LymeNet Newsletter Volume 1 Issue 19

Volume: 1
Issue: 19
Date: 12-Aug-93

Table of Contents:

Notes From The Sixth Annual Rheumatology Symposium on Lyme Disease Yale University

Newsletter:

***************************************************************************** * Lyme Disease Electronic Mail Network * * LymeNet Newsletter * ***************************************************************************** Volume 1 - Number 19 - 8/12/93

***** SPECIAL ISSUE ***** ***** NOTES FROM THE SIXTH ANNUAL RHEUMATOLOGY ***** ***** SYMPOSIUM ON LYME DISEASE *****

I. Introduction II. Special Section III. How to Subscribe, Contribute and Get Back Issues

I. ***** INTRODUCTION *****

In this issue, Frank Demarest offers us his notes from the 6th Annual Rheumatology Symposium on Lyme Disease, sponsored by the Yale University School of Medicine. As with Dr. Lloyd Miller's notes from the conference in Atlantic City, the notes are *not* abstracts written by the presenters. They represent notes taken by the attendees at the respective conferences. Special thanks to Frank for sharing his notes with us.

Warning: Some of the opinions presented in this issue are highly controversial and are by no means the final word on Lyme disease. Some individuals will be outraged at the declarations of certainty made my some physicians when unambiguous data is not present. If you are one of these individuals, please resist the urge to publicly shred this issue of the newsletter.

For example, one opinion leader declared that: You will never see a negative ELISA with a positive blot.

I had a negative ELISA and a "positive" Western Blot at Dr. Dattwyler's lab at SUNY Stony Brook.

Never say never.

-Marc.

II. ***** SPECIAL SECTION *****

Sender: Frank Demarest <[email protected]>

Notes and other information from: The Sixth Annual Rheumatology Symposium on Lyme Disease. Wednesday, June 16, 1993. Yale University School of Medicine, New Haven, CT.

Each item has the title of the presentation and the speaker's name. All the speakers are associated with Yale except as noted. The bracketed numbers refer to related articles in the proceedings, listed at the end. Text bracketed with {{ and }} are my own comments.

Disclaimer: These notes may contain errors, although I tried to accurately represent what was said. Extra care was taken with the statements shown as quotes. The opinions presented are those of the speakers.

Frank C. Demarest, July 1993. ------------------------------------------------------------

Opening remarks. Robert T. Schoen, MD.

About 160 people in attendance. Each presentation 15-20 minutes long. ------------------------------------------------------------

Lyme Disease Epidemiology. [1] Patricia Mshar (Connecticut State Dept of Health Services)

The incidence of LD in 1992 was 55 per 100,000, the highest rate for any state. The surveillance case definition is to establish uniform criteria for reporting, NOT as sole criteria for: clinical diagnosis, standard of care, guidelines for quality insurance, or reimbursement, or sole criteria for initiating a public health action.

Lyme surveillance started in CT in 1977. In 1992 they did active surveillance in the 12 towns around Lyme, and in Litchfield County (same areas studied in 1977). Passive surveillance is done through labs and health care providers. People less than 10 years old are at greatest risk. Most cases are infected during June, July, August. In 1991, 43% had EM, 57% no EM. Of those without EM: 22% met CDC case definition for late Lyme; 16% no clinical information given; 15% late Lyme, unknown serology; 5% late Lyme, negative serology; 39% no late manifestations, positive serology. Arthritis was the most frequent symptom of late Lyme with unknown or negative serology. The surveillance case definition and system has limitations. It is not sensitive enough to describe the clinical manifestations of the disease. The goal is to describe epidemiology by person, place, and time.

A case control study examined risk factors for LD, "persons with EM were more likely to live in a rural area and to have found ticks on their pets. No other variables, including those found to be risk factors in other studies, were significant. Protective measures that did not contribute significantly to the model included: wearing long pants, use of repellent sprays, and checking for ticks."

