Lyme Disease

Disease/Disorder

Definition

Lyme disease is a vector-borne infectious illness with the potential for multisystem inflammatory effects.  It is classified into three stages based upon clinical manifestation and time elapsed since infection. These stages are early localized infection, early disseminated infection, and late disseminated infection.

Etiology

It is a bacterial infection caused by the Borrelia species of spirochete with Borrelia burgdorferi being the most common etiologic organism in the United States, while B. afzelii and B. garinii are more common in Europe and Asia. The spirochetes are transmitted by the bite of an infected tick of the Ixodes genus. Lyme disease is not transmitted between people, other animals, or through food.

Epidemiology including risk factors and primary prevention

Over 63,000 cases of Lyme disease were reported to CDC by state health departments and the District of Columbia in 2022. This number reflects cases reported through routine national surveillance, which is only one way public health officials track diseases.⁴ It is the most common vector-borne illness in the United States. Recent estimates continue to suggest that approximately 476,000 people may be diagnosed and treated for Lyme disease each year in the United States, which shows that the cases reported to CDC are only a small fraction of total cases.⁴ Risk follows a geographic pattern with cases highest in the Northeast, mid-Atlantic, upper Midwest/North Central states, as well as northern California. Fourteen states in these areas represented 96% of all reported cases, and in 2022 the top 10 states accounted for over 83 percent of total reported cases. Certain occupations and activities, such as hiking and gardening, increase likelihood of exposure. The percent of total cases by age group has a bimodal distribution when looking at data from 2008 to 2022. The first peak is centered around ages 5 to 9 for both men and women, and the second peak is centered around ages 55 to 59 for both men and women. By race, white individuals represent the largest majority of cases, accounting for almost 55% of total cases from 2008 to 2022.⁴

Ixodes ticks have a three-stage life cycle (larvae, nymph, and adult), and they must feed on a blood meal during each stage. Most people contract Lyme disease from immature nymphs in late spring and early summer.

There is no human vaccine, so prevention of Lyme disease is done through reducing risk of transmission. Body checks for ticks, use of tick repellents, minimizing skin exposure, bathing within 2 hours after exposure to ticks, and proper removal of attached ticks using forceps are means of reducing transmission. Efficacy has not been established for these practices. If ticks are removed within 36 to 48 hours after attachment, then the risk of contracting Lyme disease diminishes. Furthermore, antibiotic prophylaxis is recommended after a high-risk bite, which is one that is from an Ixodes vector species, occurred in a highly endemic area, and the tick was attached for at least 36 hours. This suggests just how important it can be to remove the tick prior to the 36 hour mark if possible.¹³

Patho-anatomy/physiology

Spirochetes are inoculated into the skin by the bite of an infected tick. The saliva of the tick contains several factors that promote release of Th2 type cytokines that suppress cellular immunity and facilitate the borrelial infection. B. burgdorferi expresses proteins that allow for adherence to host integrins, proteoglycans, and glycoproteins which promote dissemination through extracellular matrix proteins. Spirochetes may also decrease antigenic expression and promote antigenic variation of surface proteins which allows for evasion of host immunologic response. It has been demonstrated that immunoglobulin sialic acid levels increase during acute Lyme disease and following antibiotic therapy and a 3-month convalescence, the sialic acid level returned to that found in healthy control subjects. One study found that after enzymatically removing the sialic acid present on Borrelia specific antibodies, the induction of cytotoxicity from acute Lyme disease patient antigen-specific IgG was significantly improved, signifying a much stronger immune response.⁸ In neural tissues, spirochetes may induce astrogliosis, disrupt gray matter connections, and secrete quinolinic acid which stimulates NMDA receptors.

