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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.


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

In 2019, approximately 35,000 cases of Lyme disease were reported to the CDC, about 4% more than the previous year. It is the most common vector-borne illness in the United States. However, a recently released estimate covering the years 2010-2018 suggests 476,000 Americans are diagnosed and treated for Lyme disease each year based on insurance records. 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. Certain occupations and activities, such as hiking and gardening, increase likelihood of exposure.

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.


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. 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: Outdoor exposure in endemic regions, skin rash and/or erythema migrans, recall the presence of a tick, fatigue, headache, fever, chills, malaise, lymphadenopathy, and eye redness/tearing.

Subacute or early disseminated disease: Expanded rash or multiple rashes, intermittent migratory polyarticular arthralgia evolving to a monoarticular arthritis typically involving the knee, ankle, or wrist; neurological disease including lymphocytic/monocytic meningitis, cranial nerve palsies (especially facial nerve), and radiculoneuritis; palpitations, carditis, ocular manifestations (conjunctivitis) and rarely encephalopathy manifesting as confusion blurred vision, dizziness, syncope, personality changes, sleep disturbances, or depression.

Chronic or late disease: Months to years after onset of infection; acrodermatitis chronica atrophicans (more common in Europe), arthritis (predominately the knee), subacute encephalopathy, mononeuropathy multiplex/axonal neuropathies, paresthesia, radiculopathy, paresis, ataxia, seizures, encephalomyelitis, bladder dysfunction, hearing loss, and cognitive impairment.

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.

Essentials of Assessment


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.

Physical examination

The first stage (within 30 days from infection) presents with erythema migrans in 80% of the patients.   Only about 20% of the cases have the “bull’s eye” appearance.  Patients can have fever, chills, and headaches.

The second stage can present with cardiac abnormalities (e.g. atrioventricular block; which may progress to sudden death), facial nerve palsy, diplopia, encephalitis, multiple erythema migrans lesions, monoarticular and pauciarticular inflammatory arthritis affecting primarily the knee, followed by the ankle and the wrist.

In the later stages, large joint arthritis of the knee becomes the hall mark musculoskeletal manifestation.  Others include axonal neuropathies, encephalomyelitis, cognitive disorders, acrodermatitis chronica atrophicans.

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. 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 with a different target 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.


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.


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 asymptomatic tick bite 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 doxycycline, amoxicillin, or cefuroxime for 14-21 days. 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, whereas ILADS recommends discussing treatment desires with the patient if clinical improvement continues while on antibiotics.

At different disease stages

Acute: Tick bite exposure without Lyme symptoms can be treated with doxycycline or left untreated. For erythema migrans, isolated cranial nerve palsy, meningitis, carditis, or lymphocytoma, oral amoxicillin, doxycycline, or cefuroxime is appropriate. If hospitalization is required for cardiac or neurologic manifestations then intravenous ceftriaxone, cefotaxime, or penicillin G are indicated. Treatment duration varies by society guidelines.

Subacute: Oral antibiotics may be continued past 6 weeks if symptoms are persistent. Arthritis should be treated with non-steroidal anti-inflammatory drugs, hydroxychloroquine, or methotrexate due to potential HLA associations with Lyme arthritis. Avoid treating joint symptoms with corticosteroids until after antibiotic treatment has been completed.

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: Intra-articular corticosteroids are not routinely recommended for Lyme arthritis; however, arthroscopic synovectomy may be needed for refractory cases.

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.

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 thorough antibiotic and supportive treatment is likely to prevent long term sequelae, which are associated with delayed treatment and inadequately treated disease.

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.

Gaps in the Evidence-Based Knowledge

There is dispute among practitioners regarding serologic testing outside of 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.



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Original Version of the Topic

Travis Coats, MD, MPH, Andreea Nitu-Marquise, MD. Lyme Disease. 7/21/2021

Author Disclosures

Ramza Malik, DO
Nothing to Disclose

Andreea Nitu-Marquise, MD
Nothing to Disclose