutoffs exist between stages. The first two stages are part of the early infection, whereas persistent disease is considered late infection. Unlike syphilis, stage 3 disease may occur within 1 year of infection, not many years later.
Stage 1 Lyme disease
Early localized Lyme disease refers to isolated erythema migrans and to an undifferentiated febrile illness. This stage occurs 1-30 days after the tick bite.
Erythema migrans, the characteristic skin rash of Lyme disease, occurs in two thirds of patients with Lyme disease and develops at an average of 7 days after the tick bite. The rash typically 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. It may be asymptomatic or it may itch or burn.
The rash typically expands over days and is not evanescent. It may not be observed until it is already full size. Clearing of portions of the rash as it expands may result in concentric rings of erythema, producing the classic bull’s-eye rash (see the image below). In the United States, however, erythema migrans is more likely to have a uniform color.
Although many patients present with erythema migrans, others first present with extracutaneous symptoms. In those cases, erythema migrans may have never occurred or may not have been recognized by the patient or correctly diagnosed by the physician.
Untreated, the rash may persist for 2-3 weeks. Eighty percent of patients with Lyme disease have only one episode of erythema migrans, whereas 20% may have recurrent episodes. Multiple lesions may occur in 20% of patients with Lyme disease; they result from hematogenous dissemination and are not the result of multiple tick bites (see the following image).
Approximately 50% of patients describe flulike symptoms within days to 1 week of infection, characterized by fever, chills, and malaise. Fever is generally low grade. Other symptoms include fatigue and myalgia (80% of patients with Lyme disease in the US but < 35% in Europe), as well as arthralgia, headache, and neck stiffness, which may resolve spontaneously even if specific therapy is not initiated. A paucity of respiratory and gastrointestinal tract symptoms may also be present.
The most common ocular manifestations of stage 1 Lyme disease are redness and tearing.
Approximately one third of all patients with erythema migrans develop no further manifestations of Lyme disease. Two thirds of patients develop further symptoms (stages 2 and 3).
It is also important to consider co-infection by other organisms transmitted by the same tick bite, in areas where those are endemic. Co-infection with Ehrlichia species and Babesia microti are reported with increased frequency; in some studies, co-infection occurs in as many as 10-15% of patients with Lyme disease. When Lyme disease is strongly suggested but some of the manifestations are atypical (eg, a high fever, especially if accompanied by rigors or a toxic appearance) these other tick-borne infections or an alternative diagnosis must be considered.
Stage 2 Lyme disease
Early disseminated Lyme disease usually develops 3-10 weeks after inoculation. Approximately 25% of individuals infected with B burgdorferi have signs and symptoms of disseminated disease at presentation.
Systemic manifestations may include fever and malaise. One or more organ systems become involved as hematologic or lymphatic spread disseminates spirochetes to distant sites. Musculoskeletal and neurologic symptoms are the most common; less common are symptoms from cardiac disturbances, such as dizziness, syncope, dyspnea, chest pain, and palpitations.
Ocular manifestations include diplopia secondary to a cranial neuropathy or Bell palsy. Blurred vision and eye pain can occur from keratitis and iritis. Unilateral blindness from panophthalmitis has been reported as well.
Intermittent inflammatory arthritis 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 symptoms after they have resolved, patients with Lyme disease are less likely to remember those symptoms that occurred before 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 1 week. Two thirds of patients have three recurrences approximately 2.5 months apart. The recurrences are more likely to involve more than one joint. 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.
Neurologic involvement, also known as Lyme neuroborreliosis, is reported in 5-20% of cases. In the United States, cranial neuropathy is the most common manifestation of early neurologic Lyme disease. Other manifestations include meningitis and encephalopathy.
Cranial neuropathies, especially facial nerve palsy (Bell palsy), develop in approximately 3% of Lyme disease patients. In endemic areas, Lyme disease is the most commonly identified cause of acquired facial palsy, especially in children. Headache, absence of previous herpetic lesions, and meningeal symptoms are noted in most pediatric Lyme disease patients with facial palsy.
When meningitis is involved, symptoms usually occur 2-10 weeks following infection. Headache, neck pain or stiffness, and photophobia typically indicate meningeal irritation. 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. Persistent headache alone is a rare presentation of Lyme disease but should be considered in patients in endemic areas during summertime.
