Original Editors - Kevin Beale from Bellarmine University's Pathophysiology of Complex Patient Problems project.
- 1 Definition/Description
- 2 Prevalence
- 3 Characteristics/Clinical Presentation
- 4 Associated Co-morbidities
- 5 Prevention
- 6 Medications
- 7 Diagnostic Tests/Lab Tests/Lab Values
- 8 Causes
- 9 Systemic Involvement
- 10 Medical Management (current best evidence)
- 11 Physical Therapy Management (current best evidence)
- 12 Differential Diagnosis
- 13 Case Reports
- 14 Resources
- 15 References
Definition/Description. Lyme disease was initially identified in young children in Lyme, Connecticut in 1976. They first recognized the “bull’s-eye” rash and an atypical type of arthritis in these children. In 1982 they recognized the relationship between the children with a history of tick bites and the infection when the Borrelia organism was found from in an individual affected with Lyme disease. 
Of those cases reported, 95% of confirmed Lyme disease cases were reported from 14 states: Connecticut, Delaware, Maine, Maryland, Massachusetts, Minnesota, New Hampshire, New Jersey, New York, Pennsylvania, Rhode Island, Vermont, Virginia, and Wisconsin. Lyme disease is primarily found in the Upper Midwest and Northeastern states of the United States, where deer and black-legged ticks are most common. 
Most cases develop during the summer months of May through August when individuals are more likely to visit wooded areas for work or recreation and tick nymphs are most active. Children 5 to 14 years of age have the highest rate of incidence with an average of 8.6 cases per 100,000 compared to 3.0 cases per 100,000 for people 20 to 24 and 7.8 cases per 100,000 for ages 55 to 59. .
Lyme disease is clinically similar to <a href="http://www.nlm.nih.gov/medlineplus/ency/article/001327.htm">syphilis</a>, a disorder which also can affect multiple organ systems and is also caused by a spirochete bacterium. It also may occur in stages, progressing from a localized presentation (Stage 1) to a widespread infection involving neurological, musculoskeletal, and cardiac findings (Stage 2) to a final stage in which infection persists chronically resulting in long-term neurological symptoms, arthritis, and cognitive deficits (Stage 3).<span class="fck_mw_ref" _fck_mw_customtag="true" _fck_mw_tagname="ref" name="Pathology" /> Because the presentation of the disease is so variable, it can be exceedingly difficult for healthcare professionals to diagnose. In addition, because it can so closely mimic other disorders such as <a href="MS Multiple Sclerosis">multiple sclerosis</a>, <a href="Fibromyalgia">fibromyalgia</a>, <a href="Chronic Fatigue Syndrome">chronic fatigue syndrome</a>, and <a href="Guillain-Barre Syndrome">Guillain-Barré syndrome</a>, it is frequently called "The Great Imitator."
The initial and most common clinical manifestation of Lyme disease is a skin lesion called erythema migrans. Other common clinical findings include early neurologic Lyme disease (10%-15%), myopericarditis (1%-2%), and Lyme arthritis (up to 30% per Centers for Disease Control and Prevention surveillance but much lower in other studies). 
- Fever, chills, headache, fatigue, muscle and joint aches, and swollen lymph nodes
- Erythema migrans (EM) rash: Occurs in approximately 70-80 % of infected persons
- EM starts at the site of a tick bite with an expected delay of 3 to 30 days (average is about 7 days)
- The rash will expand slowly over a period of days, and can expand up to 12 inches or more in width
- EM may feel warm to the touch but usually isn't itchy or painful
- Most commonly results in a target or “bull's-eye” appearance
- EM can arise on any area of the body
Later signs and symptoms (Symptoms appear days to months post tick bite.)
- Severe headaches and neck stiffness
- Additional EM rashes on other areas of the body
- Arthritis with severe joint pain and swelling, particularly the knees and other large joints.
- Facial palsy (loss of muscle tone or drooping unilaterally/bilaterally in the face)
- Intermittent pain in tendons, muscles, joints, and bones
- Heart palpitations or irregular heartbeats (Lyme carditis(https://www.cdc.gov/lyme/signs_symptoms/lymecarditis.html))
- Experiencing dizziness or shortness of breath
- Inflammation of the Central Nervous System
- Nerve pain
- Shooting pain, numbness and tingling that may extend to the hands or feet
- Problems with short-term memory loss
Other notable findings
- Fever or other general symptoms may occur even with the absence of a rash.
