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Medscape Conference Coverage, based on selected sessions at the:
14th International Scientific Conference on Lyme Disease & Other Tick-Borne Disorders CME

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Release Date: June 6, 2001; Valid for credit through June 6, 2002

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Target Audience

This activity is intended for infectious disease specialists, primary care physicians, family practitioners, internists, pediatricians, and other healthcare providers who see cases of Lyme disease.


The goal of this activity is to provide the clinician with the latest state-of-the-art tools for the recognition, clinical diagnosis, treatment, and prevention of Lyme disease and other tick-borne diseases, to enhance the care of individuals with Lyme disease, and to support quality clinical practice of healthcare professionals involved in their care.

Learning Objectives

On completion of this continuing medical education offering, participants will be able to:

  1. Differentiate between Lyme disease and other tick-borne diseases.

  2. Determine the best diagnostic tests for each stage of Lyme disease.

  3. Evaluate the most effective strategies for the treatment and prevention of Lyme disease.

  4. Recognize and contrast the diverse presentations of Lyme disease and other emerging infectious diseases.

Credits Available

All other healthcare professionals completing continuing education credit for this activity will be issued a certificate of participation.

Participants should claim only the number of hours actually spent in completing the educational activity.

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This activity is supported by an educational grant from Journal of Spirochetal and Tick-borne Diseases.


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Contents of This CME Activity

  1. Tick-Borne and Other Emerging Infectious Diseases
    Robert S. Mocharnuk, MD
    Brian A. Fallon, MD, MPH, MEd

  2. Lyme Disease: Testing the Waters
    Robert S. Mocharnuk, MD
    Julie Rawlings, MPH

  3. Clinical Aspects of Lyme Disease: Dermatologic, Cardiac, GI, and Gestational
    Harry Goldhagen, MS
    Julie Rawlings, MPH

  4. Neurologic Lyme Disease: Defining and Treating an Elusive Target
    Brian A. Fallon, MD, MPH, MEd
    Harry Goldhagen, MS

  5. Lyme Disease Controversies
    Harry Goldhagen, MS
    Julie Rawlings, MPH

  6. An Ounce of Prevention
    Robert S. Mocharnuk, MD
    Julie Rawlings, MPH

  7. Fighting Back: How B burgdorferi Persists
    Harry Goldhagen, MS
    Julie Rawlings, MPH

Tick-Borne and Other Emerging Infectious Diseases

Robert S. Mocharnuk, MD   Brian A. Fallon, MD, MPH, MEd   

To most people, Lyme disease is a risk of life near wooded regions. But not long ago, there was little suspicion that a tick-borne disease could be causing rashes, arthritis, and neurologic conditions. And before the isolation and characterization of the causative spirochete, there was widespread doubt that such a disease complex was real.

Why discuss emerging organisms at a forum on Lyme disease? With such a history, the annual Lyme disease conference has become a platform to discuss other suspected and recognized emerging diseases. Over the course of this 2-day conference, investigators presented recent data on West Nile virus, the various forms of ehrlichiosis, a new strain of Borrelia burgdorferi in Missouri, human co-infection with Bartonella, and an unusual dinoflagellate that is responsible for major fish die-offs and human disease as well.

Viruses and Idiopathic Neurologic Diseases

The West Nile virus, previously confined to Africa, Europe, and the Asian subcontinent, made its way to Northeast Queens in metropolitan New York City during the late summer of 1999. How it got there is a matter of speculation, with hypotheses running the gamut from importation (illegal or otherwise) of tropical birds, to aberrant migration of an infected bird, to human introduction via immigration of an infected individual. In a keynote presentation, Dr. W. Ian Lipkin,[1] from the Emerging Diseases Laboratory at the University of California in Irvine, provided a glimpse into the latest viral pathogen known to enter the Western Hemisphere.

Detection of the virus was made possible by current DNA technology, which permits the simultaneous display of thousands of nucleic acid sequences through polymerase chain reaction (PCR) amplification techniques.[2] These differential displays allow for recognition of conserved expression patterns, which can be isolated and subjected to further analysis, amplification, and segregation. From these data, a simple, single-stranded RNA flavivirus, distinct from the pathogen causing St. Louis encephalitis but similar to endemic West Nile virus, was identified. At the same time, over 400 cases of West Nile virus were diagnosed in Israel, with 29 fatalities. Both soft and hard-bodied ticks are known vectors for West Nile virus, and many of the bird species that tested positive for West Nile virus are natural hosts for these ticks in the United States. If current trends are predictive, it is likely that West Nile virus will become endemic to North America in the next several years.

Our experience with West Nile virus and its rapid spread throughout the eastern United States suggests that other viruses, as yet undetected and undefined, may also be involved in the pathogenesis of other idiopathic diseases. Regarding encephalitis alone, 50% to 70% of cases in the United States remain idiopathic. As the technology for cloning nucleic acids of pathogens from clinical specimens continues to advance, it is believed that more of these idiopathic entities will be identified.

Dr. Lipkin provided the example of Borna virus, which has been associated with hyperactivity, exaggerated startle responses, and dysfunction in cellular immunity in rat models in the acute setting, and with abnormal stereotypic motion behavior, dyskinesias, dystonia, and CNS lesions affecting dopamine regulation in chronic infection. Behavioral expression in adult rats is markedly different from that observed in infant rats exposed to Borna virus, and unlike chronic adult overexpression of dopamine, an upregulation of 5-hydroxytryptophan is found in the brains of infant rats, particularly in the hippocampus. Intriguing associations that have been ascribed to Borna virus include multiple sclerosis, amyotrophic lateral sclerosis, major depression disorder, bipolar disorder (where this organism has already been identified in select cases), schizophrenia, chronic fatigue syndrome, and panic disorder.

Infectious origins are suspected in other conditions, including pediatric autoimmune neuropsychiatric disorder associated with streptococcal infection (PANDAS) and Sydenham's chorea. It is hoped that the new technologies currently being used in clinical research will eventually allow investigators to sequence microbial, nutritional, and environmental toxin patterns in order to determine what, if any, effects these and other undefined factors have on individuals at age-specific points in time.

A Brief History

According to Dr. John Anderson,[3] Director of the Connecticut Agricultural Experiment Station in New Haven, the first reported human case of West Nile virus can be traced to a Ugandan woman in 1937. The first major human epidemic occurred in Israel from 1950 to 1954; the first major European outbreak was found in Romania, followed by the most recent New York and Russian outbreaks in 1999. The virus is transmitted from Culex mosquitoes to wild birds.

In 1999, West Nile virus was first identified in North America as the cause of severe encephalitis in 62 patients, resulting in 7 fatalities.[4,5] Presenting symptoms included fever, muscle weakness, headaches, photophobia, and myalgias. Eventually, 2.6% of the population of Queens showed serologic evidence of West Nile virus exposure. At the same time, scores of exotic bird deaths were recorded at the Bronx Zoo, and thousands of bird deaths occurred in the surrounding area. An additional 21 cases were reported in the United States in 2000: 14 from New York, 6 from New Jersey, and 1 from Connecticut, with 2 deaths. While mosquitoes in 4 states tested positive for the presence of the virus in 1999, that number had risen to 12 states plus the District of Columbia in 2000. Bird studies have demonstrated that at least 15 bird species are currently affected, and the virus has been found in several mammals, including raccoons, bats, cats, rats, and horses.

Dr. Anderson concurs that the West Nile virus in North America is here to stay. Dr. Anderson also believes that there are viral triggers to a host of diseases, such as multiple sclerosis and autism, waiting to be defined.

Ehrlichiosis in the Northeast United States

A number of patients appear to have atypical presentations of Lyme disease, although they are seronegative by current testing standards. Is it possible that other tick-borne diseases may be responsible for atypical presentations? A number of talks examined this issue.

Ehrlichia cause disease in both humans and domesticated animals, including dogs, horses, cattle, and deer, according to Dr. Louis Magnarelli,[6] the Vice-Director of the Connecticut Agricultural Experiment Station. Symptoms of human ehrlichiosis include fever, headaches, myalgias, and lethargy. Outbreaks generally occur in the summer, and there is usually no rash. Marked thrombocytopenia and leukopenia are characteristic, and decreases in hemoglobin have also been reported. Most importantly, like its Lyme counterpart, ehrlichiosis is a curable disease when treated with the appropriate antibiotics. Ehrlichia chaffeensis and Ehrlichia phagocytophilia are considered to be human pathogens, although the latter affects horses and cattle as well. The Ixodes scapularis tick of Lyme disease fame serves as the chief vector, although E chaffeensis has been detected in Amblyomma americanum, the lone star tick.

Antibodies to a 44 kD antigen are most commonly seen in human granulocytic ehrlichiosis (HGE), and a recombinant ELISA antigen has been created for diagnostic testing.[7] Both granulocytic and monocytic forms of ehrlichiosis exist, and these entities can be differentiated on Western Blot assay by the presence of the 44 kD band seen in HGE vs 29 kD and 28 kD bands observed in human monocytic ehrlichiosis (HME).

E phagocytophilia, the most prevalent Ehrlichia in Connecticut, is responsible for most HGE, of which there were 420 confirmed cases between 1995 and 2000 and an additional 839 suspected cases. With recent increases in the deer population, an accompanying rise in the tick population has followed, and E chaffeensis has been detected in 7.6% of ehrlichiosis cases in Connecticut and 11.5% of cases in Rhode Island.[8] Because Lyme disease, ehrlichiosis, and babesiosis are all tick-borne diseases, Dr. Magnarelli recommended that any individual suspected of having any one of these diseases be tested for the full northeastern triad. He also attempted to dispel the myth that ehrlichiosis is a mild disease, particularly in those patients who may be infected with concurrent Lyme disease.

Tick-Borne Diseases in the Show-Me State?

Shifting geographic locales, Dr. Edward Masters[9] described the state of tick infestation in Cape Girardeau, Missouri, as well as throughout the Midwest and parts beyond. While a tick vector triad certainly exists in the Northeast, Dr. Masters suggested that another triad probably exists in the South, made up of Lyme borreliosis, ehrlichiosis, and babesiosis, but with different tick vectors involved. The lone star tick appears to be the vector responsible for the prevalence of HME in Missouri. Patients often present with leukopenia, thrombocytopenia, and elevated liver enzymes. Unlike HGE, patients with HME often present with a petechial rash of the feet and/or thighs, but the course of disease is often much milder than HGE. And unlike the northeastern version of HGE, there is a southern version that has been linked to Ehrlichia ewingii.

Babesiosis appears to have its own midwestern flavor. While Babesia divergens is responsible for the babesiosis seen in Europe, Babesia microti accounts for most cases on Nantucket Island and in the East as well as the upper Midwest. One case of babesiosis in Missouri was reported in which patient serum was strongly reactive by IFA for B divergens with only minimal reactivity to B microti. This "unique" bacteria was named Babesia MO1, although Dr. Masters suspects that B divergens and MO1 are really the same.

Lyme disease in the Midwest also differs from the northeastern version, and has been dubbed Masters' disease (among other names) by local wags. Patients are usually bitten by lone star ticks and often recall the particularly distinctive markings of that tick when describing it to their physicians.[10,11] The view under the microscope usually shows a lymphocytic infiltrate, compared to the plasmacytic infiltrate more characteristic of traditional Lyme disease. The incidence of EM lesions may be greater, and there may be more central clearing in EM lesions. Seropositivity, as defined by CDC guidelines, tends to be lower. Nevertheless, Dr. Masters indicated that "absence of proof IS NOT proof of absence," and so he treats his patients accordingly.

Bartonella: More Than Cat-Scratch Disease?

In her practice at Mountainside Hospital in New Jersey, Dr. Lesley Fein[12] has seen many cases of co-infection with tick-borne illnesses and Bartonella. This raised the question of whether the same tick vector, Ixodes scapularis, is responsible for dual transmission. Traditionally, Bartonella henselae, a gram-negative bacteria, is transferred from animal to human via cat scratch, hence its association with cat-scratch fever.

