> Skip repeated content

An In-Depth Topic Review of Lyme Disease

For Physicians

  1. Definition
  2. Epidemiology
  3. Tick Life Cycle
  4. Clinical Presentation
  5. Localized
  6. Early Disseminated
  7. Disseminated Disease
  8. Chronic (Persistent)
  9. Laboratory Testing
  10. Differential Diagnosis
  11. General Treatment Considerations
  12. Specific Treatment Considerations
  13. Special Considerations
  14. Vaccine
  15. Bibliography
  16. Books and Booklets

I. Definition

Lyme disease is a tick borne illness caused by the spirochete Borrelia burgdorferi. The clinical spectrum ranges from asymptomatic, to a multisystem inflammatory illness involving skin, heart, nervous system and joints.

The illness is named after Old Lyme Connecticut; where in 1975 an astute resident reported to the health department that twelve children from a community of approximately 5000 people were diagnosed with "juvenile rheumatoid arthritis." This was a prevalence much higher than expected. At about the same time, a mother reported that she, her husband and two of their children as well as a number of their neighbors all had developed arthritis.

Photo of the Welcome to Old Lyme sign

A number of key observations were then made:

  1. The first attacks of arthritis usually occurred during the summer months.
  2. A number of patients had noted an unusual expanding rash just before the onset of arthritis.
  3. The rash was identified as Erythema Chronicum Migrans. This rash was first described in the early 1900's in Europe as being due to an agent transmitted by the sheep tick.
  4. One of the patients from Lyme Connecticut remembered a tick bite at the site of the rash!

Further studies revealed the presence of the tick I. Scapularis in the area where cases of Lyme disease were reported. In 1982 Dr. W Burgdorfer reported the isolation of a spirochete from ticks collected in Shelter Island.

Photo of lyme disease bacterium
Lyme Disease: The Bacterium
This Borrelial spirochete was subsequently named after Dr. Burgdorfer as Borrelia burgdorferi. When inoculated into animals, it causes both an illness compatible with Lyme disease, as well as a serological response. Furthermore, patients with Lyme disease have antibodies directed against this organism. And finally, it has been cultured from skin lesions, blood and CSF of Lyme disease patients. These facts confirm that Borrelia burgdorferi is the agent that causes Lyme disease.

II. Epidemiology

Lyme disease is the most common vector borne disease in the United States. Its incidence parallels the presence of its tick vectors: I. Scapularis, in the Northeast and North-Central states, and I. Pacificus in the Northwest coast. The illness is increasing in both incidence and in case reporting.

Chart with number of reported cases of lyme disease
Number of Cases Reported

Chart of number of cases per 100,000 population
Cases Per 100,000 population

Chart of seasonality of deer ticks
Seasonality of Dear Ticks

Cases have been reported from almost all of the United States. However 90% of cases emanate from just eight states: New York, New Jersey, Connecticut, Rhode Island, Massachusetts, Pennsylvania, Wisconsin and Minnesota. The peak incidence is between ages 11 - 14, as well as in young-middle aged adults.

A map of the US showing the geographical distribution of reported lyme disease cases in 1999

A map of the US showing the number of reported lyme disease cases per 100,000 population in 1999

Most cases in the Northeast and Central USA occur during the summer months; and parallels the prevalence of the tick vector. Cases of Lyme Disease have been reported from Europe and Asia. In these continents two other types of ticks serve as vectors: I. Ricinus and I. Persulatus. There are 3 varieties of Borrelia included within the Borrelia burgdorferi sensu lato group: B. burgdofer sensu stricto, B. afzelii and B. garinii. Of these, only the sesu stricto variety has been reported in the United States. It has been postulated that this may account for some of the observed differences in clinical presentation of Lyme disease in the United States vs. other continents.

III. Tick Life Cycle

A graphic showing the 2-year life cycle of the deer tick

The tick has a three-stage life cycle that spans two years. Larvae hatch from eggs in the springtime; and then feed on a number of small animals. They remain dormant through the fall and winter, then in the spring they molt into nymphs. Nymphs are voracious feeders (the white footed mouse is the preferential host).