- A small bump or redness at the site of a tick bite that occurs immediately and can resemble a mosquito bite, is common. This irritation generally goes away quickly (1-2 days) and is not an indicator of Lyme disease.
- A rash with a similar appearance to EM occurs with Southern Tick-associated Rash Illness (STARI), but has no relation to Lyme disease.
- Ticks can spread other organisms (https://www.cdc.gov/ticks/diseases/index.html) that can cause a different form of rash (https://www.cdc.gov/ticks/symptoms.html).
- 10-20% of people with untreated Lyme disease will develop chronic arthritis.
- Lyme arthritis primarily affects only a few joints (knee is the most common), but can shift from one joint to another, primarily large joints such as elbow, shoulder and hip.
- Hand and feet involvement is uncommon, which is what helps differentiate Lyme arthritis from RA. 
Babesia microti is a parasite that enters the bloodstream along with Borrelia at the time of the tick bite and attacks and destroys the host’s red blood cells. It can be potentially life-threatening, especially in individuals who are elderly, immuno-compromised, do not have a spleen, or have other diseases involving the kidney or liver. If not treated, complications can include hemodynamic instability, anemia, <a href="http://www.nlm.nih.gov/medlineplus/ency/article/000586.htm">thrombocytopenia</a>, organ failure, or death.
Chronic Fatigue Syndrome
Individuals who present with symptoms of significant fatigue and malaise consistent with a diagnosis of <a href="http://www.nlm.nih.gov/medlineplus/ency/article/001244.htm">Chronic Fatigue Syndrome</a> often test positive for Borrelia antibodies, suggesting a prior infection even in individuals with no previous clinical diagnosis of Lyme disease. In a double-blind study performed in Germany in 1999, researchers found that individuals who tested positive for Borrelia antibodies and had a history of tick bites were significantly more likely to report symptoms of fatigue and malaise than individuals who had a history of tick bites but tested negative for Borrelia antibodies.
Similar studies have found temporal links between Borrelia infection and the development of clinically diagnosable <a href="Fibromyalgia">fibromyalgia</a>, the etiology of which is generally multifactorial and can be triggered by environmental factors, trauma, stress, infection, and possibly vaccination.
Cardiac problems arising as a result of Lyme disease may occur in 4 to 10% of affected individuals. Potential problems include <a href="http://www.nlm.nih.gov/medlineplus/ency/article/000149.htm">myocarditis</a>, heart conduction block, and arrhythmia. Symptoms of cardiac involvement include bradycardia, tachycardia, irregular heartbeat, dizziness, syncope, and shortness of air.
Neurological and mental health co-morbidities develop in approximately 5% of Lyme disease patients, especially if the disease is not successfully treated initially. Neurological sequelae include radiculopathy and paresthesias in the extremities. Associated mental health changes include mild cognitive impairments, mood disorders, depression, and anxiety. 
Although controversy exists over whether or not autism is truly a co-morbidity of Lyme disease, recent research shows a correlation between the two. Chronic infectious diseases including the Borrelia organism that causes Lyme have been associated with other co-infections that may weaken the fetal or infant immune system, putting affected individuals at increased risk for developing <a href="http://www.nlm.nih.gov/medlineplus/ency/article/001526.htm">autism</a> spectrum disorders.
- Avoid tick-infested areas, especially during summer months
- Walk on cleared or paved surfaces when available, rather than tall grass
- Wear long pants, sleeved shirts, and close-toed shoes
- Light colored clothing makes it easier to locate a tick
- Always check for ticks whenever coming from outdoors. Risk of Lyme disease is minimized when tick is removed within 36 hours.