Disease progression including natural history, disease phases or stages, disease trajectory (clinical features and presentation over time)

Acute or early localized disease: Usually occurs days to weeks after the tick bite and often presents with known outdoor exposure in endemic regions with some being able to recall presence of a tick. Most common initial symptoms include skin rash and/or erythema migrans. Other symptoms are often nonspecific.¹⁵

Subacute or early disseminated disease: Usually occurs weeks to several months after the tick bite and may be the first manifestation of Lyme disease. In this stage the disease may involve the heart, kidneys, liver, eyes, lymph nodes, skin, neurologic and musculoskeletal systems.⁹

Chronic or late disease: Usually occurs months to years after onset of infection and may not be preceded by a history of early localized or disseminated Lyme disease. In this stage there may be various musculoskeletal, neurologic and cutaneous symptoms noted.⁹ 

Symptoms at different stages by organ involvement⁹    

• Early localized disease (a few days to one month after tick bite)
  • Generalized: fatigue, malaise, lethargy, headache, neck stiffness, lymphadenopathy
  • Skin: erythema migrans
• Early disseminated disease (weeks to months after tick bite)
  • Generalized: lymphadenopathy
  • Heart: AV node block, cardiomyopathy, myopericarditis
  • Neurologic: lymphocytic meningitis, cranial neuropathy, peripheral neuropathy, myelitis, encephalitis
  • Musculoskeletal: migratory arthralgias
  • Kidneys: microhematuria, proteinuria
  • Liver: hepatitis, transaminitis
  • Eyes:  conjunctivitis, iritis, choroiditis, retinitis
• Late disease (months to years after tick bite)
  • Musculoskeletal: monoarticular or oligoarticular arthritis
  • Neurologic: peripheral neuropathy, encephalomyelitis
  • Skin: acrodermatitis chronica atrophicans

Specific secondary or associated conditions and complications

In the acute phase, co-infections should be considered, with approximately 10-15% of those with Lyme disease testing positive for ehrlichiosis or babesiosis. Later, meningitis, cranial and peripheral neuropathies, blindness from panophthalmitis, intermittent migratory arthritis, acrodermatitis chronica atrophicans, cutaneous lymphocytoma, and aseptic meningitis may complicate Lyme disease. Another complication is development of post-treatment Lyme disease syndrome, which is often used to describe nonspecific symptoms which can occur in 5 to 15% of patients who completed treatment for Lyme Disease but still present with symptoms for months or years after treatment has concluded. Symptoms improve gradually over six months to one year but may last longer, and may include fatigue, arthralgia, myalgia, cognitive dysfunction and radicular pain. This can lead providers to question whether adequate treatment for Lyme Disease was completed or if a new disease process is taking place.⁹

Essentials of Assessment

History

The most common early complaint is an expanding rash with fever, chills, myalgias, and malaise occurring afterward.  A determination of the patient’s living situation, occupation, and vacations is important. 25-30% of individuals recall a tick bite. Later, a migratory mono/pauciarticular arthritis, cranial nerve neuropathies, and meningeal signs may be described. As mentioned earlier, a tick bite is considered high risk for Lyme Disease if the bite is from an Ixodes vector species, occurred in a highly endemic area, and the tick was attached for at least 36 hours. Clinicians should attempt to discover if these criteria were met while taking history from patients, however many times this information is difficult for patients to be certain of.¹³

Physical examination

The first stage (which can present anywhere from 3 days to 30 days from infection, however usually between 1 to 2 weeks) presents with erythema migrans in 80% of the patients.   Only about 20% of the cases have the “bull’s eye” appearance.  Features on exam to look for include fever, lethargy, decreased neck range of motion, tenderness to palpation of muscles and joints, and lymphadenopathy.⁹

The second stage can present with cardiac abnormalities (e.g. atrioventricular block; which may progress to sudden death), facial nerve palsy, multiple erythema migrans lesions, decreased visual acuity, erythema of the eyes and or conjunctiva, abnormal sensation to light touch, and impairments in memory, concentration, and problem solving.⁹

In the later stages, clinicians should evaluate for erythema and tenderness in large joints especially including the knee, abnormal sensation to sensory stimuli, decreased muscle strength, ataxia, incontinence of bowel or bladder, and cognitive impairments.⁹

Clinical functional assessment: mobility, self-care cognition/behavior/affective state

As Lyme disease is a multi-system illness; patients should be evaluated for musculoskeletal impairments, neuro-cognitive deficits, and cardiovascular system decline. Any of these manifestations may impact the functional status due to pain, debility, or a lack of awareness of one’s condition.