Patients infected with Bartonella first develop a papule, which eventually becomes vesicular and crusting. Regional lymphadenopathy is almost always present, and biopsy usually demonstrates a granuloma, from which the bacteria may be isolated. The incidence of neurologic involvement in a handful of patients -- including neuroretinitis, encephalopathy, radiculopathy, peripheral neuropathy, facial palsy, ataxia, myelopathy (with transverse myelitis), and positive brain biopsy for B henselae in one immunocompromised host -- led her to wonder whether co-infection with B burgdorferi and Bartonella were responsible.

To demonstrate the frequency of both B henselae and B burgdorferi in animals and ticks, Dr. Fein reviewed the medical literature. Studies in domestic cattle, cats, rodents, and deer have shown a bacteremia rate for B henselae ranging from 50% to 95%.[13] Cats are positive for B henselae in 89% of cases, and even fleas test positive 34% of the time. In select cultures of mice, 75% have been positive for B burgdorferi, while 10% have been positive for B henselae. Ticks in The Netherlands have been shown to be positive for B henselae by PCR analysis in 70% of cases, while ticks in California (Ixodes pacificus) have just recently been shown by PCR analysis to carry B henselae in 19% of those tested.

One third of all New Jersey ticks tested have been positive for B henselae. When the backyards of these tick-bitten patients who presented with severe neurologic disease were tested, B henselae was found in the ticks. Most of these patients did not respond to conventional antibiotic treatment, and the case was made in the follow-up question period that patients resistant to treatment for Lyme disease may potentially be infected with Bartonella instead, or co-infected with B burgdorferi and B henselae. An intriguing question...but one that cannot be answered from the data currently available.

Dead Fish, Toxic Cultures, and Politics

Pfiesteria piscicida, a primitive dinoflagellate, has been responsible for the deaths of millions of fish in eastern seaboard estuaries, according to Dr. JoAnn Burkholder,[14,15] Director of the Center for Applied Aquatic Biology in North Carolina. She has also shown that this microorganism can affect human health, in both acute and chronic ways. These health problems include visual changes; sleep disorders; erratic behavior; nausea; vomiting; respiratory disorders; central, peripheral, and autonomic nervous system dysfunction; cognitive impairment; and immunocompromise.

Dr. Burkholder started this work in the early 1990s in the North Carolina Albemarle-Pamlico estuary, the second largest estuary in the United States (after Chesapeake Bay), and the most important fishing hatchery in the United States. Beginning with several unexplained mass fish deaths in the 1980s, Pfiesteria was finally identified as the etiologic agent in 1991. The role that nutrient pollutants (farm and human sewage) played in the pathogenesis of these outbreaks was defined in 1992. Pfiesteria's capacity to emit toxins when stimulated by secretions from living fish was also elucidated.

The effects of Pfiesteria on human health were first reported in 1995. Ten individuals working in close proximity to Pfiesteria cultures in laboratory settings contracted symptoms after direct contact with culture water or after inhalation of aerosolized water from tank aeration systems. As described before, symptoms ranged from acute narcosis, eye irritation, respiratory distress, stomach cramps, and vomiting, to chronic skin ulcerations, cognitive impairment, and Alzheimer's-like short-term memory loss. Once contact with Pfiesteria was discontinued, these symptoms reversed over the course of several months, although peripheral nerve dysfunction and immunosuppression tended to linger for years. Anecdotal reports from individuals known to frequent these natural estuaries support these laboratory findings.[16,17]

The process of identifying the specific nature of Pfiesteria's toxic secretions has been slow. Dr. Burkholder states that the delays are largely due to political forces that have sought to deny the existence of a Pfiesteria epidemic. With pressure from the North Carolina tourist and seafood industries, several regional health agents worked to keep this information from public notice. According to Dr. Burkholder, the Centers for Disease Control and Prevention (CDC) launched its own investigative efforts that initially played into the hands of those who opposed public disclosure and directed funding to areas where no Pfiesteria outbreaks had ever been recorded. Eventually, the CDC's review panel received information that supported the findings of Burkholder and associates. Shortly thereafter, in October 2000, the review panel concluded that a health hazard existed. Unfortunately, the CDC specified that further funding would be restricted to the Pamlico estuary, where no Pfiesteria outbreak has occurred in several years. Nevertheless, the CDC's endorsement led to the allocation of $220 million in funding from the US Department of Agriculture (USDA) for elimination of nutrient pollution by North Carolina farmers.

As Dr. Burkholder sees it, economic forces first denied, then sought to bury data that could have a negative impact on the financial well-being of special interests, similar to the early experience with Lyme disease. Only when the scientific community uses its data to support individuals adversely affected by specific disease processes and strengthens its position with the help of public advocacy forums like the Sheridan Group can health policy change come to pass.


  1. Lipkin WI. Pathogen discovery: West Nile and beyond. Program and abstracts of the 14th International Scientific Conference on Lyme Disease and Other Tick-Borne Disorders; April 21-23, 2001; Hartford, Connecticut.
  2. Jia XY, Briese T, Jordan I, et al. Genetic analysis of West Nile New York 1999 encephalitis virus. Lancet. 1999;354:1971-1972. Available at: &db=PubMed&list_uids= 10622305&dopt=Abstract
  3. Anderson J. West Nile virus: a global hitchhiker. Program and abstracts of the 14th International Scientific Conference on Lyme Disease and Other Tick-Borne Disorders; April 21-23, 2001; Hartford, Connecticut.
  4. Anderson JF, Andreadis TG, Vossbrinck CR, et al. Isolation of West Nile virus from mosquitoes, crows, and a Cooper's hawk in Connecticut. Science. 1999;286:2331-2333. Available at: &db=PubMed&list_uids= 10600741&dopt=Abstract.
  5. Garmendia AE, Van Kruiningen HJ, French RA, et al. Recovery and identification of West Nile virus from a hawk in winter. J Clin Microbiol. 2000;38:3110-3111. Available at: &db=PubMed&list_uids= 10921991&dopt=Abstract
  6. Magnarelli L. Ehrlichiosis in the northeast. Program and abstracts of the 14th International Scientific Conference on Lyme Disease and Other Tick-Borne Disorders; April 21-23, 2001; Hartford, Connecticut.
  7. Magnarelli LA, Ijdo JW, Padula SJ, et al. Serologic diagnosis of Lyme borreliosis by using enzyme-linked immunosorbent assays with recombinant antigens. J Clin Microbiol. 2000;38:1735-1739. Available at: &db=PubMed&list_uids= 10790090&dopt=Abstract.
  8. Ijdo JW, Wu C, Magnarelli LA, et al. Detection of Ehrlichia chaffeensis DNA in Amblyomma americanum ticks in Connecticut and Rhode Island. J Clin Microbiol. 2000;38:4655-4656. Available at: &db=PubMed&list_uids= 11101616&dopt=Abstract.
  9. Masters E. Babesiosis, ehrlichiosis, Lyme(-like) disease variations. Program and abstracts of the 14th International Scientific Conference on Lyme Disease and Other Tick-Borne Disorders; April 21-23, 2001; Hartford, Connecticut.
  10. Masters EJ, Girardeau C. Erythema migrans in the South. Arch Intern Med. 1998;158:2162-2165.
  11. Masters E, Granter S, Duray P, et al. Physician-diagnosed erythema migrans and erythema migrans-like rashes following Lone Star tick bites. Arch Dermatol. 1998;134:955-960. Available at: &db=PubMed&list_uids= 9722725&dopt=Abstract.
  12. Fein L. Bartonella in humans. Program and abstracts of the 14th International Scientific Conference on Lyme Disease and Other Tick-Borne Disorders; April 21-23, 2001; Hartford, Connecticut.
  13. Hinrichsen VL, Whitworth UG, Breitschwerdt EB, et al. Assessing the association between the geographic distribution of deer ticks and seropositivity rates to various tick-transmitted disease organisms in dogs. J Am Vet Med Assoc. 2001;218:1092-1097. Available at: &db=PubMed&list_uids= 11318358&dopt=Abstract.
  14. Burkholder JM. The politics of discovering an emerging disease: The Pfiesteria experience. Program and abstracts of the 14th International Scientific Conference on Lyme Disease and Other Tick-Borne Disorders; April 21-23, 2001; Hartford, Connecticut.
  15. Burkholder JM. The lurking perils of Pfiesteria. Sci Am. 1999;281:42-49. Available at: 0899quicksummary.html.
  16. Glasgow HB Jr, Burkholder JM, Schmechel DE, et al. Insidious effects of a toxic dinoflagellate on fish survival and human health. J Toxicol Environ Health. 1995;46:101-122.
  17. Bowers HA, Tengs T, Glasgow HB Jr, et al. Development of real-time PCR assays for rapid detection of Pfiesteria piscicida and related dinoflagellates. Appl Environ Microbiol. 2000;66:4641-4648. Available at: &db=PubMed&list_uids= 11055905&dopt=Abstract.

Lyme Disease: Testing the Waters

Robert S. Mocharnuk, MD   Julie Rawlings, MPH   

As anyone who studies Lyme disease knows all too well, the difficulty is often not how to treat the disease, but how to arrive at the diagnosis. Several speakers examined the current state of diagnostic testing, highlighting what is currently available, what may soon be available, and in 1 case, what might have been available.

Two-Tiered Testing

Dr. Maria Aguero-Rosenfeld,[1] from the Westchester Medical Center at New York Medical College, reviewed the current standards of Lyme disease testing for most reference laboratories. Such testing employs a 2-step process, involving either an enzyme-linked immunosorbent assay (ELISA) or immunofluorescence assay (IFA), with confirmation by Western immunoblot (WB) analysis. While the detection of early-phase Lyme disease can be a clinical process based on recognition of erythema migrans (EM), presentations without rashes, atypical presentations, as well as advanced disease with multiple symptoms suggesting a host of different disease processes, necessitate corroboration by laboratory analysis.

Ideally, the identification of the Borrelia burgdorferi organism by culture or nucleic acid sequence recognition by polymerase chain reaction (PCR) would clinch the diagnosis, but these techniques are too insensitive. Consequently, the detection of antibodies against B burgdorferi became the standard basis for screening. The original tests utilized strains of B burgdorferi that were mostly devoid of immunodominant antigen expression, due to processing methods. Nonetheless, an IgM antibody to a 23 kDal antigen known as outer surface protein C (OspC), was found to be highly expressed in early disease, along with a 41 kDal protein. This early IgM antibody response gives way to IgG antibody expression, again for predictable antibodies.

A 2-tiered approach to Lyme disease testing was established by a panel convened by the Centers for Disease Control and Prevention (CDC) in conjunction with the Association of State and Territorial Public Health Laboratory Directors (ASTPHLD/CDC) meeting held in Dearborn, Michigan, in 1994.[2] These criteria defined the levels at which antibody binding constituted a positive ELISA assay (first tier). Criteria for WB (second tier) interpretation were also established at this same meeting, based on work done by Dressler[3] and Engstrom,[4] which required the presence of 2 out of 3 bands detected by IgM antibodies or 5 out of 10 bands detected by IgG antibodies.

This 2-tiered approach can be problematic.[5] There is a great degree of variability in ELISA sensitivity, based on which testing materials are used. In addition, the use of OspA vaccine renders ELISA interpretation useless, and the problem becomes greater as subsequent vaccine boosters are administered. While WB improves both sensitivity and specificity of results, the current blot interpretation criteria rely on B burgdorferi strains other than the B31 commonly used in reference labs. As indicated by Dr. Aguero-Rosenfeld, WB allows for discrimination between infection and administration of OspA vaccine, with an increase in the 31 kDal antibody[6,7]; however, additional boosters can add additional bands, making the WB indecipherable by the third vaccination. The cost of WB assays is generally high, and they are quite labor intensive. Blot reading is also a subjective process, dependent on the interpretive skills of individual technicians. In conclusion, WB assays can be highly sensitive and specific in diagnosing Lyme disease, but can be misused and abused, particularly in the wrong hands.