- Showering immediately after being outdoors reduces risk of tick attachment
- Wash clothing that's been outdoors (dryer kills ticks)
- Remove the tick only by using tweezers to pull tick directly off skin (no twisting)
- After removal of tick, wash site with soap and water and then swab area with antiseptic 
Acute cases of Lyme disease are initially treated with a 14 to 21 day course of oral antibiotics such as doxycycline, amoxicillin, or cefuroxime which are all safe and highly effective for the early stages of Lyme disease. A single 200-mg dose of doxycycline reduces the risk of Lyme disease in individuals bitten by ticks; however, these are not to be taken routinely (There's a low risk of transmission from a tick bite even in areas where the disease is most prevalent) and is contraindicated for pregnant women and children younger than 8 years of age. If an affected individual presents with neurological impairments or a third degree heart block, IV antibiotics such as ceftriaxone are administered for 14 to 28 days. Lyme-related joint and muscle pain (Lyme arthritis) is also generally treated with oral antibiotics. If Lyme arthritis persists after a first course of antibiotics, an additional four week course of oral antibiotics is recommended. . There is no evidence that patients treated for Lyme disease with persistent, nonspecific symptoms (e.g., arthralgia and fatigue) have persistent infection; the risks of prolonged treatment is substantial, and far outweighs the benefits, if any.  Arthritic symptoms that persist beyond both courses of antibiotic treatment are generally treated with antirheumatic and nonsteroidal anti-inflammatory (NSAID) medications. Immunology is not developed with the exposure to Lyme disease, meaning that patients can be re-infected after previous infection. It is important to note that Lyme disease is rarely fatal, but can have an impact on the cardiovascular system that could potentially cause life-threatening cardiac arrhythmias. 
Diagnostic Tests/Lab Tests/Lab Values
Lyme disease is generally diagnosed via a two-step process recommended by the CDC. First, the affected individual’s blood is tested for antibodies to Borrelia with either with an enzyme immunoassay (EIA) or Immunofluorescence Assay (IFA) tests. If either test is positive, the diagnosis is confirmed with a Western blot test. It should be noted that antibodies may not appear for 1 to 2 weeks after the initial infection. Therefore, blood tests may give negative results in the acute stage of the infection. In individuals with suspected Lyme arthritis, PCR is used to test the synovial fluid of affected joints. If neurological symptoms are present, PCR is used to test the individual's cerebrospinal fluid. PCR can also be used to test blood, urine, and skin. No diagnostic approach is 100% specific, which abides with current recommendations to not test patients with a low clinical probability of Lyme disease, such as those lacking objective findings and only having nonspecific symptoms such as fatigue (I-B). Serologic tests are less likely to have a reliable predictive value in geographic areas with a low prevalence of Lyme disease. 
Lyme disease is caused by spirochete microorganisms in the family Borrelia (in the United States, the specific species involved is Borrelia burgdorferi) which are transmitted primarily by blacklegged or deer ticks. Deer ticks generally feed on the blood of deer, small birds, and mice, but are opportunistic and will also feed on the blood of other hosts such as cats, dogs, horses, and humans. Infected deer ticks transmit the bacteria to their host during the process of feeding.
Risks for being bitten by a tick capable of transmitting Borrelia bacteria include spending time outdoors in wooded or grassy areas especially in the Northeast and Midwest (see Prevalence section above). Walking in wooded or grassy areas in shorts and/or short sleeves increases the risk because of the higher surface area of exposed skin. The risk of acquiring an infection also increases if a tick is allowed to remain attached to the body for more than 48 hours, allowing it to take in a full “blood meal.” If a tick is identified and removed prior to that time, the risk of infection is low.
<a href="http://www.medscape.com/viewarticle/758995">Testing for Lyme Disease: Follow the Steps</a>; CDC Expert Commentary Series Medscape
Lyme disease, especially if left untreated, may involve multiple systems as detailed in the Characteristics/Clinical Presentation section above. If the infection is allowed to progress from a localized one at the site of the tick bite to a systemic one, it may affect the central nervous, cardiac, and musculoskeletal systems.
Medical Management (current best evidence)
Because length and severity of symptoms can vary widely based on the stage at which Lyme disease is diagnosed, prevention is the key to avoiding infection. When individuals who live in tick-infested areas take appropriate preventive measures, the risk of infection is greatly reduced. The CDC has published a comprehensive guide to Lyme disease prevention and control, available <a href="http://www.cdc.gov/ncidod/dvbid/LYME/ld_prevent.htm">here</a>.
The FDA approved a vaccine for Lyme disease called LYMErix in 1998. However, the company who manufactured the vaccine ceased production in 2002 because of its high cost and lackluster sales. At this time, there are no alternative vaccinations available for the disease. Though there is little evidence as to its efficacy, some physicians recommend a single dose of the oral antibiotic doxycycline to prevent infection when ticks are found to have been attached for 36 to 72 hours.