Borrelia encephalopathy most commonly manifests as a mild confusional state accompanied by disturbances in memory, concentration, mood, sleep, personality, and/or language occurring months to years after the infection. Depression and irritability are also common.
In patients with cutaneous involvement, multiple erythema migrans lesions are present. These are relatively small erythematous macules (1-5 cm) and are often oval. Unlike primary single erythema migrans rashes, these lesions can be evanescent and do not show the typical expansion over days.
Borrelial lymphocytoma is an uncommon manifestation of early disseminated Lyme disease (though it may also occur very early in the disease course) that has been reported only from Europe. It is a bluish-red nodular swelling that typically occurs on the lobe of the ear in children (see the following image) or the areola of the nipple in adults. Occasionally, borrelial lymphocytoma lesions occur on the scrotum, nose, and extremities. Nipple lesions tend to be painful, possibly because of rubbing against clothing.
Stage 3 Lyme disease
Late or chronic Lyme disease refers to manifestations that occur months to years after the initial infection, sometimes after a period of latency. Signs and symptoms of chronic Lyme disease are primarily rheumatologic and neurologic. Acrodermatitis chronica atrophicans, the cutaneous feature of late-stage Lyme disease, is found almost exclusively in European patients.
Most patients presenting with late disease do not have a history of erythema migrans, because the rash typically leads to earlier treatment, which prevents the development of late disease. However, other manifestations of the disease may coexist or may have occurred in the past. Thus, a history of Bell palsy, aseptic meningitis, arthritis, acral paresthesias or dysesthesias (from peripheral neuropathy), or cognitive dysfunction (from CNS involvement) may be diagnostically useful.
Lyme arthritis is the hallmark of stage 3 Lyme disease. It tends to involve large joints (the knee is involved in 90% of cases). Arthritis must be differentiated from arthralgia, which is common in early disease.
The neurologic abnormalities of stage 3 Lyme disease involve both the central and peripheral nervous systems. Typical presentations include subacute encephalopathy, chronic progressive encephalomyelitis, and late axonal neuropathies, as well as symptoms consistent with fibromyalgia. 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).
Borrelia encephalomyelitis is a rare but severe syndrome. Symptoms can progress gradually or in a relapsing-remitting pattern, with partial improvement after the attacks. The most common clinical manifestations of Borrelia encephalomyelitis are hemiparesis, ataxia, seizures, cognitive impairment, bladder dysfunction, and hearing loss. Myelitis is present in 50% of patients with late neuroborreliosis. Progressive spastic paraparesis or quadriparesis is common.
Acrodermatitis chronica atrophicans most commonly affects older women. Unlike erythema migrans, acrodermatitis chronica atrophicans tends to occur acrally, especially on the dorsal surfaces of the hands, feet, knees, and elbows. Early on, a minimally symptomatic erythema tends to occur in these locations. Initially, there is discoloration and inflammation; later, severe atrophy is noted. See the image below.
In many patients with early Lyme disease, identification of erythema migrans (EM) on physical examination alone is sufficient to establish a working diagnosis of Lyme disease. Careful attention to the details often makes the difference between the need to proceed with further confirmatory tests and an empiric course of antibiotics. In particular, the examination findings must be interpreted in the epidemiologic context; this cannot be overemphasized. The location, time of year, and patient's activities can be important diagnostic clues.
Regional lymphadenopathy may be seen, and a low-grade fever is not uncommon. High fever suggests another co-infecting tick-borne organism such as Ehrlichia or Babesia species or some other diagnosis altogether, such as streptococcal cellulitis.
EM is the characteristic rash of Lyme disease. Classic EM is a flat to slightly raised erythematous lesion that appears at the site of the tick bite after 1-33 days bite (average, 7-10 days). Without therapy, erythema migrans typically fades within 3-4 weeks.
EM usually is round or oval, but can be triangular or linear. Often, a central punctum is evident at the bite site.
EM enlarges by a few centimeters per day; single lesions typically achieve a diameter of approximately 16 cm (approximately 5-6 inches), but lesions as large as 70 cm have been reported. The case definition for Lyme disease used by the US Centers for Disease Control and Prevention (CDC) specifies that EM be greater than 5 cm in size. This size cutoff is only meant to be used for epidemiologic purposes, however; EM smaller than 5 cm has occasionally been documented in culture-proven cases.