Smiles and Frowns

Dr. Paul Fawcett,[8] from the Alfred I. duPont Hospital for Children in Wilmington, Delaware, expanded on the use of WB analysis as the second step for confirming a positive or equivocal ELISA or IFA, in a presentation examining "potentials, problems, and performances." Potentially, WB analysis enhances specificity by increasing the number of identifiable antibodies to B burgdorferi components by electrophoretic separation. Unfortunately, differences in migration on the same gel can form "frown" or "smile" patterns, in which the same proteins appear to have variable molecular weights. This makes WB analysis by the Dearborn criteria a subjectively interpretive process, especially when using the commercially available MarBlot assay, according to Dr. Fawcett. Moreover, among pediatric populations, there appears to be a high level of false-positive antibody cross-reactions caused by Epstein-Barr virus infection, juvenile rheumatoid arthritis, and in healthy children undergoing orthopaedic procedures.

For these reasons, duPont has relied on its own interpretation of WB results. Any test with only 1 band is deemed nonreactive. Two to three bands that do not include those at 41 kDal, 60 kDal, or 69 kDal are unlikely to be positive. And finally, an antibody to the 41 kDal protein combined with another positive band in the 60- to 70-kDal molecular weight range, with 2 other expressed bands, is approximately 100% positive for Lyme disease. Of course, sensitivity and specificity are increased when WB analysis is reserved for individuals with high probability for having positive Lyme disease serology.

WB analysis is particularly useful in the diagnosis of Lyme re-infection. Whereas antibody expression by ELISA often remains elevated after resolution of disease, the number and/or relative intensity of bands on WB decreases in the convalescent phase. Re-infection is accompanied by an increase in the number and intensity of WB bands, and also correlates with reappearance of EM.

Getting Functional

Functional antibodies can be a valuable tool in the diagnosis of Lyme disease. Echoing Dr. Fawcett's earlier statement that WB assays are far more specific when used in patients with a high pretest probability of having Lyme disease, Dr. Steve Callister[9,10] from the Gunderson Lutheran Medical Center, La Crosse, Wisconsin, introduced a complication into the discussion -- the subject of atypical Lyme disease presentations.

One approach to improving the accuracy of diagnosis, particularly in atypical presentations, is to use a functional antibody assay, known as a borreliacidal antibody test (BAT). Borreliacidal antibodies attach to the pathologic spirochete, which in turn induces complement to form a membrane attack complex that, independent of phagocytosis, can kill the organism. A number of outer surface proteins can initiate this process, including OspA.

The findings of BAT are highly specific for Lyme disease when compared with results from a WB assay, especially among patients with early Lyme disease or patients with a single erythema migrans lesion. The improved specificity for BAT over WB derives from the use of 2 B burgdorferi sensu stricto strains in the borreliacidal assay: isolate 297 expresses OspA and OspB, and isolate 50772 expresses OspC.

According to Dr. Callister, BAT and WB assays were equivalent when used to confirm infection among patients with Lyme arthritis or Bell's palsy ( data to be published shortly). Because OspC expression is expressed in early Lyme disease, while OspA and OspB expression are more commonly seen in disseminated or arthritic Lyme disease, BAT was more sensitive in detecting early Lyme disease than WB. In this way, 11 patients (38%) who tested negative for Lyme disease on WB analysis were positive for disease on BAT. Unblinding revealed that most of these patients had atypical EM lesions in addition to other symptoms consistent with Lyme disease. BAT testing was negative for 14 patients (44%) who tested positive for WB. Again, unblinding these results revealed that these patients did not have clinical histories supportive of a Lyme disease diagnosis. Therefore, WB analysis would have misdiagnosed or failed to diagnose 25 (20%) of 124 patients with atypical symptoms in this study. Furthermore, Dr. Callister stated that BAT is inexpensive, not subject to interpretation of band color or intensity, and is not affected by previous vaccination with OspA (when the 50772 isolate is employed).

Variably Invariable

One final serodiagnostic technique was reviewed by Dr. Mario T. Philipp[11] from Tulane University Medical Center in New Orleans, Louisiana. As discussed previously, each of the current diagnostic methods for detection of Lyme disease has limitations. Further, the existence of 3 Borrelia species (particularly when European data are included), makes standardization difficult or impossible, since US-based studies reference only 1 species.

An alternative approach is to use an antigen common to all 3 species in an ELISA; this antigen should not cross-react with OspA. Dr. Philipp's group evaluated expression of antibodies to a synthetic peptide called C6, which corresponds to the invariable region (IR6) of the variable surface antigen (VIsE) of B burgdorferi.[12] This peptide was shown to be antigenic in monkeys infected by B burgdorferi strains. IR6 was immunodominantly expressed in humans as well as in dogs. Over a 7-day period, 3 of 7 humans with Lyme disease produced antibodies that reacted with IR6 antigen, while 9 of 10 produced reactive antibodies between 5 and 10 weeks after symptom onset.

Sensitivity in acute-phase Lyme disease was 74%, while 85% and 90% sensitivity rates were recorded in chronic and convalescent phases. Specificity data were also quite impressive, derived from 77 serum samples taken from patients with chronic infections, autoimmune diseases, non-B burgdorferi infections, and neurologic diseases, as well as 99 serum controls from hospitalized patients in nonendemic areas for Lyme disease. Among the combined group of patients, only 2 false positives were identified out of 176 patients (99% specificity). Antibodies generated by vaccination with Bacterin and OspA did not cross-react with C6 in dogs or monkeys studied.

Monitoring of C6 reactivity in monkeys treated for 60 days with doxycycline demonstrated dramatic reductions in anti-C6 antibody responses. Similar reductions were observed in canines following treatment with ceftriaxone. In humans, posttreatment C6 levels correlated with resistance or sensitivity to treatment, depending on whether C6 titers decreased by greater than 4 or less than 4. According to Dr. Philipp, this promising technology is relatively inexpensive and reproducible between reference laboratories. Given its advantages, its efficacy in randomized clinical trials is eagerly anticipated.


  1. Aguero-Rosenfeld ME. Serology in early Lyme disease. Program and abstracts of the 14th International Scientific Conference on Lyme Disease and Other Tick-Borne Disorders; April 21-23, 2001; Hartford, Connecticut.
  2. Centers for Disease Control and Prevention. Recommendations for test performance and interpretation from the Second National Conference on Serologic Diagnosis of Lyme Disease. Morb Mortal Wkly Rep. 1995;44:590-591. Available at: mmwrhtml/00038469.htm
  3. Dressler F, Ackermann R, Steere AC. Antibody responses to the three genomic groups of Borrelia burgdorferi in European Lyme borreliosis. J Infect Dis. 1994;169:313-318. Available at: &db=PubMed&list_uids= 8106763&dopt=Abstract
  4. Engstrom SM, Shoop E, Johnson RC. Immunoblot interpretation criteria for serodiagnosis of early Lyme disease. J Clin Microbiol. 1995;33:419-427. Available at: &db=PubMed&list_uids= 7714202&dopt=Abstract
  5. Wormser GP, Carbonaro C, Miller S, et al. A limitation of 2-stage serological testing for Lyme disease: enzyme immunoassay and immunoblot assay are not independent tests. Clin Infect Dis. 2000;30:545-548. Available at: &db=PubMed&list_uids= 10722442&dopt=Abstract
  6. Aguero-Rosenfeld ME, Roberge J, Carbonaro CA, et al. Effects of OspA vaccination on Lyme disease serologic testing. J Clin Microbiol. 1999;37:3718-3721. Available at: &db=PubMed&list_uids= 10523583&dopt=Abstract
  7. Fawcett PT, Rose CD, Budd SM, Gibney KM. Effect of immunization with recombinant OspA on serologic tests for Lyme borreliosis. Clin Diagn Lab Immunol. 2001;8:79-84. Available at: &db=PubMed&list_uids= 11139199&dopt=Abstract
  8. Fawcett PT. Western blot testing for diagnosing Lyme borreliosis: potentials, problems, performance. Program and abstracts of the 14th International Scientific Conference on Lyme Disease and Other Tick-Borne Disorders; April 21-23, 2001; Hartford, Connecticut.
  9. Callister SM, Jobe DA, Schell RF, et al. Detection of borreliacidal antibodies in dogs after challenge with Borrelia burgdorferi-infected ixodes scapularis ticks. J Clin Microbiol. 2000;38:3670-3674. Available at: &db=PubMed&list_uids= 11015381&dopt=Abstract
  10. Callister S. Clinical evaluation of the borreliacidal antibody test. Program and abstracts of the 14th International Scientific Conference on Lyme Disease and Other Tick-Borne Disorders; April 21-23, 2001; Hartford, Connecticut.
  11. Philipp MT. Serodiagnosis of Lyme disease with the C6 peptide. Program and abstracts of the 14th International Scientific Conference on Lyme Disease and Other Tick-Borne Disorders; April 21-23, 2001; Hartford, Connecticut.
  12. Liang FT, Bowers LC, Philipp MT. C-Terminal invariable domain of VlsE Is immunodominant but Its antigenicity is scarcely conserved among strains of Lyme disease spirochetes. Infect Immun. 2001;69:3224-3231. Available at: &db=PubMed&list_uids= 11292744&dopt=Abstract

Clinical Aspects of Lyme Disease: Dermatologic, Cardiac, GI, and Gestational

Harry Goldhagen, MS   Julie Rawlings, MPH   

Like syphilis at the turn of the previous century, Lyme disease can be considered the great impersonator. The myriad clinical presentations of this multisystem disease have been part of the diagnostic dilemma, especially for chronic Lyme disease. It is often difficult to determine whether specific symptoms are caused by Borrelia burgdorferi or are unrelated but occurring in a patient with serologic evidence of past infection.

A number of investigators at the 14th Lyme Disease Conference examined less common clinical presentations of Lyme disease, conditions for which B burgdorferi is not one of the usual suspects. These body systems include the gastrointestinal tract, the heart, and the skin (not counting the common dermatologic presentation of erythema migrans [EM]). And one speaker discussed the extremely rare syndrome of congenital Lyme disease.

Morphea and Lyme Disease: Are They Related?

Morphea is a rare and untreatable dermatologic condition characterized by thickening and induration of the skin from excess collagen deposition. There are at least 5 forms of the disease: localized, generalized, guttate, linear, and coup de sabre (an indentation that can extend to and damage the underlying muscle and bone). The cause is generally not known, but as with any idiopathic condition, proposed etiologies abound, including radiation damage, autoimmunity, infection, vaccination, trauma, and genetic predisposition. One of the leading infectious disease candidates in the pathogenesis of morphea is B burgdorferi, although this association is a subject of controversy.[1] A number of European studies have found a correlation, while most US studies, including a frequently cited study from the Mayo Clinic,[2] have found no evidence of B burgdorferi in morphea lesions.

Andrew G. Franks, Jr, MD,[3] of New York University School of Medicine (NYU), believes there is a connection between the 2 diseases. For instance, it can be difficult to differentiate between EM and certain morphea lesions, especially if the EM lesion is not the typical bull's-eye with central clearing. The differential diagnosis for EM-like lesions is varied and can include spider bites, herpes simplex or zoster, cellulitis, fungus or tinea, granuloma annulare, drug eruption, erythema multiforme, and subacute lupus erythematosus. In many cases, it can be difficult to culture B burgdorferi from EM lesions.

Part of the disagreement between the US and other studies may be due to differences in B burgdorferi serotypes and strains that cause morphea, according to Dr. Franks. For instance, only the sensu stricto strain is found in the United States, but all 3 pathogenic strains are found in Europe. Two skin diseases -- acrodermatitis (similar in appearance to scleroderma) and lymphocytoma -- have been identified in Europe as linked to B burgdorferi; the former is associated with the B afzelii strain, and the latter with the B garinii strain.