Current best evidence indicates the same treatments discussed in the Medications section above. Acute cases are initially treated with a 14 to 21 day course of oral antibiotics such as doxycycline or amoxicillin. If neurological impairments or a third degree heart block exists, IV antibiotics such as ceftriaxone are administered for 14 to 28 days. Lyme arthritis is also usually treated with oral antibiotics. If lyme-related muscle and joint pain persists after the first course of antibiotics, an additional four week course is recommended. Arthritic symptoms that persist beyond both courses of antibiotic treatment are treated with antirheumatic and nonsteroidal anti-inflammatories.
A systematic review of evidence from randomized and quasi-randomized controlled trials studying the treatment of neurological complications stemming from Lyme infection is currently underway by contributors to the Cochrane Collaboration. At this point, however, the only information that has been published from that investigation is the protocol for review. 
Lyme arthritis is a condition which is a late manifestation of Lyme disease. Approximately 60% of patients with untreated Lyme disease will develop Lyme arthritis. Initial treatment is antibiotics and some patients respond well but other can experience post-infectious antibiotic-refractory arthritis. According to a study that reviewed 30 patients with Lyme's Arthritis, these patients require an alternative plan for treatment.
This study that looked at 30 patients who had developed a new-onset systemic autoimmune joint disorder approximately 4 months after Lyme disease (usually manifested by erythema migrans [EM]).
“Regardless whether the occurrence of systemic autoimmune joint disease following infection is coincidental, induced nonspecifically by adjuvant effects of infection, or related to specific Lyme disease–associated autoimmune responses, an important point for clinicians is that post-infectious joint disorders that occur after recommended antibiotic treatment for Lyme disease should be treated with DMARDs (rather than with additional antibiotic),” .“Delaying appropriate DMARD treatment of autoimmune joint disorders, by pursuing further therapy with antibiotic agents, may lead to poorer clinical outcomes.”
Patients treated for Lyme disease with a recommended 2 to 4 week course of antibiotics occasionally have lingering symptoms of fatigue, pain, or joint and muscle aches at the time they finish treatment. On rare occasions, these symptoms can last for more than 6 months. Although sometimes called "chronic Lyme disease," this condition is properly known as "Post-treatment Lyme Disease Syndrome" (PTLDS).The exact cause of PTLDS is still unknown. Most medical experts believe that lingering symptoms are due to residual damage to tissues and the immune system that occurred during the infection. No matter the cause of PTLDS, studies from the CDC have failed to show that patients receiving prolonged courses of antibiotics show better results in the long run than patients treated with placebo. Additionally, long-term antibiotic treatment for Lyme disease has been linked to serious complications. On a positive note, patients with PTLDS almost always get better with time; unfortunately this can take a matter of months to feel completely well. 
Chronic Lyme disease is a condition of persistent symptoms associated with Lyme disease after the infection and the appropriate course of care and antibiotics. It is debated that patients with Chronic Lyme disease may have underlying syndromes or disease and question the presence of the infection in the individual. The symptoms associated with Chronic Lyme disease include disabling fatigue, severe headaches, and diffuse muscle or joint pain. These symptoms often mimic fibromyalgia and chronic fatigue syndrome. Studies suggest that Chronic Lyme disease is not related to the infection, evidence of the absence of the spirochete infection in the synovial fluid post treatment, while it was present during the infection. This hypothesized that Chronic Lyme disease is a result of a neurohormonal or immunological response of the body after the infection is treated.
Physical Therapy Management (current best evidence)
Early stage Lyme disease can only be treated with antibiotics and other adjunct medications such as analgesics. However, some doctors will refer patients with chronic Lyme disease symptoms that do not respond to medication to physical therapy. According to a physician's guide developed for the Lyme Disease Association, Inc., the role that physical therapy plays in the treatment of Lyme disease is primarily to relieve pain, prepare de-conditioned patients to begin a home-based exercise program, and to educate patients regarding proper exercise technique and frequency, duration, and resistance appropriate to achieve wellness benefits without exacerbating Lyme-related symptoms.
Direct physical therapy interventions include massage, range of motion, myofascial release, and modalities including ultrasound, moist heat, and paraffin. Generally, ice packs and electrical stimulation are contraindicated, though there is no research to support this. Exercise prescription is aimed at improving strength and gradually increasing the patient's conditioning level which may be severely impaired as a result of chronic Lyme infection. Whole-body workouts generally feature extensive stretching, light calisthenics, and light resistance training with low loads and high repetitions.