The entire lesion may be uniform in color or have central darkening. Central clearing is more common in European patients than in North American patients. More proximal to the clearing may be additional erythema leading to a so-called bull's eye or target appearance; however, this phenomenon, emphasized in the earlier literature, occurs only in a minority of patients (37% in one North American study of culture-proven EM). See the images below.
Atypical manifestations of EM include vesicular (see the image below) and centrally necrotic lesions. Scaling is unusual, but may be seen, especially in the center of the lesion.
Rash location is another important diagnostic clue. Unlike spider and other arthropod bites, EM rarely is found on the hands or feet. Rather, ticks tend to bite where natural barriers impede their forward motion (eg, popliteal fossa, axillary or gluteal folds, hairline, areas near elastic bands in bra straps or underwear). In children, the scalp, face, and hairline are especially common locations.[6, 31]
Approximately 20% of patients with EM have secondary lesions (see the image below). These lesions generally are smaller than the primary one, lack the central punctum, and are not necrotic or vesicular. They also tend to be more uniform in morphology than the primary lesion. Because secondary lesions result from hematogenous spread, their locations are not as restricted as those of the primary lesion.
Note that rashes very similar to erythema migrans, but from which Borrelia burgdorferi cannot be cultured, have been reported in the southern United States. This disease is called southern tick-associated rash illness (STARI), or Master disease. As a group, distinctions can be made between classic erythema migrans and this illness, but significant overlaps exist such that the differences are not useful in diagnosing individual patients.
An erythematous skin lesion present while an Ixodes tick is still attached is most likely a hypersensitivity reaction rather than EM. Hypersensitivity reactions also tend to produce lesions that are smaller and more transient than EM; typically, the lesions are less than 5 cm in size and begin to resolve within 2 days.
Less than 1% of patients with stage 2 Lyme disease, almost all of them European, develop Borrelia lymphocytoma, described as a small, bluish-red nodule or plaque. The earlobe and scrotum are the typical location in children (See the image below), whereas the nipple is the more common location in adults.
Borrelial lymphocytoma tends to occur in areas of previous (or concurrent) erythema migrans and may be up to a few centimeters in size. Regional lymphadenopathy may be present.
Other terms used to describe borrelial lymphocytoma include the following:
Lymphadenosis benigna cutis
Cutaneous lymphoid hyperplasia
Spiegler-Fendt lymphoid hyperplasia
Acrodermatitis chronica atrophicans
Acrodermatitis chronica atrophicans is a relatively uncommon physical manifestation of late Lyme disease that begins as an inflammatory phase marked by edema and erythema, usually on the distal extremities; at times, a faint bluish discoloration is found predominantly on extensor surfaces. The lesions have a predilection for the posterior heels and dorsal (extensor) surfaces of the hands, feet, elbows, and knees. The lesions also tend to become symmetric. The buttocks often become involved.
Later, atrophy supervenes and so-called cigarette-paper skin is seen, with an appearance similar to scleroderma. (See the image below.) Because of the loss of subcutaneous fat, underlying venous structures are more visible, and the skin becomes thin, atrophic, and dry. Fibrous juxtaarticular nodules or bands may be seen on the extensor surfaces of the elbows and knees. One third of patients with acrodermatitis chronicum have an associated sensory polyneuropathy.
Other dermatologic manifestations
Other skin lesions have been associated with B burgdorferi infection, but whether they are part of the syndrome of Lyme disease is controversial. The lesion for which the most evidence of causality has been reported is morphea (localized scleroderma), which develops in roughly 10% of European patients with borrelial lymphocytoma and acrodermatitis chronica atrophicans.
Other European reports less commonly link the following with B burgdorferi infection:
Progressive facial hemiatrophy (Parry-Romberg syndrome)
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.
Approximately 60% of all untreated patients develop symptoms of intermittent migratory monoarthritis. Episodes last a mean of 3 months and very often affect the knee or temporomandibular joints, although not universally. Migratory oligoarthritis involving the small or large joints can also occur. Joint symptoms develop in approximately 80% of all untreated patients within 2 years of infection.
The severity of joint involvement can range from intermittent episodes of subjective pain to frank arthritis to chronic erosive synovitis. During the attacks, the joints are swollen, hot, and painful, but they are not usually red or as severe as in a septic joint. Effusions may be large and generally recur following aspiration, as is often seen in spondyloarthropathies. Fewer than 10% of patients with arthritic sequelae develop pannus or erosion of cartilage and bone.