Dr. Franks believes that serologic testing is unreliable in morphea. He said that in published US studies of B burgdorferi antibodies in morphea patients, the investigators did not check whether the subjects received antibiotics recently. Antibiotic treatment can alter the results of serologic testing. Polymerase chain reaction (PCR) testing for B burgdorferi DNA in morphea patients may also be inaccurate in the US. For instance, the PCR tests may have been too specific and missed strains or serotypes more likely to cause morphea-like skin disease. European studies have detected B burgdorferi DNA by PCR in patients with morphea. For instance, a PCR study by Fujiwara and colleagues[4] tested for afzelii and garinii strains and found evidence of B burgdorferi in non-US cases. US PCR amplification has generally only tested for the sensu stricto strain.

Dr. Franks and colleagues at NYU have recently completed an unpublished study of the association of B burgdorferi, autoimmunity, and morphea. In this study, 82 patients (average age of 27 years; range, 2-61 years) with new-onset morphea were enrolled; 14 were male. The investigators tested for antibody to autoimmune disease and to B burgdorferi by IgG and IgM Western blot (WB), with all bands reported. They used their own criteria for diagnosis of underlying Lyme disease: more than 1 IgG band on WB was taken as a positive result for Lyme. None of the subjects had clinically defined Lyme disease during the trial. For autoimmune serology, any positive test was defined as positive.

For treatment purposes, they classified the patients into 4 groups, depending on whether they were positive by WB and/or autoimmune serology. Generally, patients with positive WB received 6 weeks of doxycycline (or an alternative antibiotic), and those with negative WB were given 3 weeks of doxycycline, with an optional additional 3 weeks if improvement was seen during the first 3 weeks.

Of the 61 patients who completed the study, 34 had clinical improvement. The WB-positive, autoimmune serology-negative group was the most likely to respond to antibiotic therapy. The Lyme WB converted to negative in many treated patients.

Dr. Franks and colleagues believe that all patients with morphea are candidates for a therapeutic antibiotic trial, regardless of serologic test results. IgM and IgG WB may be helpful in the diagnosis, but current Lyme tests are unreliable in such patients. Because the risks are minimal with antibiotics, he believes it is worth trying this approach, especially since there is no effective treatment for morphea at the present time.

The NYU group will be conducting a second trial, making use of a recombinant, nested PCR B burgdorferi assay. They are looking for patients to enroll in this and future studies. If you have any new, untreated morphea patients in your practice, call 917-816-2714 to receive a consent form and instructions for obtaining a 4-mm punch biopsy for PCR.

Lyme Disease and the Heart

Cardiac manifestations of Lyme disease are relatively uncommon and difficult to diagnose. According to Kornelia Keszler, MD,[5] of Yale University School of Medicine, the most readily recognized feature of cardiac involvement has been various degrees of heart block on ECG, which usually responds to antibiotic therapy.

Typical complaints of Lyme disease patients with cardiac involvement are chest pain, mild to moderate exertional dyspnea, and palpitations. (However, these symptoms also may be due to neuropsychiatric problems and musculoskeletal infection, so testing is important.) To evaluate such patients, cardiac testing should include thallium stress electrocardiography (ECG) and coronary angiography.

What does cardiac infection look like, and where are the organisms localized? Stanek and colleagues[6] found thickening of the walls of small endomysial vessels and infiltration by mononuclear cells. In murine studies, Pachner and colleagues[7] found 3 predominant locations for B burgdorferi in the heart. In mice infected for less than a month, spirochetes could be found mostly around blood vessels. By contrast, for longer infection periods, B burgdorferi could also be seen in cardiac myocytes, often surrounded by clear areas. B burgdorferi were also commonly found among collagen fibers.

Based on her series of cases and a review of the literature, Dr. Keszler drew the following conclusions. Thallium imaging typically reveals diffuse and patchy uptake of isotope in the myocardium, probably indicating involvement of the small vessels of the heart. Patients generally experience decreased exertional tolerance, as exhibited by a rapid increase in heart rate, but there is no ECG evidence of ischemia to account for the decreased tolerance. A variety of arrhythmias are seen, both ventricular and supraventricular, and are more common than heart block. At this time, it is not known whether treatment of Lyme disease will alter the thallium imaging. However, one study has found that cardiac abnormalities do not persist in patients treated for Lyme disease.[8]

Lyme Disease and the GI Tract

Lyme disease generally does not affect the GI tract alone, according to Martin D. Fried, MD,[9] of the Jersey Shore Medical Center, Neptune, New Jersey. Rather, GI disease is typically only one component of a systemic disease. Patients with Lyme disease can present with a variety of GI symptoms, including abdominal pain, chronic diarrhea, acid reflux, or blood in the stool. Children may develop encopresis -- the loss of bowel training -- which may indicate a neurologic effect of the spirochete.

Evaluation of patients suspected of having Lyme disease includes the ever-important history, physical examination, CBC, liver function tests, and endoscopic examination. The Lyme WB is generally not helpful, but PCR testing of biopsy specimens for B burgdorferi OspA can be useful. Silver staining of biopsy specimens can reveal spirochetes. For those who test positive by PCR, RNA polymerase testing of the biopsy sample can indicate whether the spirochetes are actively multiplying.

The differential diagnosis includes the majority of gastrointestinal diseases, such as pancreatitis, stool infections, peptic ulcer, Crohn's disease, and inflammatory bowel disease. Skin tags are an indication that the patient has Crohn's rather than a complication of Lyme disease. Crohn's patients have a malabsorption syndrome and are therefore generally underweight. By contrast, those with GI Lyme disease often also have fatigue or arthritis, and the inactivity may make them overweight.

Treatment involves antibiotics, but regular follow-up is important to detect recurrences and lack of response. Dr. Fried has seen B burgdorferi persist in the GI tract despite multiple rounds of antibiotics over many years.

Gestational and Congenital Lyme Disease

Any infectious disease contracted during pregnancy has the potential to be transmitted to the fetus. Tessa D. Gardner, MD,[10] of Washington University School of Medicine, St. Louis, Missouri, who has recently written an extensive chapter on the subject,[11] discussed the rare conditions of gestational and congenital Lyme disease (borreliosis) and the best approaches (based on limited case reports) to diagnosis and treatment.

How rare are these conditions? According to published figures, 16,000-17,000 cases of Lyme disease are reported each year in the United States. Roughly 8000 cases are in women, and approximately 1200-3400 cases are in women of childbearing age (20-49 years old). Dr. Gardner did some back-of-the envelope estimates to get a sense of how many cases of gestational Lyme disease may be occurring. If you assume that one quarter of the women in the child-bearing age group are pregnant (a gross overestimate, by Dr. Gardner's admission), and that 10% are either untreated or inadequately treated, and that one fifth transmit the organism to the fetus or newborn, this calculates to approximately 40 cases of congenital Lyme disease a year in the United States. It would be unusual for any large city to have more than 1 or 2 cases a year, and it would be extremely rare for any physician to see more than a few cases in a lifetime.

Dr. Gardner has conducted an extensive literature review (through 1998) that turned up 263 cases.[10] She found that 25% resulted in adverse outcomes: 8% resulted in fetal death and 2% in neonatal death. Fifteen percent of the babies were liveborn but were ill or had an abnormality. The effect of antibiotic therapy was dramatic in these patients: with antibiotics, 85% of neonates were normal, while 15% had an adverse outcome. In striking contrast, without antibiotics, only 33% were normal, while 67% had an adverse outcome. The conclusion: Proper, prompt diagnosis and antibiotic therapy are vital for healthy neonates born with congenital Lyme disease.

However, it can be quite difficult to recognize such a rare disease. The differential diagnosis is extensive and includes sepsis/meningoencephalitis (bacterial or viral), other congenital infectious diseases (eg, syphilis, leptospirosis, relapsing fever, toxoplasmosis), congenital heart or bone disease, inherited or infectious immunodeficiency, sudden infant death syndrome, and more. A history suggestive of Lyme disease in the mother or positive serologic or other tests for B burgdorferi can suggest the diagnosis. Dr. Gardner has provided a list of clues to the various presentations of congenital Lyme disease (Table). One interesting radiologic clue is "celery stalking" -- lucent metaphyseal bands -- on the long bones of the neonate. These are occasionally seen in infants with gestational syphilis or viral infections. In 2 neonates Dr. Gardner has treated, the bands disappeared shortly after treatment.

Table. Signs and Symptoms of Congenital Lyme Borreliosis

StageMild EarlySevere EarlyLate
OnsetUsually first 2 weeks of lifeUsually first week of lifeUsually > 2 wks and < 2 yrs of age
Maternal gestational Lyme borreliosis Usually first or second trimesterUsually first or second trimesterUsually second or third trimester
Signs and symptoms
  • Mild suspected sepsis or meningoencephalitis
  • Hyperbilirubinemia
  • Adenopathy
  • Rash
  • Intrauterine growth retardation
  • Miscellanous anomalies (eg, genitourinary [GU], skeletal, cardiac)
  • Severe suspected sepsis or meningoencephalitis
  • Respiratory distress
  • Perinatal death
  • Intrauterine growth retardation
  • Fever
  • Rash
  • Adenopathy, hepatosplenomegaly
  • Hyperbilirubinemia
  • Miscellaneous anomalies (eg, GU, skeletal, cardiac)
  • Subacute illness
  • Developmental delay/meningoencephalitis
  • Growth retardation/failure to thrive
  • Prematurity
  • Fever
  • Adenopathy
  • Rash
  • Hepatosplenomegaly
  • Miscellaneous anomalies (eg, GU, skeletal, cardiac)
Prematurity?< 4 weeks< 5 weeks--

The prognosis for gestational Lyme disease is good if diagnosed and treated adequately. The prognosis for neonates with early congenital Lyme disease depends on prompt diagnosis, especially in severe early cases. Similarly, the prognosis in late congenital Lyme depends not only on prompt diagnosis and treatment, but also on the extent of irreversible damage present at the time of diagnosis. Long-term follow-up is important for detecting possible recurrence of disease.

This summer, Dr. Gardner will be starting the North American Gestational and Congenital Lyme Disease Watch to evaluate the relationship of various factors (clinical and laboratory characteristics, antibiotic regimens) to outcomes for gestational Lyme disease, and to evaluate short- and long-term outcomes (infants, stillborns, miscarriages) of pregnancies complicated by Lyme disease and develop clinical and laboratory case definitions of these outcomes. Interested people (physicians and affected women) can enroll on the Internet once the sites are launched in July 2001:


  1. Weide B, Walz T, Garbe C. Is morphoea caused by Borrelia burgdorferi? A review. Br J Dermatol. 2000;142:636-644. Abstract available at: &db=PubMed&list_uids= 10792212&dopt=Abstract
  2. Hoesly JM, Mertz LE, Winkelmann RK. Localized scleroderma (morphea) and antibody to Borrelia burgdorferi. J Am Acad Dermatol. 1987;17:455-458. Abstract available at: &db=PubMed&list_uids= 3308981&dopt=Abstract
  3. Franks A. Evidence for Borrelia burgdorferi as an etiologic agent in morphea. Program and abstracts of the 14th International Scientific Conference on Lyme Disease and Other Tick-Borne Disorders; April 21-23, 2001; Hartford, Connecticut.
  4. Fujiwara H, Fujiwara K, Hashimoto K, et al. Detection of Borrelia burgdorferi DNA (B garinii or B afzelii) in morphea and lichen sclerosus et atrophicus tissues of German and Japanese but not of US patients. Arch Dermatol. 1997;133:41-44. Abstract available at: &db=PubMed&list_uids= 9006371&dopt=Abstract
  5. Keszler K. Cardiac manifestations of Lyme disease. Program and abstracts of the 14th International Scientific Conference on Lyme Disease and Other Tick-Borne Disorders; April 21-23, 2001; Hartford, Connecticut.
  6. Stanek G, Klein J, Bittner R, Glogar D. Isolation of Borrelia burgdorferi from the myocardium of a patient with longstanding cardiomyopathy. N Engl J Med. 1990;322:249-252.
  7. Pachner AR, Basta J, Delaney E, Hulinska D. Localization of Borrelia burgdorferi in murine Lyme borreliosis by electron microscopy. Am J Trop Med Hyg. 1995;52:128-133. Abstract available at: &db=PubMed&list_uids= 7872439&dopt=Abstract
  8. Sangha O, Phillips CB, Fleischmann KE, et al. Lack of cardiac manifestations among patients with previously treated Lyme disease. Ann Intern Med. 1998;128:346-353. Abstract available at: &db=PubMed&list_uids= 9490594&dopt=Abstract
  9. Fried M. Gastrointestinal manifestations of Lyme disease. Program and abstracts of the 14th International Scientific Conference on Lyme Disease and Other Tick-Borne Disorders; April 21-23, 2001; Hartford, Connecticut.
  10. Gardner T. Lyme disease in pregnancy. Program and abstracts of the 14th International Scientific Conference on Lyme Disease and Other Tick-Borne Disorders; April 21-23, 2001; Hartford, Connecticut.
  11. Gardner T. Lyme disease. In: Remington J, Klein JO, eds. Infectious Diseases of the Fetus and Newborn Infant. Philadelphia, Pa: WB Saunders; 2001: 519-641.

