Lyme Disease

Lyme disease is caused exclusively by infection with Borrelia burgdorferi, a spiral-shaped bacterium transmitted to humans when an infected Ixodes tick feeds on human skin for a sufficient duration. Unlike most other bacterial infections, there is no person-to-person transmission; the disease cannot be acquired through contact with other infected people, animals, or food. The route of transmission is entirely through the tick bite.

The blacklegged tick (Ixodes scapularis) in the Northeast and Midwest and the western blacklegged tick (Ixodes pacificus) on the West Coast are the only tick species capable of transmitting Borrelia burgdorferi to humans in the United States. The tick must be attached and actively feeding for a minimum of 36 to 48 hours for the spirochetes to migrate from the tick’s gut to its salivary glands and be injected into the human skin. This transmission delay is important: removing an attached tick within 24 to 36 hours eliminates nearly all risk of infection. The tick life cycle depends on animal hosts. The white-footed mouse is the primary reservoir for Borrelia burgdorferi—mice carry the bacteria without becoming ill and efficiently infect feeding ticks. Deer are important for sustaining tick populations but are not competent reservoirs for the spirochete itself; deer amplify the tick population without passing the bacteria. Nymph-stage ticks—roughly the size of a poppy seed—are responsible for the majority of human cases because their small size makes them very difficult to detect and remove before the 36-hour transmission threshold is reached.

Lyme disease risk is geographically concentrated and strongly tied to tick habitat exposure. Approximately 90% of U.S. cases occur in 15 high-incidence states in the Northeast, mid-Atlantic, and upper-Midwest regions. The disease is not distributed uniformly across these states—it is most concentrated in wooded and forest-edge communities where ticks, deer, and white-footed mice co-exist. Understanding who is at elevated risk helps target prevention and early recognition.

• High-incidence states: Connecticut, Delaware, Maine, Maryland, Massachusetts, Minnesota, New Hampshire, New Jersey, New York, Pennsylvania, Rhode Island, Vermont, Virginia, West Virginia, and Wisconsin each report 10 or more confirmed cases per 100,000 population annually. In 2022, Rhode Island (212 per 100,000), Vermont (204 per 100,000), and Maine (195 per 100,000) had the highest incidence rates in the country.
• Woodland and forest-edge habitats: Areas where wooded land meets lawn or suburban development are the highest-risk zones because deer, white-footed mice, and leaf litter all concentrate near these transitions.
• Geographic expansion: The tick’s range is moving northward each year due to climate change and land-use changes. New counties and states are reporting high human Lyme disease incidence annually, including areas of Canada that were previously unaffected.

•  Outdoor occupational exposure: Forestry workers, landscapers, farmers, park rangers, wildlife biologists, and hunters face elevated daily tick contact.
• Recreational exposure: This includes activities such as hiking, camping, trail running, gardening, and outdoor sports in endemic wooded or brushy areas.
• Not performing daily tick checks: After outdoor activity in endemic areas, a full-body tick check is essential. Ticks favor warm, hidden locations: behind the knees, in the groin, in the armpits, behind the ears, in the scalp, and around the waistband.
• Not using tick repellents: N,N-diethyl-meta-toluamide (DEET) applied to exposed skin and permethrin applied to clothing are the two most evidence-based protection measures. Failing to use them significantly increases risk.
• Allowing tick attachment time to exceed 36 to 48 hours: This is the minimum required for Borrelia transmission. Failing to find and remove an attached tick within this window is the most avoidable risk factor for developing Lyme disease.

• Age: Lyme disease has a bimodal age distribution. Children aged 5 to 9 years are one of the highest-risk groups (approximately 16.5 per 100,000 annually). Adults aged 45 to 75 years represent the second peak, with incidence doubling among adults 65 and older between 2017–2019 and 2022. The incidence for adults aged 75 to 79 reached 38.3 per 100,000 in 2022.
• Male sex: 57.3% of reported cases are male, likely reflecting greater outdoor occupational and recreational exposures.
• Seasonal timing: The seasonal peak is in late June and early July (calendar week 26), coinciding with peak nymph-stage tick activity from May through August.

There is no recommended population-based screening for asymptomatic individuals for Lyme disease. Testing is performed only in patients with clinical signs, symptoms, and an appropriate geographic and tick-exposure history. An important principle: the erythema migrans rash in a patient from an endemic area is sufficient to diagnose and begin treating early Lyme disease without waiting for laboratory confirmation—because blood antibody tests are frequently negative in the first two to four weeks of infection, when the immune system has not yet had time to produce detectable antibodies. Treating empirically on clinical grounds at this early, most curable stage is both appropriate and recommended.

Two accepted laboratory testing algorithms are available for patients with symptoms beyond the EM rash or when the diagnosis is uncertain. Both use a two-step approach designed to maximize accuracy.