Laboratory studies

Traditionally, the presence of antibodies against B. burgdorferi is detected using a two-tier process that includes screening with enzyme immunoassays (EIA), followed by confirmatory Western blot testing with additional immunoglobulin tests depending upon chronicity. IgM in the presence of IgG may indicate a recent infection, but IgM alone is not diagnostic. The presence of IgG antibodies does not confer immunity and these antibodies may remain positive long after the infection has been successfully treated, thus monitoring IgG should not be used as a means to evaluate adequate response to treatment.³ The Western blot can be difficult to perform and interpret and is prone to false positives. Recently in 2019, the Food and Drug Administration has cleared several serological assays with new indications thus allowing for the development of a modified two-tier test in which another EIA detecting a different B. burgdorferi antigen than the one detected in the first tier is used instead of a western blot as the second test. This modified two-tier process has been developed to improve relative ease of testing and interpretation of results in early Lyme disease detection. Erythrocyte sedimentation rates are typically elevated while anti-nuclear antibody and rheumatoid factor are not. Complement levels are normal to slightly elevated. Synovial fluid analysis suggests an inflammatory process with no crystals present. Lyme meningitis can result in moderate cerebral spinal fluid (CSF) pleocytosis and moderate protein elevation. CSF antibodies can also be tested but a negative test does not exclude CNS involvement. Polymerase chain reaction (PCR) tests, especially of CSF fluid, are not useful; they are frequently false positive because segments of DNA may remain present after successful disease treatment.¹⁰

Imaging

Magnetic resonance imaging of the brain may exhibit punctate lesions of the periventricular white matter which mimic those of demyelinating or inflammatory conditions. Cervical spinal cord involvement is less commonly seen in Lyme Disease as opposed to multiple sclerosis. However, MRI can show affected nerve roots in peripheral and cranial nerve involvement. Single-photon emission computed tomography (SPECT) scanning of the brain has demonstrated abnormalities of the temporal, frontal, and parietal lobes in those with clinically diagnosed Lyme disease. In one study, SPECT identified such abnormalities in 75% of these patients with MRI detecting these abnormalities in 14% of these patients. These abnormalities improved after appropriate antibiotic treatment.

Supplemental assessment tools

Lumbar puncture with cerebrospinal fluid (CSF) analysis reveals a lymphocytic pleocytosis, elevated protein concentrations, normal glucose, and negative cultures.

Biopsy of characteristic skin lesions could suggest borrelial lymphocytoma or acrodermatitis chronica atrophicans.

Serial direct facial nerve conduction studies (NCS) may be used to assess prognosis of facial nerve palsy. Electrodiagnostics may reveal a mononeuritis multiplex pattern, plexopathy, symmetric and asymmetric distal sensory predominant neuropathy, or polyradiculopathies. Signs of denervation on needle testing are possible with an irregular axonal neuropathy pattern is present in all cases of Lyme induced peripheral neuropathy.

Early prediction of outcomes

Prompt diagnosis and treatment of Lyme disease is important to avoid the associated complications. Patients with cardiac conduction abnormalities, arthritis, and neurologic manifestation typically respond well to antibiotic therapy. Often, these patients do not require long term cardiac pacing or orthopedic intervention after receiving adequate antibiotic treatment.

Environmental

Avoidance of outdoor activity in the known geographic distribution of the Ixodes tick is effective but is likely not practical. Avoiding areas with bushes, high grasses, and leaf litter may be helpful. Those with potential exposure to ticks should dress in long pants and shirts, apply tick repellents, take daily showers, and perform a thorough skin inspection for ticks.