Approximately 5-10% of untreated patients with Lyme disease have signs of cranial neuropathies, and up to 60% of patients with early neuroborreliosis develop cranial neuritis. Seventh nerve palsy is by far the most common. Bilateral facial palsy can be seen in 35% of patients and is a unique characteristic that is useful for distinguishing it from idiopathic Bell palsy and other disorders.
Typical associated findings depend on the nerve affected and can include visual or auditory disturbances, facial paresthesia, and/or vertigo. Other neurologic manifestations include diffuse or focal mononeuropathy multiplex (multifocal involvement of anatomically unrelated nerves), plexopathy, and/or radiculoneuropathy (more common in Europe). Less common presentations include myositis, pseudotumor cerebri, and cerebellitis.
Lyme meningitis is relatively common, occurring in as many as 15% of untreated patients bitten by the Ixodes tick and in 30% of Lyme disease cases, and does not manifest as the usual signs of bacterial meningitis (eg, boardlike rigidity, Kernig and Brudzinski signs). Meningitis may be accompanied by cranial or peripheral radiculoneuropathy. Neck stiffness can occur early, with or without frank meningitis.
Acute radiculoneuritis is reported in 50-85% of cases. Acute onset of motor deficits, severe radicular pain, and sensory loss are commonly seen after 2-4 weeks of infection. Multifocal asymmetric weakness is a common presentation. Although the presentation of inflammatory radiculoneuropathy is often indistinguishable from that of spinal-root compression, involvement of multiple dermatomes in the thorax and a lack of a precipitating injury can aid in diagnosis.
Chronic radicular paresthesias are usually not associated with motor or sensory deficits. The physical examination results are normal.
With peripheral neuropathy, patients usually report intermittent paresthesias. The most frequent finding upon examination is decreased vibratory sensation of the distal lower extremities. A stocking-glove distribution of epicritic sensory deficits is also a common finding. Sensory findings are more pronounced than motor findings.
With late axonal neuropathy, patients can report intermittent distal limb paresthesias months to years after infection. It is distinct from the neuropathy of early Lyme disease, because the symptoms are less severe. Acrodermatitis chronica atrophicans–associated neuropathy is common in Europe and manifests as neuropathic pain, paresthesias, and muscle cramps.
In Europe, common manifestations of Garin-Boujadoux-Bannwarth syndrome (Bannwarth syndrome) include neuritic pain, cranial neuritis without headache, and lymphocytic pleocytosis. Bannwarth syndrome has also been called tick-borne meningopolyneuritis, lymphocytic meningoradiculitis, and chronic lymphocytic meningitis.
Neuropsychiatric findings in late-stage disease may include the following:
Cardiac involvement ranges from atrial or ventricular arrhythmias to transient heart block or myopericarditis. Approximately 8% of untreated patients have acute-onset atrioventricular conduction abnormalities. Most cardiac episodes are isolated and transient, lasting less than a week. In rare instances, patients with heart block require electrical pacing.
In patients with complete heart block, cannon 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 heart failure, typical signs of chronic heart failure may be present.
Ophthalmic manifestations vary by disease stage. In stage 1 Lyme disease, the ocular manifestations are conjunctivitis and photophobia. These are mild and transient, and ophthalmologists usually need not be consulted.
Significant ophthalmic complications may appear during stage 2 Lyme disease.[32, 33, 34, 35] Blurred vision can be noted during stage 2, secondary to papilledema, optic atrophy, optic or retrobulbar neuritis, or pseudotumor cerebri. Optic nerve disease may be unilateral or bilateral, and solitary or associated with other neurologic or neuro-ophthalmologic manifestations. Some evidence exists that children are more predisposed to optic nerve disease than adults.
In late stage 2 or stage 3 Lyme disease, most of the severe ocular manifestations of the disease are seen. These include the following:
Posterior or intermediate uveitis
Exudative retinal detachment
Retinal pigment epithelial detachment
Cystoid macular edema
Branch artery occlusion
Cranial nerve palsies
Of this group, keratitis, vitreitis, and pars planitis are the most common. The keratitis usually is a bilateral, patchy, nummular stromal keratitis. Posterior segment inflammatory disease generally presents as a bilateral pars planitis associated with granulomatous iritis and vitreitis. Many of these patients also have granulomatous keratic precipitates and posterior synechiae.