Suggested Reading

MacDonald AB. Gestational Lyme borreliosis. Implications for the fetus. Rheum Dis Clin North Am. 1989;15:657-677. Abstract available at: &db=PubMed&list_uids= 2685924&dopt=Abstract

Maraspin V, Cimperman J, Lotric-Furlan S, et al. Treatment of erythema migrans in pregnancy. Clin Infect Dis. 1996;22:788-793. Abstract available at: &db=PubMed&list_uids= 8722932&dopt=Abstract

Neurologic Lyme Disease: Defining and Treating an Elusive Target

Brian A. Fallon, MD, MPH, MEd   Harry Goldhagen, MS   

What is Lyme Encephalopathy?

Encephalopathy is like fine art: Most people know it when they see it, but there is very little agreement on how to define it. At the 14th International Lyme Disease Conference, Brian A. Fallon, MD,[1] of Columbia University and the New York State Psychiatric Institute, New York, NY, tried to do just that. More importantly, he described the different ways one can define encephalopathy, the strengths and limitations of each approach, and significantly, what other aspects of life can give the impression of encephalopathy where none exists.

First, one must evaluate patients with persistent Lyme encephalopathy by asking the following questions:

Defining the Problem

The first question can pose a problem for the clinician. There is currently no agreed-upon definition of Lyme encephalopathy, and this has caused a great deal of confusion in the field. Encephalopathy was not included in the CDC's case definition of Lyme disease, so NIH-funded studies of this condition can be hard to defend without a government- or society-sanctioned definition.

For investigators in this field, there have been numerous and differing definitions of Lyme encephalopathy. One of the earlier attempts at defining the problem was made by Logigian and colleagues in 1990.[2] This group listed the chronic neurologic abnormalities of Lyme encephalopathy as memory loss, depression, sleep disturbance, irritability, and difficulty finding words. However, there is much overlap between these symptoms and those of depression unrelated to Lyme disease.

Some further possibilities for defining the condition include self reporting of cognitive deficits, self reporting plus laboratory signs of CNS involvement, objective evidence of deficits on cognitive testing, or objective deficits plus laboratory signs of central nervous system (CNS) involvement. Signs of CNS involvement have included elevated cerebrospinal fluid (CSF) protein or pleocytosis, abnormal brain scans or tests (single photon emission computed tomography [SPECT], magnetic resonance imaging [MRI], or electroencephalogram [EEG]), intrathecal antibody production, or a positive polymerase chain reaction (PCR) for Borrelia burgdorferi DNA or a positive culture. However, objective tests often do not agree with patients' perceptions. This is especially true for memory in depression.

One Deficit, or Many?

One challenge is determining which and how many cognitive deficits to include in the definition and evaluation. For instance, some investigators have looked at a single, representative deficit (ie, single-domain methods) such as memory.[3] Others have looked at numerous deficits in each patient (ie, multiple-domain methods), such as memory, verbal fluency, and attention.[4] The advantage of the single domain method is that it focuses on one main problem and makes for a more homogeneous study sample. However, such a study may exclude patients who are impaired in other cognitive areas. The multiple domain method is particularly well suited for a disease that affects multiple cognitive domains, as one would expect for a global term such as encephalopathy. However, if patients have deficits primarily in one domain, this method becomes less sensitive (by dilution with less affected cognitive areas).

A further complication is how one defines and measures these deficits. One approach is to compare to age-matched norms. A second approach is to compare to actual or estimated premorbid or general ability levels. Comparison to age-matched norms provides simple, clear criteria for measurement and comparison, a cut-off score. But if the deficit being compared is correlated with a general ability (such as memory and general intelligence), then people with higher intelligence but with memory impairment may not be detected by this method. For example, if a subject has a general intelligence IQ of 130 and a memory score of 100, his full-scale IQ is 2 standard deviations above the age-norm, while his memory score is exactly at the age-norm. Compared to age-norms, this subject would not have memory impairment. Compared to his full-scale IQ, his memory score would be 2 standard deviations below expected -- which clearly would suggest impairment. One method identifies this subject as normal, the next identifies him as impaired.

In contrast to the age-norm method, comparison to general levels of ability can allow for a more customized approach to assessing cognitive impairment, thus enhancing sensitivity. However, general abilities can be decreased by illness, regardless of a specific effect on that ability. In addition, this approach assumes that the domain of interest is strongly correlated with general ability.

The ideal screening tool for Lyme encephalopathy should have maximal sensitivity and specificity. Premorbid ability should be taken into account, by using norms adjusted for age, sex, and education level, or with balanced premorbid assessment of ability. It is still not clear whether a single- or multiple-domain definition of neurocognitive impairment should be used.

There are many screening tools for assessing premorbid ability, including verbal IQ, verbal comprehension index, vocabulary subtest score, reading subtest score (WRAT-R [Wide range achievement test-Revised]), demographic composite (Barona demographic equation), and national adult reading test (NART). Of course, different investigators have used different methods of assessing premorbid ability, thus further complicating comparisons between studies.

One of the few studies that actively evaluated patients with Lyme encephalopathy was conducted by Logigian and coworkers in 1997.[5] This study reveals some of these diagnostic problems discussed above. In this study, the investigators screened patients for Lyme encephalopathy and then evaluated the change in SPECT scan perfusion after treatment. Starting with clearly defined criteria for "definite Lyme encephalopathy" -- subjective complaints of cognitive deficits, along with either a past or present CSF abnormality (intrathecal antibodies or PCR positivity) or objective cognitive deficits (as measured by 2 standard deviations below normal on verbal or visual memory tests, or 1 SD below normal on both tests) -- they examined whether brain perfusion improved after treatment. While the brain imaging results were of interest in that all of the patients with definite Lyme encephalopathy showed improved perfusion after treatment, this study also demonstrated that the definition of Lyme encephalopathy, if restricted to cognitive testing, would have been too restrictive using their criteria. In other words, 5 of the 13 patients with "definite Lyme encephalopathy" did not have cognitive impairment using their criteria for impairment. Yet, these very same patients had abnormal SPECT scans that improved after treatment. Their cognitive criteria, which used age-norms for comparison, failed to identify 38% of patients with CNS abnormalities.

Dr. Fallon described an ongoing study of Lyme encephalopathy he is conducting at the NY State Psychiatric Institute. Because previous studies disagree about which is more accurate, single- or multiple-domain evaluation, they will collect data in 6 domains: motor skills, psychomotor skills, attention, memory, working memory, and verbal fluency. Data are preliminary, but so far the most sensitive method for the detection of impairment appears to be one that incorporates testing from multiple cognitive domains. Memory and working memory seem to be the most affected neurocognitive areas. Even so, about one quarter of the control subjects appeared to have neurocognitive deficits, compared to two thirds of the patients with complaints of memory impairment secondary to Lyme disease. Dr. Fallon suggested that the best method for detecting memory impairment in particular might be one that makes use of ethnicity- and education-adjusted norms. The Psychological Corporation is expected to publish such norms within the next year.

Complicating Factors

When determining the presence of encephalopathy in patients with Lyme disease, one must take into account other causes of cognitive complaints (Table 1), including the use of medications that can impair neurocognitive function (Table 2).

Table 1. Other Possible Causes of Cognitive Complaints in Patients With Lyme Encephalopathy

Substance abuse (often not reported by the patient, must interview family/friends)
Normal aging
Over-reading of cognitive tests
Sleep apnea
Medications/toxins (drugs associated with cognitive impairment are listed in Table 2)
HIV and other infections
Menopausal mood changes
Metabolic/endocrine disorders (eg, thyroid disease)
Alzheimer's disease
Head trauma
Other CNS diseases

Table 2. Drugs Associated With Cognitive Impairment

Antianxiety agents
Lithium, neuroleptics
Methyldopa, clonidine
Metronidazole, penicillin
Opiate-based drugs
Pain medications
Phenobarbital, phenytoin
Tricyclic antidepressants

Hysterical dementia is often overdiagnosed in patients with Lyme encephalopathy, but it is rare for this to occur alone as a conversion symptom. The label of "hysterical" is often applied when phenomena are outside the clinician's experience. For instance, females and male homosexuals more often receive this label. Based on studies over the past 50 years, many patients who are initially given the diagnosis of hysterical dementia go on to develop an organic CNS disorder.

Dr. Fallon is conducting a randomized, placebo-controlled study of brain imaging and treatment of persistent Lyme encephalopathy (Columbia University - National Institute of Neurological Disorders and Stroke [NINDS]). Treatment will involve IV ceftriaxone for 10 weeks, with a 14-week antibiotic-free follow-up period. At the end of the 24-week study, patients who had been randomized to receive placebo will be given 6 weeks of IV ceftriaxone. Evaluations will be conducted at baseline and 12 and 24 weeks. PET and MRI imaging as well as neuropsychiatric tests are being used to evaluate response to treatment. Patients will be recruited for this study over the course of the next 3 years.

An In-depth Study of Neurocognitive and Behavioral Lyme Disease

Patricia K. Coyle, MD,[6] and colleagues from the State University of New York at Stony Brook School of Medicine have conducted a prospective, controlled study to characterize the neurologic and neurobehavioral manifestations of Lyme disease in North America. They examined 3 groups: adults with acute disease, adults with chronic disease, and children with disseminated disease (ie, more than 1 erythema migrans [EM] lesion). They attempted to characterize changes to the CSF and identify pathogenetic mechanisms and predictors of outcome. This work builds on a previous study by Coyle and colleagues.[7]

The clinical syndromes studied included cranial (facial) neuropathy, radiculoneuritis, meningitis, and arthritis. The major symptoms (ie, seen in more than two thirds of patients) in adults with acute disease included fatigue, headache, sleep problems, stiff neck, and myalgia. Those with chronic disease had a different constellation of major symptoms, such as concentration difficulties, fatigue, arthralgias, myalgias, mood disturbance, memory loss, sleep problems, word-finding difficulties, knee pain, confusion, and stiff neck. Children with disseminated Lyme disease experienced major symptoms of headache and fatigue. By symptom score, the major initial defining syndrome for the acute adult group was meningitis, followed by multifocal EM, cranial nerve palsy, radiculoneuritis, and single EM; for the chronic adult group, single EM was the most common presenting symptom, followed by arthritis, cranial nerve palsy, and multifocal EM; and for children with disseminated disease, extraneural symptoms.

These investigators concluded that the children with disseminated disease are less symptomatic than adults, but they have more inflammatory CSF changes. Among the adult patients, those with chronic disease were more symptomatic than those with acute disease. They had more cognitive, mood, and joint disturbances; more severe symptoms; and more current depression, anxiety, and adjustment problems. However, it was the acute disease patients who were more likely to show objective cognitive deficits.

Surprisingly, CSF changes were not marked in either group of adult patients. In adults with acute disease,

Similarly, in the adult chronic disease group, Dr. Coyle plans to follow up with each group of patients to measure long-term (18-month) sequelae of the disease.