A study in 1991-1992 (also published in MMWR) found that only 7% of physicians from four specialties (general/family practice, internal medicine, pediatrics, and dermatology) reported LD. This suggests that either most physicians don't diagnose LD or that underreporting is common. ------------------------------------------------------------

Ecological Risk Factors in Lyme Disease. [2,3] Sam Telford, MD. (Harvard)

Studies were done in the Nantucket, Martha's Vineyard, Elizabeth Islands, Cape Cod area of Massachusetts. Number of deer in the area is related to risk of LD. Babesiosis is an emerging disease in RI and southeastern CT, also carried by the same ticks (about 40% of LD).

The population of the larval stage of the tick peaks in July-Sept., and the nymph stage peaks in May-July, showing that the larva survives nearly a full year on a single feeding. The larva normally detaches in 2-3 days in the late afternoon, in the mouse nest. The adult usually feeds in the late fall and lays eggs in about June which hatch in July. Total life cycle may be 3 or 4 years. The nymph population peak is at the same time that people come to the island for the summer. Based on the life cycle and time of infection, the nymph (size of a sesame seed, usually not noticed) is most often the carrier to humans, although the adult (size of an apple seed, usually noticed) has twice the rate of infection.

Reducing the number of deer reduces the number of ticks. Each adult tick lays 1500-2000 eggs, each deer may have 100-1000 ticks. Ticks are sensitive to drying out, require humidity > 90%. Mice in areas with woody stems had more ticks than mice in areas with grass. Piles of brush and woods between yards increase deer, mouse, and tick populations.

Doing tick drags over 10-meter sections, it was found that areas of infestation occur in clumps, half the drags gave nothing, some had as many as ten ticks. Not all clumps are infective. Half the clumps are not infected, others clumps range from 20% to 100% infection. In one example an average of 16% of the ticks were infected, but almost 50% of the clumps had some infected ticks, half the ticks in each infected clump was infected. Not all animals can act as reservoir hosts, lizards cannot infect ticks, incompetent hosts can reduce the number of infected clumps.

The concept of enzootic overflow was presented, where there are more ticks than the host population can support. This increases the chances of people being infected.

{{ He referred to Ixodes dammini as a distinct species of tick that they first discovered on Nantucket. This has recently been found to be the same as Ixodes scapularis.}} ------------------------------------------------------------

Tick bites; Prevention and Prophylaxis. [4] Eugene D. Shapiro, MD.

The risk of a tick bite is related to the proportion of infected ticks and the duration of attachment. The risk is substantial if a nymph has been attached 36-48 hours, or an adult has been attached 48-72 hours. A clinical trial was done treating tick bites with either amoxicillin (250mg TID) or a placebo for 10 days. In the area of the study, 4% of larva, 12% of nymphs, and 28% of adult ticks were infected. Active surveillance was done for 1 year. The risk of infection was determined to be 1.2% for a placebo, or 0% for amoxicillin. Conclusion is that risk "is so low that prophylactic antimicrobial treatment is not routinely indicated."

{{ A question was asked if tick removal technique affects risk, the reply was no, unless you have an opening in the skin, but did not address risk if the tick is squeezed while still attached. Dr. Telford recommends treatment if the tick has been attached more than 48 hours. (The LDF recommends treatment in all cases.) }} ------------------------------------------------------------

Differential Diagnosis of Erythema Migrans. [5] Irwin Braverman, MD.

A presentation of slides showing many variations of ECM. ECM is slowly expanding, usually leaving a clear center. The edge is usually elevated due to edema, does not have a solid feel. There may be concentric rings, may be necrosis in center, may look like cellulitis.

Other rashes that may look like ECM are: erythema annularis centripitum (looks similar but may persist for many months), ringworm, granulum annularis, subacute cutaneous lupus erythematosus (large lesions), erythema pershing, or erythema marginatum. ------------------------------------------------------------

Lyme Carditis. [6] Janine Evans, MD.