In addition, many patients with specific neurological complications such as <a href="Facial Palsy">facial nerve paralysis</a> may also be referred for physical therapy. Electrical stimulation of paralyzed or weak facial muscles following Lyme-related neurological insult is considered a fairly common practice, though the research does not fully support its use. There are few randomized controlled trials investigating its effectiveness and those that do exist indicate that it may be neither harmful nor beneficial with many therapists taking a conservative approach and waiting several months between symptom onset and initiation of an e-stim program to allow natural neurological recovery to occur.  Neuromuscular retraining has been demonstrated to be beneficial in facial palsy, as has EMG biofeedback.
Physical Therapists should be aware of the signs of Lyme Arthritis which typically manifests approximately four months after Erythema Migrans. It is most common in the knee but can be found in multiple joints.
Here is a link to a short video about Lyme Disease and physical therapy management: https://www.youtube.com/watch?v=QUIu1bvnC-8&sns=em
The diagnosis of Lyme disease requires the practitioner to consider the different presentations that may occur based on the acuity of the Borrelia infection. Thus, the list of differential diagnoses below is categorized by Lyme disease stage - localized infection (Stage I), disseminated infection (Stage II), and persistent infection (Stage III).
Stage I: Localized infection
- Clinical manifestation: Erythema migrans --> Other diagnoses: Streptococcal cellulitis, Erythema multiforme, Erythema marginatum, Tinea corporis (ringworm), Nummular eczema, Granuloma annulare
Stage II: Disseminated infection
- Clinical manifestation: Facial nerve palsy --> Other diagnoses: Idiopathic Bell palsy, CNS tumor, Myocarditis, Acute rheumatic fever
- Clinical Manifestation: Carditis --> Other diagnoses: Endocarditis
- Clinical Manifestation: Meningitis --> Other diagnoses: Viral meningitis, Parameningeal infections, Postinfectious meningoencephalitis, Leptospiral meningitis, Tuberculous meningitis, Listeria, Bacterial meningitis, Subacute (to chronic) meningitis
- Clinical Manifestation: Arthritis --> Other diagnoses: Acute rheumatic fever, Malignant effusion, Post-traumatic effusion, Hemophilia, Pyogenic arthritis
Stage III: Persistent infection
- Clinical manifestation: Arthritis --> Other diagnoses: Juvenile rheumatoid arthritis, Henoch-Schรถnlein purpura, Serum sickness, Collagen vascular disease, Psoriatic arthritis, Postinfectious arthritis, Chronic fatigue syndrome
- Early Lyme disease: solving the subtle clinical clues in an elderly patient [<a href="http://www.clinicalgeriatrics.com/article/7054">view article in Clinical Geriatrics</a>]
- The Changing face of lyme disease - rural to urban [<a href="http://www.turner-white.com/memberfile.php?PubCode=hp_jan05_lyme.pdf">view article in Hospital Physician</a>]
- Unusual Presentation of Lyme Disease: Horner Syndrome with Negative Serology [<a href="http://www.jabfm.org/cgi/content/full/22/2/219">view article in Journal of the American Board of Family Medicine</a>]
- Late Diagnosis of Early Disseminated Lyme Disease: Perplexing Symptoms in a Gardener [<a href="http://www.jabfm.org/cgi/content/abstract/21/3/234?maxtoshow=&hits=10&RESULTFORMAT=&fulltext=lyme&andorexactfulltext=and&searchid=1&FIRSTINDEX=0&sortspec=relevance&resourcetype=HWCIT">view article in Journal of the American Board of Family Medicine</a>]
- CDC Division of Vector-Borne Infectious Diseases - <a href="http://www.cdc.gov/ncidod/dvbid/Lyme/">http://www.cdc.gov/ncidod/dvbid/Lyme/</a>
- American Lyme Disease Foundation - <a href="http://www.aldf.com">http://www.aldf.com</a>
- Canadian Lyme Disease Foundation - <a href="http://www.canlyme.com">http://www.canlyme.com</a>
- Lyme Disease Map Project - <a href="http://sites.google.com/site/LYMEDISEASEMAPproject/home">http://sites.google.com/site/LYMEDISEASEMAPproject/home</a>
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- Morrison C, Seifter A, Aucott JN. Unusual presentation of lyme disease: horner syndrome with negative serology. J Am Board Fam Med 2009;22:219-222.
- Salzman BE, Stonehouse A, Studdiford J. Late diagnosis of early disseminated lyme disease: perplexing symptoms in a gardener. J Am Board Fam Med. 2008;21(3):234-236.