Feder HM Jr. Lyme disease in children. Infect Dis Clin North Am. 2008 Jun. 22(2):315-26, vii. [Medline].
Centers for Disease Control and Prevention. Two-step Laboratory Testing Process. CDC. Available at http://www.cdc.gov/lyme/diagnosistesting/LabTest/TwoStep/index.html. March 26, 2015; Accessed: March 14, 2016.
Centers for Disease Control and Prevention. Lyme Disease Data. CDC. Available at http://www.cdc.gov/lyme/stats/index.html?s_cid=cs_281. September 24, 2015; Accessed: March 14, 2016.
Project Plan: Guidelines for the Prevention, Diagnosis, and Treatment of Lyme Disease by the Infectious Disease s Society of America, the American Academy of Neurology, and the American College of Rheumatology. Infectious Diseases Society of America. Available at http://www.idsociety.org/uploadedFiles/IDSA/Guidelines-Patient_Care/PDF_Library/LD%20Project%20Plan%20March%202015%282%29.pdf. Accessed: March 14, 2016.
Edlow JA. Bull's Eye - Unraveling the Medical Mystery of Lyme Disease. 2nd ed. New Haven: Yale University Press; 2004.
Wormser GP, McKenna D, Carlin J, et al. Brief communication: hematogenous dissemination in early Lyme disease. Ann Intern Med. 2005 May 3. 142(9):751-5. [Medline].
Masters EJ, Grigery CN, Masters RW. STARI, or Masters disease: Lone Star tick-vectored Lyme-like illness. Infect Dis Clin North Am. 2008 Jun. 22(2):361-76, viii. [Medline].
Wormser GP, Brisson D, Liveris D, et al. Borrelia burgdorferi genotype predicts the capacity for hematogenous dissemination during early Lyme disease. J Infect Dis. 2008 Nov 1. 198(9):1358-64. [Medline]. [Full Text].
Wormser GP, Nowakowski J, Nadelman RB, Visintainer P, Levin A, Aguero-Rosenfeld ME. Impact of clinical variables on Borrelia burgdorferi-specific antibody seropositivity in acute-phase sera from patients in North America with culture-confirmed early Lyme disease. Clin Vaccine Immunol. 2008 Oct. 15(10):1519-22. [Medline]. [Full Text].
Bernardino AL, Myers TA, Alvarez X, Hasegawa A, Philipp MT. Toll-like receptors: insights into their possible role in the pathogenesis of lyme neuroborreliosis. Infect Immun. 2008 Oct. 76(10):4385-95. [Medline]. [Full Text].
Stanek G, Strle F. Lyme disease: European perspective. Infect Dis Clin North Am. 2008 Jun. 22(2):327-39, vii. [Medline].
Pritt BS, Mead PS, Johnson DKH, et al. Identification of a novel pathogenic Borrelia species causing Lyme borreliosis with unusually high spirochaetaemia: a descriptive study. Lancet Infect Dis. February 05, 2016. [Full Text].
Varela AS, Luttrell MP, Howerth EW, et al. First culture isolation of Borrelia lonestari, putative agent of southern tick-associated rash illness. J Clin Microbiol. 2004 Mar. 42(3):1163-9. [Medline]. [Full Text].
Adams D, Fullerton K, Jajosky R, Sharp P, Onweh D, Schley A, et al. Summary of Notifiable Infectious Diseases and Conditions - United States, 2013. MMWR Morb Mortal Wkly Rep. 2015 Oct 23. 62 (53):1-122. [Medline]. [Full Text].
Bacon RM, Kugeler KJ, Mead PS. Surveillance for Lyme disease--United States, 1992-2006. MMWR Surveill Summ. 2008 Oct 3. 57(10):1-9. [Medline].
Smith R, Takkinen J. Lyme borreliosis: Europe-wide coordinated surveillance and action needed?. Euro Surveill. 2006 Jun 22. 11(6):E060622.1. [Medline].
Centers for Disease Control and Prevention. Lyme disease statistics: 2009. CDC. Available at http://www.cdc.gov/ncidod/dvbid/lyme/ld_statistics.htm. Accessed: January 4, 2011.
Lyme disease--United States, 2003-2005. MMWR Morb Mortal Wkly Rep. 2007 Jun 15. 56(23):573-6. [Medline].