Social role and social support system

Patients’ social support systems should emphasize continued follow up monitoring with primary care providers and specialists to evaluate for chronic sequelae of Lyme disease. Traditional therapies may not be efficacious in such patients and new treatment modalities may be pursued.

Professional issues

Chronic Lyme disease remains a nebulous term among medical literature and has become the center of ethics debates. Patients diagnosed with chronic Lyme disease require an empathetic practitioner who will thoroughly examine the history, physical examination, laboratory data, and imaging results to reach an evidence-based treatment model.

Post-treatment Lyme Disease Syndrome (PTLDS) is characterized by fatigue, myalgias, arthralgias, and cognitive complaints persisting for six months or more after appropriate antibiotic treatment. Risk for PTLDS include delayed diagnosis, increased symptom severity, and neurologic symptoms. However, prolonged treatment with antibiotics after adequate treatment of Lyme disease are not indicated and have not been associated with clinical improvement.

Rehabilitation Management and Treatments

Available or current treatment guidelines

The Infectious Diseases Society of America (IDSA) and International Lyme and Associated Diseases Society (ILADS) have both released official treatment guidelines. For an asymptomatic tick bite which the provider can classify as high risk with a fair degree of certainty, the IDSA recommends one 200 mg dose of doxycycline whereas the ILADS recommends doxycycline 100 mg BID for 20 days. For erythema migrans the IDSA recommends either a 10-day course of doxycycline or a 14-day course of amoxicillin or cefuroxime rather than longer treatment courses. ILADS recommends 28-42 days of therapy with the same antibiotics or azithromycin for at least 21 days. The IDSA does not recommend additional antibiotics after this, as long as there is no objective evidence of reinfection or treatment failure, whereas ILADS recommends discussing treatment desires with the patient if clinical improvement continues while on antibiotics.

At different disease stages

There are different preferred treatment options depending on time course of disease and which organ systems are involved. Treatment options with antibiotic selection and duration are listed below.⁹

• Early disease with erythema migrans
  • Doxycycline 100mg po bid for 10 days, alternative agent amoxicillin 500mg po tid for 14 days
• Neurologic disease
  • Mild to moderate disease including cranial nerve palsies, meningitis, radiculoneuropathy can be treated with doxycycline 100mg po bid for 14-21 days
  • Severe disease including encephalitis can be treated with ceftriaxone 2g IV daily for 14-28 days
• Carditis
  • Mild to moderate disease can be treated with doxycycline 100mg po bid for 14-21 days, alternative agent amoxicillin 500mg po tid for 14-21 days
  • Severe disease can be treated with ceftriaxone 2g IV daily for 14-21 days
• Arthritis
  • Initial arthritis can treat with doxycycline 100mg po bid for 28 days, alternative agent amoxicillin 500mg po tid for 28 days
  • Persistent arthritis can be treated with ceftriaxone 2g IV daily for 14-28 days, alternative agent doxycycline 100mg po bid for 28 days

Oral antibiotics may be continued past 6 weeks if symptoms are persistent. Post-antibiotic Lyme arthritis should warrant consideration of a consult to rheumatology or other Lyme disease specialist who is able to weigh risks and benefits of disease modifying drugs (such as hydroxychloroquine and methotrexate), intraarticular steroids and arthroscopic synovectomy with patients. Avoid treating joint symptoms with corticosteroids until after antibiotic treatment has been completed.⁹

The placement of a temporary pacemaker device may be necessary for advanced heart block Lyme carditis. Lifelong placement is not typically necessary.

Oral or topical corticosteroids may be indicated for cases of recurrent Lyme keratitis or uveitis that are not amenable to antibiotic treatment alone.