Lyme carditis is relatively uncommon, reported in about 8% of those untreated. It is less common now due to early treatment. LD can cause heart block (1st degree to complete, may fluctuate), myocarditis, pericarditis, dilated cardiomyopathy (in Europe), and ventricular tachycardia. Typically are self-limiting and resolve in several weeks, even without antibiotics. Seven cases were summarized, 2 recalled a tick bite, 3 had an EM rash. Many had other symptoms first, fatigue, palpitations, shortness of breath, headache, fever, arthralgias. One patient was seronegative, then seroconverted. All improved within 48 hours on treatment. Conclusion that Lyme Carditis is a significant problem, with a dramatic presentation, expect complete resolution with rarely long term sequelae. ------------------------------------------------------------

Evaluation of Neurologic Manifestations of Lyme Disease. [7] Thomas N. Byrne, MD.

Lyme disease is a clinical diagnosis, with supporting laboratory data. Often anxiety contributes to depression, mood disturbances, and memory problems. Early disease, within a month or so after EM, may have pain, headache, symptoms of meningitis. Bell's palsy (7th nerve) is most common, meningitis sometimes seen, also radiculoneuritis. Pleocytosis common, glucose usually normal, protein usually elevated, all 12 bands frequently present. Spinal fluid is not important in diagnosis of peripheral neuropathy. Neuropsychological testing is difficult to interpret.

{{Much of this material was from L. Reik's book "Lyme Disease and the Nervous System" (1991). He also referred to a paper in JAMA in spring 1992 (Luft), 1990 NEJM paper on chronic neurological manifestations (Logigian), and Jan. 1993 paper in Neurology. }} ------------------------------------------------------------

Lyme Arthritis. [8] Robert T. Schoen, MD.

Diagnosis uses recognition of clinical features. Knee involvement common, both here and in Europe. Reviewed old studies of cases before antibiotics were used. Most have EM, exposure in geographic area, onset of symptoms in characteristic time of year. Most patients (> 95%) are ELISA positive by the time they have arthritis. Difference between mild and severe cases may involve both the infection and host immunogenetic response. Organism disseminates widely, and to certain preferential sites. Severity of onset of disease correlates with later arthritis. Host antibody response increases with time. HLA-DR4 and HLA-DR2 seen in patients with chronic arthritis. Failures of antibiotic therapy in late Lyme disease may underlie an immunogenetic susceptibility on the part of the host. "When you evaluate treatment protocols and success rates in treatment of Lyme Disease, particularly late Lyme disease, you need to consider ... whether you're getting a sampling that is biased by refractory cases." Reported on study
of 50 patients, 80% arthritis and 20% neurological problems, who had 2 or 4 weeks of ceftriaxone, success at completion of treatment about 50%, 6 month follow-up showed 85% success rate. Success of 2 and 4 week therapy about the same. Suggests 2-4 week treatment, then watching for several months. Oral treatment for mild arthritis and children, parenteral therapy for severe arthritis. There is no "head-to-head" comparison of oral versus intravenous therapy. A few refractory cases were discussed.

{{ He seems more concerned with absolute certainty in diagnosing and treating the average case than with the seronegative or difficult cases. }} ------------------------------------------------------------

Laboratory Testing in Lyme Disease. Mark Mamula, Ph.D.

Connecticut has 10% of the US total cases of LD. Testing relies either on detecting the Borrelia burgdorferi organism (culture - not easy; or PCR), or detecting the immune response (serum antibody response - IIF, ELISA; WB; or T-cells - for late disease or serologically negative). Antibody response has early IgM and later IgG response. Factors that influence test accuracy are timing (too early), quality assurance of test, syphilis, relapsing fever, and rheumatoid factor. They have developed a more sensitive and specific test using the P39 with ELISA. One study found 6% of ELISA negatives were positive for P39. This test also has promise for earlier detection of Lyme disease.

LD diagnosis is both a clinical an laboratory one. Single positive ELISA may be good enough with clear clinical criteria. With ambiguous clinical criteria, use both ELISA and Western blot. If the Western blot has only a positive 41kD band (not specific), then use the P39 ELISA.

