Volume: 2 Table of Contents: I. LYMENET: 1994 LDF Conference Notes by Lloyd Miller, DVM II. Q&A: Raised Rash? (Q) III. Q&A: Raised Rash? (A) IV. Q&A: Lyme Transmittal Time (Q) V. Q&A: Lyme Transmittal Time (A) VI. How to Subscribe, Contribute, and Get Back Issues Newsletter: *********************************************************************** * The National Lyme Disease Network * * LymeNet Newsletter * *********************************************************************** IDX# Volume 2 - Number 09 - 6/10/94 IDX# INDEX IDX# IDX# I. LYMENET: 1994 LDF Conference Notes by Lloyd Miller, DVM IDX# II. Q&A: Raised Rash? (Q) IDX# III. Q&A: Raised Rash? (A) IDX# IV. Q&A: Lyme Transmittal Time (Q) IDX# V. Q&A: Lyme Transmittal Time (A) IDX# VI. How to Subscribe, Contribute, and Get Back Issues IDX# QUOTE OF THE WEEK: "Lyme disease is a clinical diagnosis... until you make it." -- Edwin Masters, M.D. I. LYMENET: 1994 LDF Conference Notes by Lloyd Miller, DVM ------------------------------------------------------------- Sender: Lloyd E. Miller, DVM <[email protected]> Notes from the Lyme Disease State of the Art Conference held in Stamford, CT on April 22-23, 1994. Every effort has been made to present accurate information. Corrections and/or additions will be gladly accepted. The primary focus of the conference was the neurologic manifestations of Lyme disease. It is apparent that neurologic manifestations are far more common than was thought several years ago. The discussions and presentations primarily dealt with the diagnosis, pathogenesis, symptoms, and Rx of neurologic LD. The following conventions are used throughout the notes: Bb = Borrelia burgdorferi ; LD = Lyme disease; CNS = central nervous system; CSF = cerebrospinal fluid ; PCR = polymerase chain reaction; Rx = treatment; * = brand name drug. It was my impression from listening to Dr. Edwin Masters (Cape Girardeau, MI) that his efforts to identify the Lyme-like illness he has been describing in Missouri will turn out to be LD caused by different strain of Bb. This, if it turns out to be the case, will prove to be very important because it will show that there are definitely different strains of Bb in different geographic areas within the United States. Dr. Patricia Coyle (SUNY, Stony Brook, NY) pointed out that the nervous system is definitely a target of Bb. The symptoms may occur early or late in the course of disease and are referable to both the central and peripheral nervous systems. She emphasized that the full spectrum of the neurologic manifestations have not yet been described. Neurologic effects include meningitis, Bell's palsy, radiculoneuritis, encephalopathy, peripheral neuropathy, encephalomyelitis, cerebrovascular disease, intracranial hypertension, psychiatric disturbances, neuromuscular disease, dementia, chronic fatigue and fibromyalgia. She made the point that in her experience 40% of symptomatic patients have neurologic symptoms. Whether all the nervous system effects are due to infection or "post-Lyme syndrome" is yet to be determined. Dr. Coyle through her studies and using several experimental tests is trying to clarify this situation. She made the important point that normal CSF does not rule out the diagnosis of LD. She made several comments about some of the research tests now available: CSF culture: It takes weeks and has a very low yield (about 7%) OspA detection in CSF: It proves antigen is present but does not prove Bb viability; is less sensitive than PCR; is negative several months following successful Rx; is a good test to run along with PCR - complement each other. PCR testing of CSF: It is very sensitive; specificity depends on primers used; does not indicate Bb viability (others feel it does); it is not known how long it remains positive following successful Rx. Immune complex detection in CSF: It is Bb specific; is a marker of active CNS disease - appears to indicate active CNS infection but may not necessarily; (note the distinction made between CNS disease and infection). Interleukin 1B detection in CSF: It may increase in LD. It is my impression that Dr. Coyle's research studies, when completed, will add significantly to what we know about neurologic LD. There were several excellent presentations about the neuropsychiatric manifestations of LD. The question still remains as to how much of the depression seen in LD is due to infection and how much to other factors. However, the discussions certainly made it sound like the significant factor was Bb infection. It was said that tricyclic antidepressants often aggravated the depression. It can take 4-8 weeks for Prozac* to produce a response. Response to Zoloft* and Paxil* can be seen in 1-2 weeks and were recommended as worth trying. Start with the dose recommended for the elderly and gradually increase if no response is seen. It was suggested that Desyrel* be tried for insomnia. Some patients may need psychomotor stimulation (especially apathetic patients). Ritalin* was specifically recommended in this instance. Some doctors use low dose tricyclics for pain relief and combine with Zoloft* or Paxil* for depression. Confirmatory information about the cognitive difficulties encountered in LD was presented. The