An image showing different sizes of the deer tick as it ages

A photo of a white-footed mouse

They are so small that they are hard to detect on the skin, and therefore account for much of Lyme disease transmission. After this meal, nymphs molt into adult ticks. The adult ticks mate on deer.

The eggs are deposited on the forest floor to begin the cycle anew. Fortunately, trans-ovarian infection is not thought to occur- thus newly hatched larvae are uninfected.

IV. Clinical Presentation

Lyme disease has been generally viewed as having three stages: Early Localized, Disseminated (including Early Disseminated) and Chronic-Persistent-Late. As with most systems of classification, it is somewhat overlapping and arbitrary. And indeed, some patients will have one of the late manifestations as the first sign of Lyme disease.

V. Localized

A photo show a rash due to lyme disease

The hallmark of this stage is the pathognemonic rash of Erythema Migrans (EM). It first occurs at the site of the tick bite. (Although most patients may not be aware of having been bitten). EM may not occur, or not be noticed in up to one-third of patients who present with one of the later manifestations of the disease. EM occurs within days to a month of the bite. One-half of patients will have EM within 7 days The hallmark of EM is that it expands over a period of days and attains a median diameter of 15 cm The lesions typically occur in warm, moist areas such as the groin, axillae, popliteal fossa and belt line. The rash may be uniformly red, or exhibit central clearing or even a bull's eye pattern. Rarely they may demonstrate a bluish center, vessiculation or even central necrosis. Although EM is most often asymptomatic, patients may complain of dysesthesias, burning, itching or even pain.

VI. Early Disseminated

Photo of a patient with indications of lyme disease

Photo of a patient with indications of lyme disease

Within days to weeks after infection, many patients will develop generalized symptoms such as headaches, fever, chills, malaise, arthralgias and myalgias. In addition, secondary EM lesions develop due to hematogenous spread of the spirochete. They may occur anywhere on the body, but tend to be smaller. They lack the central punctum, which is due to the bite of the tick.

VII. Disseminated Disease

After the early signs and symptoms subside, most patients will develop findings of disseminated disease.

Cardiac. Within a few weeks to a few months 8 - 10% will develop cardiac disease. The most common manifestation of Lyme carditis is fluctuating heart block. Cases have been described where the rhythm changes from first degree heart block to complete heart block within minutes to hours- and back again. Heart block usually resolves over weeks, even without antibiotic treatment. It may require a temporary pacemaker, but rarely requires a permanent one. Myo-pericarditis, and chronic cardiomyopathy are rare, but have been reported.

Neurologic. A variety of neurologic syndromes have been described. Many patients with early disease complain of headache, lethargy, photophobia and irritability.

Lyme meningitis is associated with intense headache, stiff neck, photophobia and a lymphocytic pleocytosis.

Cranial Nerve Palsy. When Lyme disease affects the cranial nerves, it most frequently involves CN VII- causing Bell's palsy. None-the-less, even in endemic areas- most Bell's palsy is not caused by Lyme disease. However, when a patient presents with sequential Bell's palsy, it is most often due to Lyme disease.

Peripheral Neuropathy. A variety of peripheral neuropathies have been described. These include both sensory and motor. Carpal tunnel syndrome, Mononeuritis multiplex as well as painful radiculopathies have also been described. They may resolve spontaneously.

Arthritis. If left untreated, most people will develop arthritis. Early in the course attacks of pain are brief, intermittent and migratory. This pattern may persist for months- until in 60% of patients, overt synovitis occurs. Most often mono or oligo articular arthritis occurs. The knee is the most frequently involved joint, and effusions may be quite sizable. A predominantly PMN effusion occurs with WBC counts up to 25,000 cells/mm2. The attacks typically last a few days to a few weeks and over time tend to diminish in intensity, duration and frequency.

VIII. Chronic (Persistent)

In some patients a chronic and Persistent pattern may ensue- particularly in joints, nervous system and skin.

Chronic Arthritis. Chronic arthritis occurs in 29% of patients with untreated Lyme disease, particularly in the knee.

Photo of a patient with indications of lyme disease

Erosions and joint destruction are very unusual, but have been reported. Chronic arthritis appears to be associated with the HLA DR-4 (as well as DR-2). A symmetric small joint polyarthritis, which can be confused with RA, is very rare if it occurs at all.