Cognitive Remediation: Getting Back up to Speed

Cognitive remediation should not be confused with cognitive therapy, stated Leo J. Shea III, PhD,[8] of the NYU School of Medicine. Cognitive therapy attempts to change the way a person thinks about his or her problems. By contrast, cognitive remediation improves a cognitive deficit, either directly or indirectly. Dr. Shea has taken his experience working with patients with brain injury and applied these techniques to patients with chronic Lyme disease with cognitive deficits.

The overall goal of cognitive remediation is to improve the life of the patient, by first addressing the neurocognitive deficits, using preserved capabilities as a base to develop compensatory strategies, ameliorating cognitive impairments, improving functional capabilities, and hopefully, enhancing life satisfaction.

Dr. Shea favors the compensatory model for improving deficits, rather than the restorative model. Whereas the restorative approach attempts to recreate tasks directly with a repetitive, saturation approach, the compensatory model uses an indirect approach of finding strategies or alternatives to "get around the roadblocks" and improve function. He also favors the process-specific approach, rather than a shotgun (trying to cover many deficits) or a functional approach. One of the benefits of the process-specific approach is that it can be customized for each client.

A structured approach to cognitive remediation is the 3-step PIE model used at NYU: Preparation, Implementation, and Evaluation. The preparation/orientation step involves getting to know the patient's problems. One of the most time-consuming tasks is getting hold of the medical records for review, since some of these patients have seen numerous physicians and therapists. Dr. Shea also suggests interviewing the referring physician, as well as adjunct physicians and therapists. Interviewing family and other supportive people can also provide valuable information. The patient undergoes evaluation during this step, including neuropsychological assessment and measurement of specific cognitive deficits. The patient also provides a self-analysis of his or her problems during the clinical interview.

In the implementation step, the patient and therapist prepare long-term (6-month) and short-term (1- to 3-month) goals, and formalize this in a patient contract. The therapist selects the first cognitive remediation task, which is sometimes a task the patient is already good at, to build a positive attitude about the process. With each task, the therapist administers a baseline test, training, and a posttest.

During the evaluation and analysis step, the therapist evaluates domain-specific results, as well as generalization of the learned tasks to other deficits and the ecological validity of the learning. The therapist prepares a progress report each month, and a cognitive progress index is prepared quarterly. This is a time-consuming process, but necessary for insurance reimbursement. In fact, one can expect difficulties with health insurance companies, even when following guidelines. The therapist and patient revise short-term goals quarterly, and long-term goals semiannually.

A number of cognitive domains are addressed in patients with Lyme disease, including attention/concentration, memory, spatial/perceptual ability, efficient processing (both accuracy and speed), fluency, higher-level reasoning, and executive functioning.

The therapist monitors 4 cognitive markers to gauge the patient's state of mind about the process. One of the most important markers is the patient's awareness of the deficit. Not surprisingly, greater awareness can at first lead to depression and anxiety, as the patient realizes the impact these deficits have on his or her daily functioning and life in the long term. Other markers include an openness and willingness to face the deficit, acquiring the skills or the ability to compensate for the deficit, and acceptance. This can be especially hard on the patient, such as accepting that one can no longer handle one's previous career.

Dr. Shea has conducted a small study of 9 patients who underwent cognitive remediation. All met CDC diagnostic criteria for Lyme disease. He measured attention, concentration, processing efficiency (speed and accuracy), and depression, and asked the patients for self-ratings of physical, cognitive, emotional, and behavioral functioning. A number of training programs were used to address deficits in these areas, as well as intravenous antibiotic therapy. The results are listed in Table 3. Overall, in this small study, patients improved significantly with cognitive remediation.

Table 3. Results of Cognitive Remediation in 9 Patients With Lyme Disease

 Baseline8 Weeks of Intervention3 Months After Intervention
Attention2 below 1 SD7 avg, 2 mild9 avg
Concentration2 below 1 SD5 avg, 2 mild, 2 mod9 avg
Processing Efficiency9 below 1 SD

  • Accuracy
 5 avg, 3 mild, 1 mod6 avg, 3 mild
  • Speed
 2 avg, 3 mild, 4 mod4 avg, 3 mild, 2 mod
Zung Depression Index2 normal, 2 mild, 3 mod, 2 sev2 normal, 5 mild, 2 mod4 normal, 3 mild, 2 mod
Self-rating of Functioning2 or more impaired categoriesimproved in most categories

-- no improvement in emotion in 4 subjects or in behavior in 3 subjects

improved in all categories

-- no improvement for 2 subjects in emotion

SD = standard deviation; avg = average; mod = moderate deficit; sev = severe deficit

Neurologic Lyme Disease in Children: Points to Consider When Evaluating Encephalopathy

Pediatric neurologic Lyme disease is rare, and presentations are highly variable, thus complicating recognition, diagnosis, and treatment. Dorothy Pietrucha, MD,[9] of the Jersey Shore Medical Center, Neptune, New Jersey, has treated many children and adolescents with neurologic symptoms of Lyme disease, and she provided a series of case reports to illustrate the heterogeneity of presentations, the difficulties of diagnosis, and the often protracted courses of treatment and recovery.

Dr. Pietrucha highlighted the following recommendations:

  1. Do not assume that Lyme is causing an encephalopathic problem. There are many static encephalopathic problems in children, for example, attention-deficit hyperactivity disorder, learning disabilities, obsessive-compulsive disorder, mental retardation, cerebral palsy, and Tourette's. In the majority of cases, Lyme disease is not causing the disease, but it could be making it worse. Avoid jumping to conclusions.

  2. Pediatric Lyme disease has heterogeneous presentations. Keep an open mind about Lyme disease. It is vital to perform a thorough differential diagnosis.

  3. Be cautious how you assess the published literature, especially for rare diseases. Most physicians have not seen cases of rare disease, such as congenital Lyme disease, but this does not mean the disease doesn't exist. Jumping to conclusions, and even worse, publishing poorly researched studies claiming rare diseases do not exist, can cause problems with insurance company reimbursement.


  1. Fallon BA. Differential diagnosis of Lyme encephalopathy. Program and abstracts of the 14th International Scientific Conference on Lyme Disease and Other Tick-Borne Disorders; April 21-23, 2001; Hartford, Connecticut.
  2. Logigian EL, Kaplan RF, Steere AC. Chronic neurologic manifestations of Lyme disease. N Engl J Med. 1990;323:1438-1444. Available at: &db=PubMed&list_uids= 2172819&dopt=Abstract.
  3. Kaplan RF, Jones-Woodward L, Workman K, et al. Neuropsychological deficits in Lyme disease patients with and without other evidence of central nervous system pathology. Appl Neuropsychol. 1999;6:3-11.
  4. Krupp LB, Elkins LE, Coyle PK, et al. Post Lyme syndrome: contrasts with recovered Lyme patients on cognitive and symptom measures. J Spiro Tick Diseases. 1999;6:112-116.
  5. Logigian EL, Johnson KA, Kijewski MF, et al. Reversible cerebral hypoperfusion in Lyme encephalopathy. Neurology. 1997;49:1661-1670. Available at: &db=PubMed&list_uids= 9409364&dopt=Abstract
  6. Coyle PK. Neurologic Lyme disease. Program and abstracts of the 14th International Scientific Conference on Lyme Disease and Other Tick-Borne Disorders; April 21-23, 2001; Hartford, Connecticut.
  7. Belman AL, Reynolds L, Preston T, Postels D, Grimson R, Coyle PK. Cerebrospinal fluid findings in children with Lyme disease-associated facial nerve palsy. Arch Pediatr Adolesc Med. 1997;151:1224-1228. Available at: &db=PubMed&list_uids= 9412598&dopt=Abstract
  8. Shea L. Cognitive remediation. Program and abstracts of the 14th International Scientific Conference on Lyme Disease and Other Tick-Borne Disorders; April 21-23, 2001; Hartford, Connecticut.
  9. Pietrucha DM. Pediatric neurologic Lyme disease. Program and abstracts of the 14th International Scientific Conference on Lyme Disease and Other Tick-Borne Disorders; April 21-23, 2001; Hartford, Connecticut.

Suggested Reading

Fallon BA, Kochevar JM, Gaito A, Nields JA. The underdiagnosis of neuropsychiatric Lyme disease in children and adults. Psychiatr Clin North Am. 1998;21:693-703. Available at: &db=PubMed&list_uids= 9774805&dopt=Abstract

Fallon BA, Schwartzberg M, Bransfield R, et al. Late-stage neuropsychiatric Lyme borreliosis. Differential diagnosis and treatment. Psychosomatics. 1995;36:295-300.

Fallon J, Bujak DI, Guardino S, Weinstein A. The Fibromyalgia Impact Questionnaire: a useful tool in evaluating patients with post-Lyme disease syndrome. Arthritis Care Res. 1999;12:42-47. Available at: &db=PubMed&list_uids= 10513489&dopt=Abstract

Pietrucha DM, Sensakovic JW. Treating Lyme disease: different approaches. N J Med. 1996;93(7):51-4.

Related Link

Lyme Disease Research Studies, from Columbia University

Lyme Disease Controversies

Harry Goldhagen, MS   Julie Rawlings, MPH   

Lyme Vaccine and Disease Reactivation?

The Lyme disease vaccine (outer surface protein A [OspA], LYMErix) appears quite beneficial for those at moderate to high risk of infection. But Sam Donta, MD,[1] of Boston University School of Medicine, Boston, Massachusetts, has raised concerns about the development of arthritis and other symptoms of chronic Lyme disease, in vaccine recipients who have previously been infected with Borrelia burgdorferi. He noted that this apparent disease reactivation has occurred more often after the second or third dose of the vaccine. His work is preliminary and anecdotal, but he has seen 16 patients who developed the triad of fatigue and musculoskeletal and neurocognitive symptoms shortly (from days to a month) after receiving the vaccine.

It should be noted that this possible association is quite controversial. Some investigators do not believe that vaccine-related disease reactivation is supported by the data.[2,3] And there is currently a class-action lawsuit against SmithKline Beecham (now Glaxo SmithKline), maker of the Lyme disease vaccine, claiming that this product leads to autoimmune arthritis in approximately one third of vaccine recipients genetically predisposed to the disease.[4]

Nevertheless, some intriguing information can be gleaned from Dr. Donta's case studies. The Western blot (WB) results in his patients show an IgM response to OspA, but in addition, there are both IgM and IgG responses to other B burgdorferi antigens, suggesting previous infection. Although the cause of reactivation is not known, autoimmunity, an underlying infection that was not adequately treated, or an interaction between the two could be responsible for this condition. Dr. Donta drew a parallel between these cases and the development of zoster in those with recent exposure to a case of varicella.

Additional case reports on vaccine use and disease reactivation were provided by Paul T. Fawcett, PhD,[5] of the A. I. duPont Hospital for Children, Wilmington, Delaware, during an unscheduled presentation. While conducting a small-scale serologic survey of 20 employees of the hospital who received the Lyme disease vaccine, he came across 2 patients who subsequently developed arthritis. They developed arthritis within 24 hours of the second dose of the vaccine. Neither had a previous history of B burgdorferi infection. Dr. Fawcett also presented 2 case reports of children who developed arthritis after receiving the vaccine; the data suggested that one child became infected during the vaccine trial.

There has been evidence in animals linking the Lyme disease vaccine and chronic symptoms. In one study, hamsters given OspA developed arthritis after challenge with various strains of B burgdorferi.[6]

Both Dr. Donta and Dr. Fawcett suggest that patients with apparent reactivation from the vaccine be treated as if they have chronic Lyme disease, with a tetracycline, a macrolide, or hydroxychloroquine. Further observation and investigation are definitely needed. Dr. Donta suggests that the Food and Drug Administration show greater caution in recommending who receives the vaccine. For instance, it might be prudent for those who have had Lyme disease to avoid getting vaccinated with the current vaccine. He believes that those at high risk for Lyme disease, such as landscapers and outdoor workers, should still get vaccinated.