Three years ago they did a comparison among Yale, Tufts, and U of Minnesota, and found 96% (IgM) to 100% (IgG) correlation of negative results, and 73% (IgM) to 78% (IgG) correlation of positive results.

{{ 78% correlation is no comfort if you are among those going undiagnosed. They seem more concerned with false positives than false negatives.}} ------------------------------------------------------------

Differential Diagnosis of Late Lyme Disease. [9,10] Leonard Sigal, MD. (Robert Wood Johnson University Hospital, New Brunswick, NJ)

Early disseminated neurologic disease occurs weeks to months into the infection. Children more often develop meningitis, and adults more often develop radiculoneuritis. "Tertiary neuroborreliosis can be differentiated from the early disseminated neurologic disease by the fact that it is later, very frequently in association with inflammatory joint disease, but quite frequently it will be on its own, and sometimes it will be the very first manifestation of Lyme disease." The IgG and IgM responses may be delayed. The IgG and IgM responses may be suppressed, the potential for seronegative Lyme exists but is "a very, very, uncommon phenomenon".

Immunoglobulin level may stay elevated despite adequate therapy. Chronic inflammatory disease can cause false positives in ELISA but not Western Blot. Use a lab doing clinical research in Lyme disease for best results. A major problem is overdiagnosis. Lyme is often an incorrect diagnosis in pediatric and adolescent fibromyalgia (Paper in Pediatrics, Oct. 1992).

Treat fibromyalgia with tricyclic antidepressants at bedtime, and exercise. There is a paper to be published in the Annals of Internal Medicine. Another study of 77 patients with fibromyalgia, mostly female, found 43 had prior Lyme, 25 not Lyme, and 9 Lyme. Using estimates for overdiagnosis of Lyme disease, and extrapolating, the cost to find and cure one case of Lyme disease in Montana, where Lyme is uncommon, will be approximately twenty million dollars.

{{Dr. Sigal often mixes his opinions with his data. He made several interesting comments during this presentation:}}

"People in practice in New Jersey, certainly not Connecticut but in New Jersey anyway will wind up drawing test after test after test to see whether or not the person is cured. The patient is asymptomatic but is still seropositive and so obviously we treat patients and not blood tests."

In "a university laboratory much more care is taken and certainly if you have a question about the results the likelihood is that you are going to get somebody who probably knows something about Lyme disease as opposed to a technician who barely knows how to spell the thing."

"Kids who have been treated and treated and treated and treated a mean of 1.8 times per patient have been tested and tested and tested and tested I believe the mean is 2.4 tests per patient. ... 40% of these kids describe a major disruption in their lives due to their chronic illness. No one's going to school, home tutoring, which is by the way destroying the budgets of the boards of education of a variety of counties of central and southern New Jersey. Some of these kids have been out of school for as long as two years now. Psychological stresses were found in 30% of these children, divorces, child abuse, sexual abuse, major arguments with parents, that sort of thing. Prior tick bite was relatively uncommon." ------------------------------------------------------------

Case Presentation. Robert T. Schoen, MD.

The case presented was a 43 year old male in Stamford, CT. This case was picked as an example of a real diagnosis that had "shades of gray".

4/90 Multiple deer tick bites, physician documented EM, treated with amoxicillin, improved.

5/90 Recurrence of EM, treated with doxycycline for 28 days.

6/90 While on doxycycline, developed stiff right shoulder.

6/90-7/90 ceftriaxone, 6 weeks, 2g BID. Developed more significant arthritis of hands, shoulders, neck, and knees. Symptoms fairly symmetric. Patient believed increased symptoms related to treatment.

7/90-6/91 Full symmetrical polyarthritis with morning stiffness. RF negative, ANA negative, HLA-B27 negative, Lyme titer 1:1280, 5 bands on western blot. Received 2 more courses of IV antibiotics, both approx. 4 weeks ceftriaxone.