Steere AC, Angelis SM. Therapy for Lyme arthritis: strategies for the treatment of antibiotic-refractory arthritis. Arthritis Rheum. 2006 Oct. 54(10):3079-86. [Medline].
Kugeler KJ, Griffith KS, Gould LH, et al. A review of death certificates listing lyme disease as a cause of death in the United States. Clin Infect Dis. 2011 Feb. 52(3):364-7. [Medline].
Seltzer EG, Gerber MA, Cartter ML, Freudigman K, Shapiro ED. Long-term outcomes of persons with Lyme disease. JAMA. 2000 Feb 2. 283(5):609-16. [Medline].
Shadick NA, Phillips CB, Sangha O, et al. Musculoskeletal and neurologic outcomes in patients with previously treated Lyme disease. Ann Intern Med. 1999 Dec 21. 131(12):919-26. [Medline].
Sood SK, Salzman MB, Johnson BJ, et al. Duration of tick attachment as a predictor of the risk of Lyme disease in an area in which Lyme disease is endemic. J Infect Dis. 1997 Apr. 175(4):996-9. [Medline].
American Association of Pediatrics Committee on Environmental Health. Follow safety precautions when using DEET on children. Available at http://aapnews.aappublications.org/content/22/5/200399.full. Accessed: January 5, 2011.
Tibbles CD, Edlow JA. Does this patient have erythema migrans?. JAMA. 2007 Jun 20. 297(23):2617-27. [Medline].
Nigrovic LE, Thompson AD, Fine AM, Kimia A. Clinical predictors of Lyme disease among children with a peripheral facial palsy at an emergency department in a Lyme disease-endemic area. Pediatrics. 2008 Nov. 122(5):e1080-5. [Medline].
Dandache P, Nadelman RB. Erythema migrans. Infect Dis Clin North Am. 2008 Jun. 22(2):235-60, vi. [Medline].
Weber K, Wilske B. Mini erythema migrans--a sign of early Lyme borreliosis. Dermatology. 2006. 212(2):113-6. [Medline].
Nadelman RB, Nowakowski J, Forseter G, et al. The clinical spectrum of early Lyme borreliosis in patients with culture-confirmed erythema migrans. Am J Med. 1996 May. 100(5):502-8. [Medline].
Edlow JA. Erythema migrans. Med Clin North Am. 2002 Mar. 86(2):239-60. [Medline].
Karma A, Seppala I, Mikkila H, Kaakkola S, Viljanen M, Tarkkanen A. Diagnosis and clinical characteristics of ocular Lyme borreliosis. Am J Ophthalmol. 1995 Feb. 119(2):127-35. [Medline].
Lesser RL. Ocular manifestations of Lyme disease. Am J Med. 1995 Apr 24. 98(4A):60S-62S. [Medline].
Lesser RL, Kornmehl EW, Pachner AR, et al. Neuro-ophthalmologic manifestations of Lyme disease. Ophthalmology. 1990 Jun. 97(6):699-706. [Medline].
Steere AC, Sikand VK. The presenting manifestations of Lyme disease and the outcomes of treatment. N Engl J Med. 2003 Jun 12. 348(24):2472-4. [Medline].
Rothermel H, Hedges TR 3rd, Steere AC. Optic neuropathy in children with Lyme disease. Pediatrics. 2001 Aug. 108(2):477-81. [Medline].
Klig JE. Ophthalmologic complications of systemic disease. Emerg Med Clin North Am. 2008 Feb. 26(1):217-31, viii. [Medline].
Deanehan JK, Kimia AA, Tan Tanny SP, et al. Distinguishing Lyme from septic knee monoarthritis in Lyme disease-endemic areas. Pediatrics. 2013 Mar. 131(3):e695-701. [Medline].
Cohn KA, Thompson AD, Shah SS, et al. Validation of a clinical prediction rule to distinguish Lyme meningitis from aseptic meningitis. Pediatrics. 2012 Jan. 129(1):e46-53. [Medline].
Steere AC, McHugh G, Damle N, Sikand VK. Prospective study of serologic tests for lyme disease. Clin Infect Dis. 2008 Jul 15. 47(2):188-95. [Medline].
Ang CW, Notermans DW, Hommes M, Simoons-Smit AM, Herremans T. Large differences between test strategies for the detection of anti-Borrelia antibodies are revealed by comparing eight ELISAs and five immunoblots. Eur J Clin Microbiol Infect Dis. 2011 Aug. 30(8):1027-32. [Medline]. [Full Text].