There are additional vaccine candidates in development, and it is not known whether they will have any effect on disease reactivation.

A Critique of the IDSA Guidelines for Treatment of Lyme Disease

Practice guidelines for the diagnosis, treatment, and prevention of Lyme disease were drafted by a committee convened by the Infectious Diseases Society of America (IDSA) and published in July 2000.[7] [You can read the complete guidelines online at] The guidelines cover a wide variety of presentations, including early Lyme disease (erythema migrans, acute neurologic involvement, heart block, and cranial nerve palsy), arthritis, late neuroborreliosis, and recurrent disease (arthritis after an oral antibiotic regimen and objectively confirmed encephalopathy), with treatment recommendations and alternatives for each stage. As with the other IDSA guidelines, they provide a framework for physicians to provide treatment based on a careful examination and rating system of the available data. However, these guidelines have generated some disagreement among physicians. The most controversial sections are the approach to Lyme encephalopathy and chronic Lyme disease, and the repeated or prolonged use of antibiotics to treat recurrences.

But why be concerned? Guidelines are not ironclad rules for treatment. Physicians generally individualize treatment, using their clinical judgement when a presentation varies from the typical, or when the patient doesn't respond to first-line treatment. Individualization is the basis of medical care.

If only that were still true. In the United States, most medical care is paid for by insurance companies -- managed care organizations, preferred provider organizations, and other healthcare companies. Insurance companies use guidelines from respected medical groups to determine whether treatments should be "covered" and which should not. Therefore, if a set of guidelines suggests that there is no evidence to support certain types of treatment, it can be difficult or impossible for the patient and physician to receive reimbursement from the insurance company.

At the 14th Lyme Disease Meeting, Daniel J. Cameron, MD,[8] of Westchester, New York, presented a critique of the guidelines as well as other issues in the diagnosis and treatment of Lyme disease. His major areas of concern were the lack of acceptance of subjective symptoms of encephalopathy in the diagnosis of recurrent Lyme disease (only encephalopathy confirmed by objective tests is included in the guidelines), resistance to using long-term antibiotic treatment for both acute and recurrent Lyme disease in the United States, and exclusion of patients from clinical trials who do not meet the current diagnostic criteria for Lyme disease (the 2-tier approach to diagnosis, based on a positive ELISA test and a positive IgG Western blot [WB]).

Dr. Cameron expressed 5 additional concerns about the guidelines and the committee that drafted them:

A number of physicians attending this conference agreed with some of these concerns about the guidelines. Sam Donta, MD, Boston University School of Medicine, who was originally part of the expert committee that drafted the guidelines, believes that there was not enough published information to create guidelines for late or chronic disease. Dr. Donta eventually removed himself from the committee because of these disagreements. Late disease was included in the guidelines, even though Dr. Donta believed the data were mostly anecdotal or comprised of small, uncontrolled studies. "We don't have enough information upon which to have guidelines for late or chronic disease," he said. However, he stated that it was never in contention as to whether chronic Lyme exists. Dr. Donta said, "I believe we are suffering the consequences of that paper, because there are insurance companies quoting that very tricky statement, " 'there are no convincing published data' -- there are no data!" Insurance companies are using the statement of "no convincing data" to deny reimbursement for treatment of late/chronic disease.

Patricia Coyle, MD, SUNY at Stony Brook School of Medicine, was a member of the expert committee that drafted the IDSA guidelines. She also noted that guidelines are used negatively by insurance companies to deny treatment.

There is a parallel between these guidelines and the original diagnostic criteria for AIDS. Early on, a number of opportunistic infections (OIs) were not included as indicative of AIDS. Patients developing only these OIs were therefore not diagnosed with AIDS, and had greater difficulty receiving reimbursement from insurance companies and other benefits afforded to people with AIDS. This was eventually remedied when the Centers for Disease Control and Prevention (CDC) revised the diagnostic criteria to include other common OIs.

Encephalopathy and Prolonged Antibiotic Treatment

Encephalopathy has been defined in many ways; one definition, by Logigian and colleagues[9] in 1990, included memory loss, depression, sleep disturbances, difficulty finding words, fatigue, headache, and irritability. (See Neurologic Lyme Disease: Defining and Treating an Elusive Target) Common recurrent symptoms of encephalopathy that are not objectively measurable include fatigue, poor concentration, memory loss, crying or sadness, irritability, headaches, dizziness, numbness, tingling, muscle pain, joint pain, back pain, and blurred vision. However, these symptoms are not included in the guidelines for the diagnosis of Lyme neuroborreliosis. Dr. Cameron believes that subjective symptoms should be included in the diagnostic criteria of Lyme encephalopathy.

Dr. Cameron also believes that long-term treatment of Lyme disease should be explored in greater detail. The guidelines state[7]:

"Randomized controlled studies of treatment of patients who remain unwell after standard courses of antibiotic therapy for Lyme disease are in progress. To date, there are no convincing published data that repeated or prolonged courses of either oral or IV antimicrobial therapy are effective for such patients. The consensus of the Infectious Diseases Society of America (IDSA) expert-panel members is that there is insufficient evidence to regard 'chronic Lyme disease' as a separate diagnostic entity."

The guidelines recommend 14-21 days of therapy for erythema migrans and 14-28 days for other forms of Lyme disease. However, small studies, especially from Europe, suggest that longer-term treatment may be more effective. For instance, Oksi and colleagues[10] had a 90% success rate with 100-day treatment.

In addition, a few studies suggest that recurrence is common, and that longer treatment initially may reduce the recurrence rate. For example, Shadick and colleagues[11] conducted a population-based, retrospective study of 38 patients and found that 13 (34%) had long-term sequelae from Lyme disease: 6 with arthritis or recurrent arthralgias, 4 with neurocognitive impairment, and 3 with neuropathy or myeloneuropathy. Similarly, Asch and coworkers[12] conducted a retrospective evaluation of 215 patients a mean of 3.2 years after initial evaluation. They found that 19 (9%) required retreatment for synovitis or worsening objective neurologic features, and they thought that 114 (53%) should be observed for post Lyme sequelae (persistent symptoms of arthralgia, arthritis, cardiac or neurologic involvement with or without fatigue).

Dr. Cameron believes that longer treatment may improve outcomes. Three randomized, double-blind, placebo-controlled clinical trials -- 2 that are ongoing -- specifically examine this issue: those conducted by Klempner and colleagues, Fallon and colleagues, and Cameron. Dr. Klempner's trial involved 4 weeks of IV ceftriaxone + 2 months of oral doxycycline. According to Dr. Cameron, this trial was closed before completion because no benefit was seen. Dr. Fallon's trial uses 10 weeks of IV ceftriaxone, and Dr. Cameron's trial uses 12 weeks of oral amoxicillin.

Other Concerns

Dr. Cameron believes the spinal tap is overused in the diagnosis of neurologic Lyme disease. His main criticism is that it is not a sensitive, objective test for encephalopathy, since pleocytosis is a rare finding. For example, in the study by Logigian and associates,[13] only 1 subject had pleocytosis, and only 1 patient had a CSF:serum antibody index greater than 1.

Dr. Cameron also believes that the guidelines for treatment of fibromyalgia need to be revised. Treatment currently consists of an antidepressant and an exercise routine. However, in a study by Dinerman and Steere,[14] only 6 of 15 patients showed some improvement using this regimen, and illness was resolved in only 1 of those patients after 2.5 years of treatment.


  1. Donta S. Reactivation of Lyme disease following Lyme OspA vaccine. Program and abstracts of the 14th International Scientific Conference on Lyme Disease and Other Tick-Borne Disorders; April 21-23, 2001; Hartford, Connecticut.
  2. Rahn DW. Lyme vaccine: issues and controversies. Infect Dis Clin North Am. 2001;15:171-187. Abstract available at: &db=PubMed&list_uids= 11301814&dopt=Abstract
  3. Poland GA, Jacobson RM. The prevention of Lyme disease with vaccine. Vaccine. 2001;19:2303-2308. Abstract available at: &db=PubMed&list_uids= 11257352&dopt=Abstract
  4. Livni E. Vaccine victims? The controversy surrounding SmithKline Beecham's LYMErix. Available at:
  5. Fawcett PT, Rose CD, Budd SM, et al. Effect of immunization with recombinant OspA on serologic tests for Lyme borreliosis. Clin Diagn Lab Immunol. 2001;8:79-84. Abstract available at: &db=PubMed&list_uids= 11139199&dopt=Abstract
  6. Croke CL, Munson EL, Lovrich SD, et al. Occurrence of severe destructive Lyme arthritis in hamsters vaccinated with outer surface protein A and challenged with Borrelia burgdorferi. Infect Immun. 2000;68:658-663. Available at: view=full&pmid=10639430
  7. Wormser GP, Nadelman RB, Dattwyler RJ, et al. Practice guidelines for the treatment of Lyme disease. The Infectious Diseases Society of America. Clin Infect Dis. 2000;31(suppl 1):1-14. Available at: 000342/000342.html
  8. Cameron DJ. 21st century Lyme disease. Program and abstracts of the 14th International Scientific Conference on Lyme Disease and Other Tick-Borne Disorders; April 21-23, 2001; Hartford, Connecticut.
  9. Logigian EL, Kaplan RF, Steere AC. Chronic neurologic manifestations of Lyme disease. N Engl J Med 1990;323:1438-1444.
  10. Oksi J, Nikoskelainen J, Viljanen MK. Comparison of oral cefixime and intravenous ceftriaxone followed by oral amoxicillin in disseminated Lyme borreliosis. Eur J Clin Microbiol Infect Dis. 1998;17:715-719. Available at: &db=PubMed&list_uids= 9865985&dopt=Abstract
  11. Shadick NA, Phillips CB, Logigian EL, et al. The long-term clinical outcomes of Lyme disease. A population-based retrospective cohort study. Ann Intern Med. 1994;121:560-567. Available at: &db=PubMed&list_uids= 8085687&dopt=Abstract
  12. Asch ES, Bujak DI, Weinstein A. Long term clinical outcomes of Lyme disease. Ann Intern Med. 1995 Jun 15;122(12):961.
  13. Logigian EL, Kaplan RF, Steere AC. Chronic neurologic manifestations of Lyme disease. N Engl J Med. 1990;323:1438-1444. Available at: &db=PubMed&list_uids= 2172819&dopt=Abstract.
  14. Dinerman H, Steere AC. Lyme disease associated with fibromyalgia. Ann Intern Med. 1992;117:281-285. Available at: &db=PubMed&list_uids= 1637022&dopt=Abstract

An Ounce of Prevention

Robert S. Mocharnuk, MD   Julie Rawlings, MPH   

It ought to be safe to take a walk in the woods. Can we return to such environments, without endangering ourselves? Two speakers at the 14th Lyme disease meeting focused on strategies for prevention of Lyme disease.

Dr. Edward Bosler[1] from the State University of New York at Stony Brook School of Medicine, discussed passive and active host-targeted abatement programs to remove potentially infective ticks from mice and other small mammals on which the ticks like to feed. Previous attempts to eradicate tick nymphs have been unsuccessful. A passive system designed to kill ticks by treating mice with pesticide-impregnated cotton balls resulted in no reduction in Borrelia burgdorferi infection rates (although Dr. Bosler noted that the treated mice appeared to be healthier and happier with their tick burdens removed!).

A Rube Goldbergesque contraption was devised to address the role played by larger mammals in maintaining both tick and spirochete life cycles. This device, activated by a trip pedal, sprayed raccoons, opossums, squirrels, chipmunks, and rats with pyrethrin and other pesticides. Although a dramatic reduction in tick infestations was demonstrated, approval to use this tool has not been granted by the Centers for Disease Control and Prevention (CDC). Instead, bait houses in which pesticide bait was consumed were approved. These devices proved to be most unsuccessful, due to the effects of human and raccoon vandalism and prolonged inclement weather. In spite of its unconventional design, Dr. Bosler is currently pleading for the CDC to reconsider and approve the mechanical sprayer.