6/91-1/92 Because of lack of response to treatment, and pattern of symmetric polyarthritis, decided that it was seronegative rheumatoid arthritis. Started on therapy for arthritis.

4/92 Arthritis flared, IV corticosteroids for arthritis - little improvement.

4/92-3/93 Continued joint problems. Headaches, impaired concentration, fatigue, depression.

3/93 Lumbar puncture, protein 9.5, 6 mononuclear cells, 41 red cells, 8 bands on western blot.

Patient has been out of work most of this time. Discussion followed. Dr. Schoen asked for a show of hands:

Not Lyme in CNS? - A few people. Definitely Lyme in CNS? - A few people. Might be Lyme in CNS? - Most people. Treat it? - Most people.

Then we heard a short report from the patient's doctor. They chose to start IV penicillin. After 6 weeks, patient was marginally improved, Lyme serologies have fallen, and Western blot is now negative.

{{ This is a good example of how serious Lyme disease can be, even with prompt treatment. I would consider a case like this a red flag, rather than a "gray area". The "experts" should be researching better treatment of cases like this, rather than complaining about overdiagnosis. }} ------------------------------------------------------------

A short mention was made, and a slide was shown, of an advertisement in a local newspaper to call 1-800-TICK-BITE if you think you may have Lyme disease. The ad was from an infusion company. It was viewed simply as the infusion company's attempt to increase business. ------------------------------------------------------------

Panel Discussion (Answers from various doctors.)

Comments: You will never see a negative ELISA with a positive blot.

Q: Is 28 days of treatment enough? A: It is 90-95% effective for early Lyme. If there are secondary lesions, then it is a later stage.

Q: What do you do if you keep treating and have several consecutive treatment failures?

A: Then it is either not Lyme disease, or the symptoms may be slow to go, sometimes months are required. Neuropsychological testing for some cases to reduce subjective complaints.

Q: (inaudible) A: For early disseminated disease, 10 days is too short, 21 is needed, and continue for at least a week after patient is feeling okay. Probenecid is not used any more, not very helpful and increases possibility of allergy to antibiotics. ------------------------------------------------------------

Polymerase Chain Reaction. Stephen E. Malawista, MD.

The urine antigen test was never validated and is not useful. The PCR test can detect the DNA of the spirochete. It was first used to test ticks from museums. There was a brief description of the amplification process, which can amplify a single piece of genetic material several million or trillion times, in 30 to 45 doublings. Contamination is a problem, because the large amount of multiplied DNA in the lab can produce all positive or false positive results. They use isopsoralen which is activated by UV light after the processing and binds with the amplified DNA so it cannot be multiplied anymore. They prefer working with spinal fluid or synovial fluid, urine is more difficult to get right. They would be happy to receive samples for testing. ------------------------------------------------------------

Lyme Disease Vaccine. [11] Erol Fikrig, MD.

The reasons for a Lyme vaccine are that there are some refractory cases, the EM rash is not always present, and the tick bite is sometimes missed. OSPA antibodies can protect against 10,000 spirochetes, OSPB antibodies can only protect against 100. OSPC antibodies can offer some protection. Bb can survive in the presence of neutralizing antibodies, both in vitro and in vivo. There are different strains of Bb, protection against one may not protect against others. They have developed both OSPA and OSPB vaccines which appear to work, even with wild ticks. The vaccine also appears to kill the spirochetes in infected ticks that feed on vaccinated mice. ------------------------------------------------------------

Lyme Disease Animal Model. [12] Stephen W. Barthold, DVM, Ph.D.