The standard two-tier testing (STTT) algorithm has been in use for decades. The first step is an enzyme immunoassay (EIA) or immunofluorescence assay (IFA) blood test that detects combined IgM and IgG antibodies to Borrelia burgdorferi. If this test is positive or equivocal, a second confirmatory test—the Western blot immunoblot—is performed. The IgM Western blot is used only during the first four weeks of symptoms; the IgG Western blot is used from four weeks onward. The sensitivity of STTT in early Lyme disease is only 29–40%—meaning many early cases will test negative even when the disease is present—but rises to 87–99% in late disseminated disease when antibody levels are higher.

The modified two-tier testing (MTTT) algorithm was U.S. Food and Drug Administration (FDA)-cleared in 2019 as an acceptable alternative to STTT. It replaces the Western blot with a second blood-based EIA or chemiluminescence immunoassay, eliminating the immunoblot entirely. MTTT detects approximately 28% more early infections than STTT while maintaining high specificity (a low false-positive rate). Multiple FDA-cleared commercial MTTT options are available, and both STTT and MTTT are endorsed by the CDC. It is important to know that antibody levels remain elevated for months to years after successful treatment—a positive test after completing antibiotics does not mean the infection is still active, and a negative test in very early disease does not rule it out.

The hallmark and most recognizable symptom of Lyme disease is the erythema migrans (EM) rash—an expanding, circular or oval red skin lesion that gradually enlarges over days to weeks and may develop a classic bull’s-eye appearance with central clearing. It appears at the site of the tick bite in approximately 70–80% of infected individuals and is at least 5 centimeters (about 2 inches) in diameter. This rash is the clinical trigger for empiric antibiotic treatment even before confirmatory testing. Symptoms beyond the rash vary substantially by disease stage.

• Erythema migrans (EM) rash: expanding oval or circular red rash at the bite site, at least 5 centimeters across. May have central clearing (“bull’s-eye”) or be uniformly red. Usually not itchy or painful. May be warm to the touch. Can be harder to see on darker skin tones. Not present in approximately 20–30% of infected individuals.
• Fever and chills: low-grade to moderate
• Severe fatigue: often disproportionate to other symptoms
• Headache: diffuse, not localized to one area
• Muscle aches (myalgia) and joint aches (arthralgia): diffuse; no visible joint swelling at this stage
• Swollen lymph nodes: near the tick bite site

Neurological symptoms (Lyme neuroborreliosis)—affecting approximately 15% of untreated patients:

• Facial nerve palsy (Bell’s palsy): sudden weakness or complete paralysis of one or both sides of the face. Drooping of the eyelid or corner of the mouth. Difficulty closing the eye fully. This is the most common neurological manifestation of Lyme disease in the United States. Inability to close the eye fully can cause corneal drying and requires protective eye care.
• Meningitis: severe headache, stiff neck, sensitivity to light (photophobia), and fever. From inflammation of the membranes surrounding the brain and spinal cord.
• Radiculoneuritis: sharp, shooting, or burning pain radiating from the spine down an arm or leg; numbness or weakness in limbs. Can closely resemble a herniated disc or nerve compression.
• Behavioral and mood changes: This happens particularly in children: irritability, mood disturbance, and decline in school performance may be the only visible signs of nervous system involvement.
• Double vision (diplopia) and other cranial nerve palsies: This is less common; from involvement of the cranial nerves controlling eye movement.

Cardiac symptoms (Lyme carditis)—affecting approximately 5% of untreated patients:

• Palpitations: sensation of a racing, fluttering, or skipping heartbeat
• Chest pain or tightness, shortness of breath, lightheadedness: from disruption of the heart’s electrical conduction system (atrioventricular or AV block)
• Fainting (syncope): in the most severe cases of complete (third-degree) AV block, when the lower chambers of the heart are no longer receiving the signal from the upper chambers

Other Stage 2 manifestations:

• Multiple erythema migrans rashes: Additional EM lesions on body areas distant from the original bite site, indicating the bacteria have traveled through the bloodstream.
• Migratory arthralgias: Joint and muscle pain moving between different joints without visible swelling.

• Lyme arthritis: intermittent or persistent swelling, warmth, and pain in one or a few large joints, most commonly the knee. The swelling is often marked—sometimes dramatically so, while pain may be relatively mild. Approximately 60% of untreated patients develop Lyme arthritis.
• Late encephalopathy: subtle difficulty with memory, word-finding, and concentration; chronic fatigue; mood disturbance. These are mild compared to the severity of some other neurological conditions, but can meaningfully affect daily function.
• Peripheral neuropathy: This can present as persistent tingling, numbness, or mild weakness in the hands and feet.