[Guideline] Wormser GP, Dattwyler RJ, Shapiro ED, 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. 2006 Nov 1. 43(9):1089-134. [Medline].
Li X, McHugh GA, Damle N, Sikand VK, Glickstein L, Steere AC. Burden and viability of Borrelia burgdorferi in skin and joints of patients with erythema migrans or lyme arthritis. Arthritis Rheum. 2011 Aug. 63(8):2238-47. [Medline].
Rupprecht TA, Pfister HW. What are the indications for lumbar puncture in patients with Lyme disease?. Curr Probl Dermatol. 2009. 37:200-6. [Medline].
Roos KL, Berger JR. Is the presence of antibodies in CSF sufficient to make a definitive diagnosis of Lyme disease?. Neurology. 2007 Sep 4. 69(10):949-50. [Medline].
Halperin JJ, Shapiro ED, Logigian E, 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. 2007 Jul 3. 69(1):91-102. [Medline].
Blanc F, Jaulhac B, Fleury M, et al. Relevance of the antibody index to diagnose Lyme neuroborreliosis among seropositive patients. Neurology. 2007 Sep 4. 69(10):953-8. [Medline].
Agosta F, Rocca MA, Benedetti B, Capra R, Cordioli C, Filippi M. MR imaging assessment of brain and cervical cord damage in patients with neuroborreliosis. AJNR Am J Neuroradiol. 2006 Apr. 27(4):892-4. [Medline].
Donta ST, Noto RB, Vento JA. SPECT brain imaging in chronic Lyme disease. Clin Nucl Med. 2012 Sep. 37(9):e219-22. [Medline].
Aguero-Rosenfeld ME. Lyme disease: laboratory issues. Infect Dis Clin North Am. 2008 Jun. 22(2):301-13, vii. [Medline].
[Guideline] Cameron DJ, Johnson LB, Maloney EL. Evidence assessments and guideline recommendations in Lyme disease: the clinical management of known tick bites, erythema migrans rashes and persistent disease. Expert Rev Anti Infect Ther. 2014 Sep. 12(9):1103-35. [Medline]. [Full Text].
Johnson L, Stricker RB. Attorney General forces Infectious Diseases Society of America to redo Lyme guidelines due to flawed development process. J Med Ethics. 2009 May. 35(5):283-8. [Medline].
Final Report of the Lyme Disease Review Panel of the Infectious Diseases Society of America (IDSA). April 22, 2010. Available at http://www.idsociety.org/Lyme_Final_Report/. Accessed: June 25, 2014.
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. 2003 May 6. 138(9):697-704. [Medline].
Kowalski TJ, Tata S, Berth W, Mathiason MA, Agger WA. Antibiotic treatment duration and long-term outcomes of patients with early lyme disease from a lyme disease-hyperendemic area. Clin Infect Dis. 2010 Feb 15. 50(4):512-20. [Medline].
Halperin JJ. Nervous system lyme disease: diagnosis and treatment. Rev Neurol Dis. 2009 Winter. 6(1):4-12. [Medline].
Maraspin V, Cimperman J, Lotric-Furlan S, Pleterski-Rigler D, Strle F. Treatment of erythema migrans in pregnancy. Clin Infect Dis. 1996 May. 22(5):788-93. [Medline].
Fish AE, Pride YB, Pinto DS. Lyme carditis. Infect Dis Clin North Am. 2008 Jun. 22(2):275-88, vi. [Medline].
Borg R, Dotevall L, Hagberg L, et al. Intravenous ceftriaxone compared with oral doxycycline for the treatment of Lyme neuroborreliosis. Scand J Infect Dis. 2005. 37(6-7):449-54. [Medline].
Ljostad U, Skogvoll E, Eikeland R, et al. Oral doxycycline versus intravenous ceftriaxone for European Lyme neuroborreliosis: a multicentre, non-inferiority, double-blind, randomised trial. Lancet Neurol. 2008 Aug. 7(8):690-5. [Medline].
Ogrinc K, Logar M, Lotric-Furlan S, Cerar D, Ruzic-Sabljic E, Strle F. Doxycycline versus ceftriaxone for the treatment of patients with chronic Lyme borreliosis. Wien Klin Wochenschr. 2006 Nov. 118(21-22):696-701. [Medline].