Chronic Neurological Syndromes Months to years after the onset of Lyme Disease a sensory motor polyneuropathy may occur. Patients may complain of distal paresthesias or radicular pain. Nerve conduction velocities and electromyography and somatosensory evoked potentials may be used to make a definitive diagnosis. Encephalopathy may also occur, causing changes in mood and cognitive function; as well as in sleep patterns. Neuro-psychiatric testing can help with evaluation but are not diagnostic of Lyme disease.

Skin. Acrodermatitis chronicum atrophicans is a skin lesion that occurs primarily in Europe. It is characterized by swelling, atrophy and violaceous discoloration in acral areas. In addition, a benign lymphoma-like skin lesion has been described called Borrelial.

IX. Laboratory Testing

The most common and useful lab tests measure a patient's serologic response to Borrelia burgdorferi. IgM responses are first detected within two weeks of infection, peak at three to six weeks, then falls to normal by six months. IgG can usually be detected by four to six weeks; and peak many months after onset of disease. The IgG response lasts for many years.

The ELISA (Enzyme Linked Immuno-Sorbent Assay) is most often used to screen a patient for these antibodies, and for Lyme Disease. It is generally considered preferable to the IFA (Immunoflourescence Assay).

False positive screening test results may occur for a number of reasons. Most often false positives are due to: a) Cross reactivity with epitopes on other bacteria (such as those spirochetes which occur in the oral cavity) or b) A generalized activation of immunity- such as may be seen with some rheumatic diseases such as SLE.

The Western Blot is useful to rule out most false positive results. This assay relies on antibodies directed against polypeptides specific for Borrelia burgdorferi. The criteria currently used are those developed at a CDC conference in 1994.

The IgM Western Blot is positive if two or three of the following bands are found: 24 kDa (OspC), 39 kDa (BmpA) and 41 kDa (fla = flagellar). The IgG Western Blot is positive if five of the following ten bands are found: 18 kDa, 21 kDa (OspC), 28 kDa, 30 kDa, 39 kDa (BmpA), 41 kDa (fla), 45 kDa, 58 kDa, 66kDa, and 93 kDa.

Photo of the Western Blot
The Western Blot

False Negative serologies have also been reported. Of particular concern is the observation that a false negative serology may occur after a patient is treated with antibiotics early in the course of Lyme Disease, but with non-curative doses. This may ablate the antibody response, but not eliminate the disease.

Cerebro Spinal Fluid (CSF) Testing may be performed to aid in the diagnosis of Central Nervous System (CNS) Lyme disease. Ongoing CNS infection may be inferred if the ratio of specific Lyme antibodies : total immunoglobulin is higher in the CSF than in the serum.

Culture. Lyme disease may also be diagnosed on the basis of culture. Borrelia burgdorferi has been cultured from skin, CSF, blood and joint fluid. However the yields are very low, and special media is required. Polymerase Chain Reaction (PCR) has also been used to identify genetic material from Borrelia burgdorferi. However the technique requires scrupulous technique and controls to avoid false positive results. In addition, it raises theoretical questions and concerns. Finding genetic material does not mean that the organism is still viable and causing ongoing infection and invasion. But it also raises the specter that there may be ongoing antigen stimulation of the host, which may in itself cause "reactive" inflammatory disease- particularly in genetically pre-disposed individuals.

Who should be tested. One of the most important issues in making the diagnosis of Lyme disease is deciding who should be tested. As with any lab test, the usefulness depends on how likely the patient is to have the disease. If even before the blood is drawn, the likelihood of having the disease is very low, then the value of the test is limited. In addition, if the serology is obtained for symptoms not characteristic of lyme disease- then a positive test is probably unrelated to a patient's symptoms.

X. Differential Diagnosis

The differential diagnosis of Lyme Disease is quite extensive, and varies with the organ system involved.
Skin. Erythema Migrans should be distinguished from a number of types of dermatitis, including:

  • Cellulitis: sudden onset, fever, leukocytosis, lymphangitis, and toxicity
  • Tinea: thin raised borders, scaly, stable size over weeks - months
  • Granuloma annulare- spreads over weeks to months, present for years
  • Erythema annulare centrifugum: scaly, pruritic, gyrate border
  • Erythema multiforme: palms soles and mucous membranes involved
  • Fixed drug Reaction: history of drug use, face & genital involvement, burning sensation.