severity of the impairment fluctuates day-to-day (even within the day) and week-to-week. This fluctuation seems to be a specific characteristic of the cognitive disturbance in LD and not generally observed in other chronic diseases according to Dr. Marian Rissenberg (Mt. Kisko, NY). Examples given included the inability to start projects, difficulty doing two things at once, difficulty in organizing thoughts and tasks, speech difficulties, getting lost going places, concentration problems, memory loss, confusion, personality changes, decreased initiative, and irritability. In cognitive testing defects are seen across all tested parameters. Treatment requires cognitive remediation teaching techniques. The neuropsychiatric effects of LD were discussed. Aggravated depression is often seen in patients. Psychiatric symptoms can be the sole presenting symptom. Some patients with psychiatric symptoms and negative Lyme tests will be unresponsive to psychiatric drugs but will respond to antibiotic therapy. Dr. Brian Fallon (Columbia University / NYS Psychiatric Institute) reported that neuropsychiatric impairment is usually mild; however, dementia-like symptoms do occur. Psychiatric problems associated with LD include depression, panic disorder, bipolar disorder, paranoia, schizophrenia, anorexia nervosa, obsessive compulsive disorder and, in children, attention deficit disorder. Depression occurs in up to 66% of LD patients. Like other symptoms, psychiatric symptoms can relapse following antibiotic Rx. The reader is referred to the following two references for excellent discussions on the neuropsychiatric aspects of LD. 1. Fallon BA, Nields JA et al: The neuropsychiatric manifestations of Lyme borreliosis. Psychiatric Quarterly 1992;63(1):95-117. 2. Fallon B, Nields J et al: Psychiatric Manifestations of Lyme Borreliosis. J Clin Psychiatry 1993;54(7):263-68. Dr. Claude Garon (NIH Rocky Mountain Labs) remade the point made at last year's conference that very few Bb sequestered in parts of the body produce an enormous amount of extracellular material which is probably responsible for many of the symptoms of LD. This material binds IgM and may be a mechanism by which Bb can evade the immune system. The material contains a strong B-cell mitogen which can produce autoimmune effects. It is his feeling that this material will prove to be very important in diagnosing LD and in the pathogenesis of LD. Dr. Scott Samuels (NIH Rocky Mountain Labs) has shown that Bb can develop antibiotic resistance through single point mutation in the DNA gyrase B gene. Certain populations of Bb produce resistant varieties. Few mutations develop. All mutants are susceptible to other antibiotics. This finding is significant in that this phenomenon could explain why patients initially respond to an antibiotic, but then eventually relapse while on the antibiotic and then respond when a second antibiotic is administered only to have the same thing happen. Unfortunately the research has not been carried through several Bb antibiotic resistant generations against multiple antibiotics to see if this could be the explanation. Other possible reasons for bacterial antibiotic resistance were enumerated during the conference. These included: 1. The organism's ability to keep antibiotics from entering its cells 2. The organism pumping the antibiotic back out once it enters 3. The destruction of the organism by the antibiotic 4. The changing of the antibiotic target location, rendering the antibiotic ineffective. Information was presented that vaccination of previously infected individuals may not protect against subsequent reinfection. Bb adapts in tissue to resist OspA antibody. Late stage Lyme patients have an anti-OspA effect and therefore may destroy the vaccine recombinant OspA. An OspA vaccine would probably not be effective in eliminating already established Bb. Information presented demonstrated that Bb antigen can induce various degrees of suppression of lymphocyte response to mitogens and antigens. This suggests that immune modulation may play a role in the pathogenesis of LD. This response could help explain how a person can be reinfected and why a second infection can be more serious than the initial infection. Dr. Ron Schell (University of Wisconsin) presented information about whole cell vaccine reactions. Hamsters were vaccinated with a whole- cell preparation of formalin-inactivated Bb sensu stricto isolate C-1-11 in adjuvant. A severe destructive arthritis was readily evoked in vaccinated hamsters challenged with the homologous Bb sensu stricto isolate C-1-11 before high levels of protective borreliacidal antibody developed. Once high levels of C-1-11 borreliacidal antibody developed, hamsters were protected from homologous challenge and the development of arthritis. Vaccinated hamsters, however, still developed severe destructive arthritis when challenged with other isolates of the three genomic groups of Bb sensu lato (Bb sensu stricto isolate 297, B. garinii isolate LV4 and B. afzelii isolate BV1), despite high levels of C-1-11 specific borreliacidal antibody. The induction of the destructive arthritis requires the vaccine to contain whole spirochetes in adjuvant but