A community-based strategy, focused on ways in which the public can prevent Lyme disease, was presented by Dr. Kirby Stafford III,[2] Director of the Connecticut Agricultural Experiment Station in New Haven. Campaigns have been moderately successful in getting individuals to use topical repellants, wear protective clothing, and check for ticks after going outside. Vaccination drives have been less successful. Residential tick control through landscape management -- involving leaf clearance and use of wood chips -- has proven to be effective, particularly when combined with pesticide use.

Both the CDC and the United States Department of Agriculture are also supporting community-based tick eradication programs. One such program, utilizing the fipronil bait box, was originally tested in Colorado and showed a 100% rodent tick eradication rate, with effects lasting for 7 weeks. Further testing with fipronil is ongoing throughout Connecticut. Another program, started in 1997 throughout 5 northeastern states, is known as "Target Lyme Disease." A 4-post device topically treats white-tailed deer in an effort to reduce tick infestation. To date, more than 90% of local deer have been exposed to the device. In Connecticut alone, tick populations have declined by more than 70% in the treatment areas, and the average number of ticks per deer has decreased from 34 to 3.5.


  1. Bosler EM. Host-targeted acaricidal treatments on rodents to control densities of Ixodes scapularis subadult ticks. Program and abstracts of the 14th International Scientific Conference on Lyme Disease and Other Tick-Borne Disorders; April 21-23, 2001; Hartford, Connecticut.
  2. Stafford K. Community programs: new technologies in tick control. Program and abstracts of the 14th International Scientific Conference on Lyme Disease and Other Tick-Borne Disorders; April 21-23, 2001; Hartford, Connecticut.

Suggested Reading

des Vignes F, Piesman J, Heffernan R, et al. Effect of tick removal on transmission of Borrelia burgdorferi and Ehrlichia phagocytophila by Ixodes scapularis nymphs. J Infect Dis. 2001;183:773-778. Available at: &db=PubMed&list_uids= 11181154&dopt=Abstract

Wang IN, Dykhuizen DE, Qiu W, et al. Genetic diversity of ospC in a local population of Borrelia burgdorferi sensu stricto. Genetics. 1999;151:15-30. Available at: full&pmid=9872945

Ijdo JW, Wu C, Magnarelli LA, Stafford KC 3rd, et al. Detection of Ehrlichia chaffeensis DNA in Amblyomma americanum ticks in Connecticut and Rhode Island. J Clin Microbiol. 2000 Dec;38(12):4655-6. &db=PubMed&list_uids= 11101616&dopt=Abstract

Stafford KC 3rd, Massung RF, Magnarelli LA, et al. Infection with agents of human granulocytic ehrlichiosis, Lyme disease, and babesiosis in wild white-footed mice (Peromyscus leucopus) in Connecticut. J Clin Microbiol. 1999 Sep;37(9):2887-92. &db=PubMed&list_uids= 10449470&dopt=Abstract

Fighting Back: How B burgdorferi Persists

Harry Goldhagen, MS   Julie Rawlings, MPH   

Persistence Is a Virtue

That spirochetes tend to persist in the human body has been demonstrated in both syphilis, caused by Treponema pallidum, and Lyme disease, caused by Borrelia burgdorferi. What accounts for this ability to evade or suppress an effective immune response? According to Charles Pavia, PhD,[1] of the New York College of Osteopathic Medicine, New York Institute of Technology, Old Westbury, New York, there are at least 6 potential explanations:

Immune Suppression

Is there evidence that any of these mechanisms allow B burgdorferi to persist in the human body? As of now, not much. However, there have been a few suggestive studies in animals that support immune suppression as a possible explanation. For instance, a study by Chiao and colleagues[2] showed that B burgdorferi is capable of suppressing the immune response. When sonicated Borrelia were added to lymphocytes, the ability of the lymphocytes to proliferate -- a measure of the immune system's ability to respond to an infectious challenge -- was inhibited.

A similar study by Giambartolomei and coworkers[3] showed that Borrelia can stimulate interleukin-10 (IL-10) production, a downregulator of the immune system. In this series of experiments, heat-killed B burgdorferi caused peripheral blood mononuclear cells of humans and rhesus monkeys to produce this cytokine. Another study, by Keane-Myers and Nickell,[4] found that B burgdorferi could suppress T-cell responses in mice, specifically T-helper cells.

Even the tick itself may play a role in immunosuppression. Urioste and colleagues[5] showed that the saliva of Ixodes dammini ticks contains an uncharacterized substance that can suppress the immune response, specifically suppressing lymphocyte proliferation and other markers of immune system activity.

Looking at the issue of immune suppression from the other side -- that is, by boosting the immune response with the use of cytokines -- Zeidner and colleagues[6] showed that tumor necrosis factor alpha (TNF-alpha), IL-2, and interferon-gamma could suppress B burgdorferi infection in mice.

By contrast, it appears that infection with B burgdorferi can also overstimulate the immune system, and this may explain many of the symptoms of both acute and chronic Lyme disease. For instance, Lim and colleagues[7] showed that CD4+ T cells play a role in the arthritis seen in the hamster model of Lyme disease.

Immune Evasion by Antigen Variation

A second mechanism that may be part of the B burgdorferi survival repertoire is evasion of the immune response. Antigenic variation[8] -- the periodic alteration of surface proteins resulting in the presentation of new antigens that the immune system has not seen before -- has been a successful strategy for tick-borne relapsing fever Borrelia, and it is possible that such a mechanism occurs in B burgdorferi as well.

Richard T. Marconi, PhD,[9,10] of the Medical College of Virginia at Virginia Commonwealth University, Richmond, has examined potential candidate proteins for antigenic variation in Lyme disease. The most likely candidate, based on his research, is outer surface protein E (OspE). The genes for these surface-exposed lipoproteins have 2 hypervariable domains (the variation is due to insertions and deletions in the gene) as well as repeat regions (which can lead to recombination with other genes, and thus new antigens). OspE variation has been shown to occur in vivo, at least in mice. A number of variants have been shown to be antigenically distinct and to arise at different times during infection.

By contrast, the OspF genes are stable; that is, they do not show the variability seen with OspE genes. However, different members of the OspF family are expressed at different times during infection, suggesting that this surface protein may also play a role in antigenic variation.

Other investigators have suggested that VlsE may be involved in immune evasion as well, since VlsE genes exhibit both variation and mutation during infection. However, Dr. Marconi's work suggests that the resulting VlsE are not antigenically distinct. In other words, even though the VlsE genes mutate during infection, the changes in the second or third generation VlsE proteins are not sufficient to evade the antibodies produced against the first generation of VlsE surface protein. Therefore, he believes it is unlikely VlsE plays a prominent role in immune evasion.

Under Stress

A different way for an organism to avoid being killed is to destroy the harmful compounds before they do their damage! For example, many bacterial species produce beta-lactamases. These enzymes degrade beta-lactam antibiotics before they block bacterial cell-wall synthesis.

It appears that B burgdorferi may have its own approach to fighting back. John T. Skare, PhD,[11] of Texas A&M University Health Science Center, College Station, examined one such battle tactic Borrelia use against humans: resisting oxidative stress. (Oxidative stress is the use of hydrogen peroxide, superoxide, and other active oxygen radicals to kill invading organisms.)

Dr. Skare's group has examined a gene called BB0647 to see what role it may play in resisting oxidative stress. Originally, this gene was thought to resemble a ferric uptake regulator, or Fur. Oddly enough, though, Borrelia don't require iron. This puzzling finding prompted Dr. Skare to search databases for genes that more closely resemble BB0647. He found that the most homologous gene is one that produces a peroxide regulatory protein, PerR. This protein controls the expression of catalases and peroxidases, enzymes that play a major role in defending cells against oxidative stress. To confirm these findings, Dr. Skare showed that B burgdorferi containing an active form of the BB0647 gene was indeed able to resist hydrogen peroxide, around 3000 times better than a strain containing a mutated form of the gene.

More Basic Science: All Coiled Up

How does B burgdorferi know when to express certain proteins? For instance, when B burgdorferi is inside ticks, at approximately 23°C, the surface of the spirochete is covered with OspA and OspB. But when the organism gets into mammals, at an average temperature of 35-37°C, OspC is the predominant surface antigen. So, does temperature affect gene expression?

Dr. Scott Samuels, PhD,[12] of the University of Montana, Missoula, presented some highly technical research on how the Lyme disease spirochete manages this transformation. The process appears to be mediated by supercoiling of DNA. (For a description and pictures of DNA supercoiling, see the handy Web site from the Mount Sinai School of Medicine.[13]) Supercoiled DNA can be visualized as a coiled phone cord; the more you twist it, the more tightly wrapped it becomes. Untwisting the DNA opens up the loops and coils.

It turns out that the degree of supercoiling is determined by the temperature: at the lower temperature of ticks, B burgdorferi DNA is more supercoiled, and the OspC gene is expressed at only a low level. By contrast, at the higher temperatures seen in mammals, DNA is less supercoiled, and the OspC gene is expressed at higher levels. The next step for Dr. Samuels' team is to determine what is affecting expression of the other 2 surface protein genes.


Borrelia have evolved in numerous ways to avoid the immune system. The better we can understand these molecular defense strategies, the sooner we can develop better approaches to diagnosis and treatment.


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  2. Chiao JW, Pavia C, Riley M, et al. Antigens of Lyme disease of spirochaete Borrelia burgdorferi inhibits antigen or mitogen-induced lymphocyte proliferation. FEMS Immunol Med Microbiol. 1994;8:151-155. Abstract available at: &db=PubMed&list_uids= 8173554&dopt=Abstract
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  8. Introduction to Antigenic Variation, from the Laboratory of Molecular Parasitology, The Rockefeller University. Available at:
  9. Marconi RT. Comparative analysis of the immune evasion systems employed by the Lyme disease spirochetes. Program and abstracts of the 14th International Scientific Conference on Lyme Disease and Other Tick-Borne Disorders; April 21-23, 2001; Hartford, Connecticut.
  10. Sung SY, McDowell JV, Carlyon JA, Marconi RT. Mutation and recombination in the upstream homology box-flanked OspE-related genes of the Lyme disease spirochetes result in the development of new antigenic variants during infection. Infect Immun. 2000;68:1319-1327. Available at: &pmid=10678944
  11. Skare J. How Borrelia burgdorferi responds to oxidative stress. Program and abstracts of the 14th International Scientific Conference on Lyme Disease and Other Tick-Borne Disorders; April 21-23, 2001; Hartford, Connecticut.
  12. Samuels S. Regulation of outer surface protein gene expression. Program and abstracts of the 14th International Scientific Conference on Lyme Disease and Other Tick-Borne Disorders; April 21-23, 2001; Hartford, Connecticut.
  13. Supercoiling, from the Department of Biomathematical Sciences, Mount Sinai School of Medicine. Available at:

Authors and Disclosures


Brian A. Fallon, MD, MPH, MEd

Director, Lyme Disease Program, NYS Psychiatric Institute. Dr. Fallon is Associate Professor of Clinical Psychiatry, Columbia University, New York City.

Disclosure: Brian A. Fallon, MD, receives clinical grant funding from National Institutes of Health.

Harry Goldhagen, MS

Managing Editor Medscape Infectious Diseases

Disclosure: Harry Goldhagen, MS, has no financial interest to disclose.

Robert S. Mocharnuk, MD

Clinical Instructor of Hematology, University of Southern California Keck School of Medicine, Los Angeles, California

Disclosure: Robert S. Mocharnuk, MD, has no financial interest to disclose.

Julie Rawlings, MPH

Director, Sections of Reporting and Surveillance and Vector-Borne Disease, Infectious Disease Epidemiology and Surveillance (IDEAS) Division, Texas Department of Health, Austin, Texas.

Disclosure: Julie Rawlings, MPH, has no financial interest to disclose.

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