Neurologic. There are a myriad of diseases that are in the differential of neurologic Lyme disease. The most important clue to the correct diagnosis is that Lyme disease frequently involves multiple levels of the neuro-axis. In the proper epidemiological setting, a Bell's palsy (representing the cranial nerve level) with a thoracic radiculopathy and a predominately sensory peripheral neuropathy is highly suggestive of Lyme disease.

Lyme meningitis is similar in presentation to viral meningitis, but should occur after EM. It is generally more protracted, and the course is characterized by relapses and remissions.
Peripheral neuropathy must be distinguished from other causes of predominately sensory neuropathy.
Demyelinating encephalopathy must be distinguished from multiple sclerosis. Positive CSF serologies for Lyme disease are useful.
Arthritis The typical Lyme disease patient with mono-arthritis (usually of the knee) needs to be distinguished from;
Reactive arthritis (i.e. Reiters)-arthritis, urethritis, sacroilleitis
Septic arthritis (particularly some of the less virulent organisms) where the culture should be positive.
Crystal disease (chronic gout or pseudogout) more acute, +polarized microscopy
Rheumatoid Arthritis monarticular presentation (unusual). +rheumatoid factor. Brief and recurrent attacks of arthritis that become more frequent and last longer is typical of the diagnosis of Lyme disease.
Fibromyalgia-Chronic Fatigue. Patients with fibromyalgia, fatigue, aches and pains, depression, and chronic fatigue have been diagnosed as suffering from Lyme disease. Sometimes these patients have little clinical or serologic evidence of Lyme disease. Yet they have been given the diagnosis, and treated with prolonged and recurrent courses of oral and intravenous antibiotics. Since the treatment for these entities are so different, great care should be used when diagnosing patients with these syndromes.

XI. General Treatment Considerations

It should be emphasized that Lyme Disease is a bacterial infection, and as such is quite responsive to treatment with antibiotics. This is particularly true if treatment is initiated early in the course of the disease. According to one author, the most common cause of lack of response to antibiotic therapy is the lack of Lyme disease (i.e. incorrect diagnosis of the illness) !! Treatment has been based on both clinical experience as well as on clinical trials. "Culture and sensitivity" in vitro has not proved helpful in predicting clinical response to antibiotics.
When antibiotics are given early in the course of Lyme disease, EM resolves more quickly, and late disease is generally prevented. Even with evidence for systemic dissemination such as fever arthralgias and secondary IM- as long as there are no neurological symptoms, three weeks of oral treatment is thought to be sufficient.

XII. Specific Treatment Considerations

Carditis. May resolve spontaneously- Heart block responds to both antibiotic treatment as well as anti-inflammatories. This suggests that inflammation is a contributing factor to the conduction abnormalities. A temporary pacer may be needed but it is very rare to require permanent pacing.
Neurological Disease should be evaluated and treated aggressively, to avoid under treatment and development of chronic neurological syndromes years later.
Bells palsy has typically been treated with oral antibiotics based on anecdotal and historical experience. However it can be argued that CSF examination should be performed in all patients with Bells palsy, and IV antibiotics be given if there is involvement of the CSF.
Meningitis is usually treated by a 10-14 day course of Ceftriaxone. Resolution of the CSF pleocytosis may lag behind clinical resolution.
Radiculo-Neuropathy probably does not respond to antibiotic treatment as well as other manifestations. Resolution may occur over months, and may be incomplete.
Arthritis. Has been treated with both oral and IV regimens. Resolution may occur slowly, months after completion of antibiotic therapy. Failure to resolve may be due to an aberrant host immune response, and is usually associated with the HLA haplotype DR 4. These patients are PCR negative, and may respond to intra-articular steroids and arthroscopy.

XIII. Special Considerations

Herxheimer reactions (characterized by an increase in fever and arthritis) have been described after treatment has begun.
Some authors advocate probenecid when amoxicillin is used, however there appears to be an increased incidence of rash with this combination.

Doxycycline should not be used in pregnant women and in children due to dental staining.

Tetracyclines can predispose to photosensitivity and severe sunburn. Caution is advised in the summer months.