• Persistent fatigue: debilitating, not relieved by rest
• Widespread musculoskeletal pain: diffuse aching in muscles and joints not explained by other findings
• Cognitive difficulties (“brain fog”): impaired memory, concentration, and processing speed

Symptoms must persist for six months or more after completing recommended antibiotics to qualify as PTLDS. Occurs in an estimated 10–20% of treated Lyme disease patients.

Lyme disease is diagnosed by combining the clinical history (including tick exposure and residence in an endemic area), physical examination findings, and laboratory testing—with the approach varying significantly by stage. In early localized disease, the EM rash in a patient with endemic-area exposure is sufficient for diagnosis and treatment initiation without waiting for laboratory results, because antibody tests are frequently negative in the first two to four weeks when the immune response has not yet matured. For disseminated or late disease, serologic testing is required. Diagnosis is genuinely challenging: up to 30% of infected individuals never develop the EM rash, early serology has limited sensitivity, and the symptoms of disseminated Lyme disease overlap with many other conditions, including multiple sclerosis, fibromyalgia, and inflammatory arthritis.

• Skin inspection: EM rash size (at least 5 cm), shape, uniformity or central clearing, warmth, and presence of satellite rashes indicating disseminated disease
• Neurological examination: facial symmetry testing for Bell’s palsy; cognitive assessment; deep tendon reflexes; sensory testing of extremities for numbness or tingling
• Joint examination: presence of joint effusion (swelling and excess fluid), range of motion, warmth and tenderness, particularly in the knees
• Cardiac examination: auscultation for irregular rhythm; vital signs for bradycardia (slow heart rate indicating AV block); electrocardiogram (EKG) for all patients with cardiac symptoms

The standard two-tier testing (STTT) algorithm begins with an enzyme immunoassay (EIA) or immunofluorescence assay (IFA) blood test that detects IgM and IgG antibodies to Borrelia burgdorferi. A positive or equivocal result proceeds to a confirmatory Western blot immunoblot. The IgM Western blot (used only in the first four weeks of symptoms) requires two of three specific protein bands. The IgG Western blot (used from four weeks onward) requires five of ten specified bands. Early-stage sensitivity is only 29–40%; late-stage sensitivity is 87–99%. The modified two-tier testing (MTTT) algorithm, FDA-cleared in 2019, replaces the Western blot with a second blood-based EIA or chemiluminescence immunoassay (CLIA), detecting approximately 28% more early infections while maintaining equivalent specificity and is now an acceptable alternative per CDC guidance.

When Lyme neuroborreliosis is suspected, a lumbar puncture (spinal tap) is performed. Classic CSF findings include an elevated lymphocyte count (lymphocytic pleocytosis) and elevated protein with normal glucose—the hallmarks of aseptic meningitis. An elevated ratio of Borrelia-specific antibodies in the CSF compared to the blood (the intrathecal antibody index) confirms local central nervous system antibody production and is the most reliable confirmation of Lyme neuroborreliosis. Lumbar puncture is not required for isolated facial nerve palsy without other meningeal signs.

An electrocardiogram (EKG/ECG) is performed on all patients with symptoms suggesting Lyme carditis. It detects and grades the severity of AV block (first-degree, second-degree, or complete/third-degree). Patients with high-degree AV block or symptomatic cardiac disease require continuous cardiac telemetry monitoring in a hospital setting. Echocardiography evaluates for myocarditis or pericardial fluid when cardiovascular compromise is present.

Joint aspiration (arthrocentesis) of an affected knee or other joint yields synovial fluid for white blood cell count (elevated but not as high as in septic bacterial arthritis), culture (negative in Lyme disease), and PCR testing for Borrelia DNA. Synovial PCR has approximately 70% sensitivity in untreated Lyme arthritis and high specificity. A negative PCR result after antibiotic treatment indicates antibiotic-refractory autoimmune arthritis rather than ongoing infection—this distinction drives the treatment decision toward disease-modifying anti-inflammatory drugs rather than more antibiotics.

Magnetic resonance imaging (MRI) of the brain with gadolinium contrast can reveal enhancement of cranial nerves affected by Lyme neuroborreliosis (in 57% of LNB patients in one study, most commonly the facial and oculomotor nerves), white matter signal changes in late neuroborreliosis, and nerve root enhancement in radiculoneuritis. MRI of the spine and joints helps evaluate structural damage and rule out alternative diagnoses.

Lyme disease is curable with appropriate antibiotic therapy, particularly when initiated early. Treatment success rates exceed 95% for early localized EM disease. Response rates remain high for disseminated disease, though complete resolution of symptoms—especially for arthritis and neurological manifestations—may take weeks to months after antibiotics are finished. PTLDS, when it occurs, does not respond to additional antibiotic therapy per four NIH-sponsored placebo-controlled trials. Treatment is determined by disease stage, severity, neurological or cardiac involvement, patient age, and pregnancy status per the IDSA/AAN/ACR 2020 guidelines. Your treating physician will select the right antibiotic, dose, and duration for your specific situation.