Chronic/stable: For chronic Lyme arthritis, experts recommend initially treating with oral antibiotic therapy, followed by IV antibiotic therapy if oral is ineffective. For persistent synovitis, a trial of intraarticular steroids would be the next step. For refractory cases, still with persistent synovitis after 6-12 months despite these treatments, arthroscopic synovectomy is usually indicated at that time. The pathogenesis of chronic Lyme arthritis is, at least in part, an autoimmune mediated attack on the synovium, with evidence of villous hypertrophy, vascular proliferation, and infiltration of mononuclear cells such as in other forms of chronic inflammatory arthritis. Therefore, arthroscopic synovectomy to remove the inflamed synovium is usually very effective and frequently leads to full resolution of joint inflammation. The benefits of this procedure need to be weighed against the risks, which include septic arthritis, rupture of the joint capsule, infection of the operative skin incision, hemarthrosis, severe postoperative pain, risk of future synovitis relapse, and thromboembolism being the most common adverse events.¹⁷

Physical and occupational therapy evaluation for assistive devices and orthoses prescription can increase the independence in patients with significant motor and sensory disturbances due to neurologic involvement or arthritis.

Enact environmental modifications, such as keeping grass and shrubbery trimmed and using tick repellant, to prevent further exposure to Ixodes ticks and re-inoculation with spirochetes.

Coordination of care

Lyme disease is a multi-system illness, and a multi-disciplinary approach will be beneficial. Primary care providers, cardiologists, neurologists, rheumatologists, infectious disease specialists, and physiatrists may work together for patients who experience chronic complications due to Lyme disease. Rehabilitation professionals may be needed for continued functional disturbances.

Patient & family education

Patients and family members should be counseled about the importance of environmental modifications and exposure prevention techniques. Strict medication compliance is also needed for adequate treatment. Providers should also express the need for follow up and monitoring of symptoms as chronic Lyme disease sequelae may be subtle and long lasting.

Measurement of treatment outcomes

Functional Independent Measures are often used for individuals participating in acute inpatient rehabilitation. Pain and function may be validated with the short-form McGill Pain Questionnaire, brief pain inventory short form, West Haven-Yale Multidimensional Pain Inventory, or even the Visual Pain Scale.

One large study evaluating the long term outcomes of Lyme disease utilized the 36-Item Short-Form Health Survey and the Center for Epidemiologic Studies Depression scale for the evaluation of patients between 1 to 11 years after the diagnosis of Lyme disease and then compared these results to healthy controls.

One study focused on using Global Rating of Change (GROC) survey questions to measure response to treatment. The GROC produces a 15 point Likert scale which ranges between −7 and 7, with 0 as the midpoint for unchanged. Patients then could be separated into categories including non-responders, who answered between −7 and 0, indicating there was no improvement in symptoms. Low responders, were those who answered between 1 and 3, indicating there was slight improvement. High responders, were those who answered between 4 and 7, indicating there was substantial improvement.¹⁹

Translation into Practice: practice “pearls”/performance improvement in practice (PIPs)/changes in clinical practice behaviors and skills

Clinical suspicion for Lyme disease should be high in those presenting with exposure in Lyme endemic regions and with typical Lyme symptoms. Rapid diagnosis and completing a full course of antibiotic treatment along with supportive care is likely to prevent long term sequelae.  Long term complications become much more common with delayed treatment and inadequately treated disease.⁹

Individuals who did not receive proper treatment duration, or have never seen a practitioner for Lyme disease previously, should have a thorough history and physical examination. The practitioner must avoid reinforcing pseudoscientific ideas related to chronic Lyme disease, while simultaneously providing compassionate and appropriate care.

Cutting Edge/Emerging And Unique Concepts And Practice

As described previously, progress has been made with serological testing of Lyme disease to allow for a more effective way of interpreting and diagnosing the disease. Looking forward, researchers have been studying biomarkers that can allow for point-of-care testing for Lyme disease. A research paper published in the Journal of Clinical Microbiology in 2019 demonstrates testing of a microfluidics assay that can rapidly detect B. burgdorferi antibodies in serum (as a point-of-care test) and compared it to the traditional two-tier testing. Results are promising as the test demonstrates adequate if not greater sensitivity and specificity.