They did experiments with a type of mouse (C3H) that develops visible leg swelling after infection. After infection with either a syringe or a tick, the mouse develops symptoms of disseminated disease in 5 days. In 15 to 30 days, the disease is at its peak, with polysynovitis, carditis, and vasculitis. At 90 days, the disease goes into regression. At 180 to 360 days, there is exacerbation, then persistent infection. Many spirochetes in early acute stage of disease. Smaller number of organisms in late disease. The antibodies rise after 180 days. The antibodies in the serum of a chronically infected mouse will protect another mouse, but are apparently not sufficient to clear the disease. Serum antibodies given another mouse 24 hours after infection offer no protection. ------------------------------------------------------------

Pathogenesis of Lyme Disease. [13] Leonard Sigal, MD. (Robert Wood Johnson University Hospital, New Brunswick, NJ)

This discussed possible autoimmune reactions that cause symptoms not directly caused by the Borrelia burgdorferi.

Bb is alive at the site of inflammation, induces septic process, cytokine production.

Persisting antigen, organism may be dead. Antigen induced arthritis. Immune complex formation. Vasculitis.

Molecular mimicry, organism may be absent. Component of microorganism resembles human tissue. Immune response causes human tissue damage. May also occur in Lyme neurologic disease. ------------------------------------------------------------

Panel Discussion:

Borrelia does not destroy tissue with septic process, it is a very good antigen. That is why Lyme treatment with corticosteroids worked before antibiotics were used. Much of disease is not because of lots of organisms, but because they are very good antigens. ------------------------------------------------------------

{{ It is interesting to note that little or no useful information was presented on seronegative Lyme disease, ophthalmologic problems, persistent infection, or Lyme during pregnancy. }} ------------------------------------------------------------

1. "Lyme disease in Connecticut"; Matthew Cartter, MD; State of Connecticut Department of Health Services.

2. "Clustering of host-seeking nymphal deer ticks (Ixodes dammini) infected by Lyme disease spirochetes (Borrelia burgdorferi"; SR Telford III, SS Urioste, & A Spielman; Am J Trop Med Hyg, 47(1), 1992, pp 55-60.

3. "Deer reduction & control of Ixodes dammini populations"; SR Telford; Ecology & Environmental Management of Lyme Disease ed. H. Ginsberg. Rutgers U. Press, 1993 In press.

4. "A controlled trial of antimicrobial prophylaxis for Lyme disease after deer-tick bites"; ED Shapiro MD, MA Gerber MD, NB Holabird LPN BS, AT Berg PhD, HM Feder Jr MD, GL Bell BLT, PN Rys MS, DH Persing MD PhD; N Engl J Med 1992; 327:1769-73.

5. "Diagnosis of Lyme disease based on dermatologic manifestations"; MS Malane MD, JM Grant-Kels MD, HM Feder Jr MD, SW Luger MD; Annals of Internal Medicine 1991:114:490-498.

6. "Lyme Carditis"; J Evans, L Rosenfeld, RT Schoen.

7. "Neurological involvement in Lyme disease"; TN Byrne MD.

8. "Epidemiology, clinical features, and diagnosis of Lyme disease"; JD Cooper MD, RT Schoen MD; Current Opinion in Rheumatology 1992, 4:520-528.

9. "Lyme disease: Recommendations for diagnosis and treatment"; DW Rahn MD, SE Malawista MD.; Annals of Internal Medicine 1991; 114:472-481.

10. "Lyme disease: testing and treatment"; LH Sigal MD; Rheumatic disease clinics of North America; V19 N1 Feb 1993 pp 79-93.

11. "A recombinant vaccine for Lyme disease"; E Fikrig, SW Barthold, JE Sears, SR Telford III, A Spielman, FS Kantor, RA Flavell; Lyme Disease: Molecular and Immunologic Approaches; Cold Spring Harbor Laboratory Press.

12. "Lyme Borreliosis in the laboratory mouse"; SW Barthold, M de Souza, E Fikrig, DH Persing; Lyme Disease: Molecular and Immunologic Approaches; Cold Spring Harbor Laboratory Press.

13. "Possible autoimmune mechanisms in Lyme disease"; LH Sigal; Lyme Disease: Molecular and Immunologic Approaches; Cold Spring Harbor Laboratory Press.

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