Aberer E, Breier F, Stanek G, Schmidt B. Success and failure in the treatment of acrodermatitis chronica atrophicans. Infection. 1996 Jan-Feb. 24(1):85-7. [Medline].
Centers for Disease Control and Prevention. Post-Treatment Lyme Disease Syndrome. CDC. Available at http://www.cdc.gov/lyme/postLDS/index.html. 2014 Feb 24; Accessed: June 27, 2014.
Klempner MS, Hu LT, Evans J, et al. Two controlled trials of antibiotic treatment in patients with persistent symptoms and a history of Lyme disease. N Engl J Med. 2001 Jul 12. 345(2):85-92. [Medline].
Baker PJ. Perspectives on "chronic Lyme disease". Am J Med. 2008 Jul. 121(7):562-4. [Medline].
Kemperman MM, Bakken JS, Kravitz GR. Dispelling the chronic Lyme disease myth. Minn Med. 2008 Jul. 91(7):37-41. [Medline].
Hassett AL, Radvanski DC, Buyske S, et al. Role of psychiatric comorbidity in chronic Lyme disease. Arthritis Rheum. 2008 Dec 15. 59(12):1742-9. [Medline].
Maraspin V, Strle F. How do I manage tick bites and Lyme borreliosis in pregnant women?. Curr Probl Dermatol. 2009. 37:183-90. [Medline].
Nadelman RB, Nowakowski J, Fish D, et al. Prophylaxis with single-dose doxycycline for the prevention of Lyme disease after an Ixodes scapularis tick bite. N Engl J Med. 2001 Jul 12. 345(2):79-84. [Medline].
Warshafsky S, Lee DH, Francois LK, Nowakowski J, Nadelman RB, Wormser GP. Efficacy of antibiotic prophylaxis for the prevention of Lyme disease: an updated systematic review and meta-analysis. J Antimicrob Chemother. 2010 Jun. 65(6):1137-44. [Medline].
Centers for Disease Control and Prevention. Vaccines and preventable diseases: Lyme disease vaccination. CDC. Available at http://www.cdc.gov/vaccines/vpd-vac/lyme/default.htm#vacc. Accessed: January 5, 2011.
Nadelman RB, Wormser GP. A clinical approach to Lyme disease. Mt Sinai J Med. 1990 May. 57(3):144-56. [Medline].
- Table 1. Clinical presentation and therapy for the stages of Lyme Disease
- Table 2. Adult and Pediatric treatment options, dosages, and routes of administration
- Table 3. Comparison of Infectious Diseases Society of America (IDSA) and International Lyme and Associated Diseases Society (ILADS) recommendations for Lyme disease treatment
|Early localized||Erythema migrans||Oral||14-21 days|
|Early disseminated||Multiple erythema migrans||Oral||14-21 days|
|Isolated cranial nerve palsy||Oral||14-21 days|
|Meningitis||Intravenous or oral||14-21 days|
|-Hospitalized||Intravenous followed by oral||14-21 days|
|Borrelial lymphocytoma||Oral||14-21 days|
|Recurrent arthritis after oral therapy||Oral or intravenous||28 days or 14-28 days|
|Acrodermatitis chronica atrophicans||Oral||14-28 days|
|Treatment||Adult Dose||Pediatric Dose|
(patients =8 y)
|100 mg twice a day||4 mg/kg (up to 100 mg)
twice a day
|Amoxicillin||500 mg three times a day||50 mg/kg (up to 500 mg)
three times a day
|Cefuroxime axetil||500 mg twice a day||30 mg/kg (up to 500 mg)
twice a day
|Intravenous therapy||Ceftriaxone||2 g once a day||50-75 mg/kg (up to 2 g)
once a day
|Cefotaxime||2 g every 8 h||150-200 mg/kg (up to 2 g) every 8 h|
|Penicillin G||18-24 million U/d divided
every 4 h
(up to 2 g) every 8 h
|Treatment of a tick bite without symptoms of Lyme disease||Doxycycline, 200 mg as a single dose||Doxycycline, 100 mg bid for 20 days|
|Erythema migrans||Doxycycline, amoxicillin, or cefuroxime for 14-21 days||Doxycycline, amoxicillin, or cefuroxime for 28-42 days or azithromycin for at least 21 days|
|“Persisting symptoms of Lyme disease”||No antibiotic therapy||Multiple agents (individually or in combination) are mentioned without specific doses or duration recommended|