Penicillin allergic children can be treated with erythromycin. However this may be less effective than other treatments.

Delayed resolution. Even with successful treatment, some patients have delayed resolution of headache, musculoskeletal pain, and fatigue. This is particularly true if initial symptoms were severe, or there was a delay in treatment.

Pregnancy. The vast majority of Lyme disease in pregnancy does not affect the fetus. However stillbirths and neonatal deaths have been reported. It is generally thought that asymptomatic seropositivity or a previous history of Lyme disease is not associated with adverse fetal events. However, on balance, most authors opt to treat Lyme disease occurring during pregnancy aggressively.

Graphic on the treatment of lyme disease

Tick Bites. Avoidance is still the best policy. Try to limit exposure to tick habitats (woods, forest and brush) in endemic areas, especially during the spring and summer.
Wear light colored clothing, so ticks may be seen. Tuck pants legs into socks. Wear long sleeves. Use insect repellent containing DEET on exposed skin and clothing. Inspect skin after exposure to tick infested areas.
If an imbedded tick is discovered, use a pointed "jeweler's" forceps to gently pull at the site of attachment of head parts to the skin. Avoid pressure on the body of the tick since this may inoculate infected blood back into the host.

The decision whether to treat after a tick bite is a complicated matter. Certainly if the tick is not one known to be associated with the transmission of Lyme disease, then treatment is not warranted. In addition, it is generally accepted that transmission of Borrelia burgdorferi from the tick to human rarely occurs before 48 hours after attachment. It is thought that in most cases, the risk of an adverse event to antibiotics and the economic burden of treatment outweigh the benefit of treating all those who have had tick bites. However, some clinicians will treat patients under certain circumstances:

  1. Extreme patient (or physician) anxiety
  2. Those unlikely to follow up or report symptoms of Lyme disease
  3. Where the tick is engorged. Others will simply observe those who have had bites to see if EM or other symptoms/signs of Lyme disease develop, or determine if seroconversion occurs.

XIV. Vaccine

In 1998, the FDA approved LYMErix, a Lyme disease vaccine utilizing a recombinant OspA antigen. The approval was based on large clinical studies that demonstrated its safety and effectiveness. Subsequently, some clinicians raised concerns that the vaccine itself might be causing a "reactive" arthritis in some genetically pre-disposed people. The manufacturer recently withdrew the product due to poor sales, leaving many people living in endemic areas without this additional modality of protection.

XV. Bibliography

Rahn DW, Malawista SE. Lyme disease: recommendations for diagnosis and treatment. Ann Intern Med. 1991;114(6): 472-81. An excellent review, supplemented by years of clinical experience with the disease.

Sigal LH. Summary of the first 100 patients seen at a Lyme disease referral center. Am J Med. 1990; 88(6):577-81. Only 37 of the 100 patients actually had Lyme disease. Most had other explanations for their problems. A "wake-up call".

Steere AC. Lyme disease. N Engl J Med 1989 Aug 31; 321(9):586-96. An early, but informative review.

Steere AC, Malawista SE, Syndman DR, et al. Lyme arthritis: an epidemic of oligoarticular arthritis in children and adults in three Connecticut communities. Arthritis Rheum 1977 Jan-Feb;20:7-17. A bit of history.

Tugwell P, Dennis DT, Weinstein A, et al. Clinical guideline 2: laboratory evaluation in the diagnosis of Lyme disease. Ann Intern Med 1997 Dec 15; 127:1109-23. A discussion and model of who to test.

XVI. Books and Booklets

Am J Med 1995 Apr 24;98(4A): Supplement to the American Journal of Medicine. A wonderful series of articles covering all aspects of Lyme disease.

Klippel JH, Dieppe PA (eds). Rheumatology. 2nd edition. London: Mosby, 1998. A standard text with many helpful graphs and pictures. Very good bibliography.

Rahn DW and Evans J (eds.) Lyme disease. Philadelphia, PA: American College of Physicians, 1998. Highly relevant easily read paperbound text covering most all clinical scenarios.


Headshot of Steven K. Magid, MD
Steven K. Magid, MD
Attending Physician, Hospital for Special Surgery
Professor of Clinical Medicine, Weill Cornell Medical College

Related Professional Content