For Stage 1 (early localized, erythema migrans), first-line treatment for adults and children 8 years and older is oral doxycycline 100 mg twice daily for 10 to 14 days. Doxycycline is preferred because it also treats Anaplasma co-infection if present. Side effects include gastrointestinal upset (take with food) and photosensitivity (use sun protection). Doxycycline is contraindicated in pregnancy and in children under 8 years. For pregnant patients, women who are breastfeeding, and children under 8, oral amoxicillin 500 mg three times daily for 14 days is the first-line alternative. Cefuroxime axetil 500 mg twice daily for 14 days is a second-line oral alternative with equivalent efficacy demonstrated in clinical trials for patients who cannot tolerate doxycycline or amoxicillin.

For Stage 2 neurological disease, oral doxycycline is equally effective as intravenous antibiotics for facial nerve palsy, meningitis, and radiculoneuritis in patients who can take oral medications—a finding confirmed in multiple randomized controlled trials. Oral doxycycline 100 mg twice daily for 14 to 21 days is the recommended treatment for these presentations. Intravenous ceftriaxone 2 g once daily for 14 to 28 days is reserved for patients with severe neurological involvement, such as central nervous system (CNS) parenchymal inflammation or encephalitis. For Lyme carditis, mild disease (first-degree AV block, PR interval less than 300 milliseconds, no symptoms) is treated with oral doxycycline for 14 to 21 days. Moderate to severe Lyme carditis (higher-degree AV block, prolonged PR interval, or symptoms) is treated with intravenous ceftriaxone, transitioning to oral doxycycline once the AV block has improved, completing a 14 to 21-day total course. Complete (third-degree) heart block with hemodynamic instability requires hospital admission and continuous cardiac monitoring, and may require temporary transvenous cardiac pacing—a catheter-based temporary pacemaker—until antibiotic treatment restores normal conduction. A permanent pacemaker should not be placed during the acute phase of Lyme carditis before antibiotics have been given adequate time to work.

For Stage 3 (Lyme arthritis), the first course is oral doxycycline 100 mg twice daily for 28 days or oral amoxicillin 500 mg three times daily for 28 days. If the first course fails and synovial fluid PCR remains positive (indicating ongoing active infection), a repeat 28-day oral course or a switch to intravenous ceftriaxone 2 g daily for 28 days is given. For antibiotic-refractory Lyme arthritis—in which synovial PCR is negative after two antibiotic courses, indicating an autoimmune rather than infectious mechanism—antibiotics are stopped, and treatment shifts to anti-inflammatory approaches: hydroxychloroquine (Plaquenil®) 400 mg daily, Nonsteroidal anti-inflammatory drugs (NSAIDs) such as naproxen or ibuprofen, and in severe refractory cases, methotrexate as a disease-modifying immunomodulatory agent. For late Lyme neuroborreliosis, intravenous ceftriaxone for 14 to 28 days is first-line; oral doxycycline for 28 days is an alternative for mild peripheral neuropathy without central nervous system involvement.

NSAIDs (naproxen 500 mg twice daily or ibuprofen 400 to 600 mg three times daily) provide relief from joint pain, muscle aches, and headaches at all stages. For Bell’s palsy with incomplete eyelid closure, topical lubricating eye drops during the day and eye ointment at night are essential to prevent the cornea from drying and sustaining damage. An eye patch during sleep may be recommended. Most cases of Lyme-associated Bell’s palsy resolve completely within two to six months. Physical therapy aids rehabilitation of joint function, range of motion, and gait after Lyme arthritis or neurological involvement.

Surgical intervention is rarely needed for Lyme disease. Arthroscopic synovectomy—surgical removal of the inflamed joint lining in the knee—is reserved for severe antibiotic-refractory Lyme arthritis that fails to respond to oral disease-modifying therapy. It is uncommon. Temporary transvenous cardiac pacing is the procedure used during hospitalization for complete heart block—a catheter is guided through a vein into the heart to provide temporary electrical pacing until the antibiotics restore normal conduction. This is removed once conduction recovers and is not a permanent implant.

PTLDS does not respond to additional antibiotic therapy—four separate NIH-sponsored, double-blind, placebo-controlled trials found no significant benefit to continued or repeated antibiotics for this condition, and longer antibiotic courses carry real risks, including Clostridioides difficile (C. diff) colitis and serious intravenous (IV) line infections. Treatment for PTLDS is supportive and rehabilitative. Cognitive behavioral therapy (CBT) addresses fatigue, sleep disturbance, and cognitive coping strategies. Graded exercise therapy with carefully progressive physical activity addresses the deconditioning that accompanies chronic fatigue. Neuropathic pain medications and referral to a multidisciplinary pain clinic are options for refractory pain.