One study discussed research on creating a new vaccine for preventing Lyme disease. It described an OspA-ferritin nanoparticle vaccine which was shown to elicit markedly high Ab titers in mice, and the antibody titer is maintained at high levels for at least 6 months. Further testing would need to be completed prior to human trials.¹⁰

Gaps In The Evidence-Based Knowledge

There is dispute among practitioners regarding serologic testing outside of the acute phase of the illness. Some clinicians believe late serologic tests lead to misdiagnosis, inappropriate diagnostic testing, and support of pseudoscientific claims about the nature of chronic Lyme disease. Arthropathies, neuropathies, pain and fatigue are chronic symptoms of Lyme disease that may have the potential to be addressed by rehabilitation. However, there is a significant gap in physiatric literature regarding the functional outcomes (especially long-term) in these patients. Further research is warranted to guide the potential rehabilitation management of patients with Lyme disease.

References

1. Arumugam, et. al. A Multiplexed Serologic Test for Diagnosis of Lyme Disease for Point-of-Care Use. J Clin Microbiol. 2019 Nov 22;57(12):e01142-19. doi: 10.1128/JCM.01142-19. PMID: 31597750; PMCID: PMC6879297.
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7. Halperin. Nervous system lyme disease: diagnosis and treatment. Rev Neurol Dis. 2009 Winter; 6(1):4-12.
8. Haslund-Gourley et al. Host glycosylation of immunoglobuins impairs the immune response to acute Lyme disease. eBioMedicine, Volume 100, 104979.
9. Hu. Clinical manifestations of Lyme disease in adults. In: UpToDate, Connor RF (Ed), Wolters Kluwer. February 6, 2024. (Accessed on 8/26/2024.)
10. Kamp, H.D., Swanson, K.A., Wei, R.R. et al. Design of a broadly reactive Lyme disease vaccine. npj Vaccines 5, 33 (2020). https://doi.org/10.1038/s41541-020-0183-8.
11. Lantos. Chronic Lyme Disease. Infect Dis Clin North Am. 2015 June ; 29(2): 325–340. doi:10.1016/j.idc.2015.02.006.
12. Mead, Petersen, Hinckley. Updated CDC Recommendation for Serologic Diagnosis of Lyme Disease. MMWR Morb Mortal Wkly Rep 2019;68:703. DOI: http://dx.doi.org/10.15585/mmwr.mm6832a4external icon.
13. Nguyen, Cifu, Pitrak. Prevention and Treatment of Lyme Disease. JAMA. 2022;327(8):772-773. doi:10.1001/jama.2021.25302.
14. Ogrinc, Lusa , Lotrič-Furlan, Bogovič, Stupica, Cerar, Ružić-Sabljić, & Strle. Course and Outcome of Early European Lyme Neuroborreliosis (Bannwarth Syndrome): Clinical and Laboratory Findings. Clin Infect Dis. 2016 Aug 1;63(3):346-53. doi: 10.1093/cid/ciw299. Epub 2016 May 8. PMID: 27161773.
15. Rebman, Yang, Powell, Geller, Aucott. Initial Presentation and Time to Treatment in Early Lyme Disease. Am J Trop Med Hyg. 2023 Feb 6; 108(4):734-737. doi: 10.4269/ajtmh.22-0437. PMID: 36746657; PMCID: PMC10077021.
16. Sanchez, Vannier, Wormser, & Hu. Diagnosis, Treatment, and Prevention of Lyme Disease, Human Granulocytic Anaplasmosis, and Babesiosis: A Review. JAMA. 2016;315(16):1767-1777. doi:10.1001/jama.2016.2884
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Original Version of the Topic

Travis Coats, MD, MPH, Andreea Nitu-Marquise, MD. Lyme Disease. 7/21/2017

Previous Revision(s) of the Topic

Ramza Malik, DO, Andreea Nitu-Marquise, MD. Lyme Disease. 12/9/2021

Author Disclosures

Brandon Mazal, MD
Nothing to Disclose

Andreea Nitu-Marquise, MD
Nothing to Disclose