was not dependent on the isolate of Bb sensu lato or the type of adjuvant. These studies demonstrate that caution is necessary when employing whole spirochetes in adjuvant for vaccination to prevent Lyme borreliosis. Additional studies are needed to identify the antigen(s) responsible for the induction and activation of arthritis and to define the immune mechanisms involved. The hamsters were immunocompetent. The vaccine did not protect against challenge with the homologous strain for 3 to 5 weeks following administration. It was during this period that challenge with homologous strain of Bb produced the arthritis. Following this period challenge with the homologous strain did not result in arthritis but did develop when challenged with other strains. Studies done showed the arthritis was not due to immune complexes, strain of Bb, adjuvant used, or inactivating agent. The author made the point that this reaction may be species specific to hamsters. The same response is not seen in mice. This type of reaction has not been reported in dogs. The author made the point that whole cell vaccines present some risks not yet fully determined and recommended that subunit vaccines also be tested to see if the same type reaction might occur with them. Dr. Mario Phillip (Tulane Regional Primate Research Center) reported on LD research in primates. Five rhesus macaques were infected with Bb by Ixodes scapularis bite. The following abnormalities were reported. All five developed chronic arthritis especially in the knee and elbow. Very interesting was the observation that although there were very significant histopathologic lesions in all five monkeys only one had swollen joints. Lesions demonstrated, although not necessarily in all monkeys, were articular cartilage necrosis, degenerative arthropathy, synovial cell hyperplasia, and mononuclear infiltrates. Significant nerve tissue pathology was found and included nerve sheath fibrosis, demyelination of peripheral nerves and spinal cord. Findings in other organ systems included focal myocarditis, perivascular lymphocytic infiltrates in muscle, lung and kidneys. Bb was localized in periarticular and nerve tissue. An interesting finding was that the animal showing the most severe peripheral neuropathy also showed the highest level of circulation immune complexes. The disease in the rhesus monkey is similar to the human disease in both early and late phases. Therefore the study of LD in the monkey should provide very important information concerning LD in people. It was reported by both Dr. Daniel Cameron (Mt. Kisko, NY) and Dr. Philip Paparone (Absecon, NJ) that LD in patients over 65 years of age does not appear to differ from LD in younger patients. Dr. Derrick DeSilva Jr., (Edison, NJ) reported on the finding of Bb in the breast milk of three nursing mothers and suggested that until the significance of this finding is more fully studied that patients with LD not breast feed their babies. He is following the babies of these mothers to see if any evidence of infection occurs. Others in attendance felt that Bb would be destroyed by gastric acid and poses no threat. It was pointed out that no cases of orally contracted LD are reported. Dr. Sam Donta (Boston University Medical Center) presented some new treatment ideas. He made the point that Rx should take into account the possible intracellular localization of Bb which he feels even occurs in nerve tissue. He stated that LD especially affects the sensory nervous system. He also pointed out that Bb goes into periods of latency as do other disease producing spirochetes. Macrolide antibiotics access intracellular locations and require a neutral Ph. He commented that it is possible for Bb to reside within its own compartment within a cell and that it could produce an acid environment which would render the macrolide antibiotic ineffective. He suggested combining macrolide (clarithromycin or azithromycin) with hydroxychloroquine (Plaquenil* 200mg twice daily). Hydroxychloroquine has several side effects that some patients can't tolerate. He reported he has had several patients do well on the combination but that some patients do relapse. Another combination suggested was tetracycline (1.5gm/day - some patients can't tolerate this dose) with ceftriaxone (2gm/day). He also reported successful treatment of several patients with this combination but that not all patients responded. He suggested that gamma interferon should be included in some treatment trials. He suggested as others have that treatment duration is more important than treatment intensity and that pulse therapy or taking medication two to three time per week may be effective over the long course of treatment. =====*===== II. Q&A: Raised Rash? (Q) ------------------------------------------- Sender: Marc A. Calabrese <[email protected]> Can an infected tick bite result in a raised bump in the area of the bite without the bullseye? If so, for how long? =====*===== III. Q&A: Raised Rash? (A) --------------------------------------------- Sender: John Setel O'Donnell <[email protected]> Often there's a prompt inflammatory response to the tick bite itself, a papule with some swelling, redness, warmth, and discomfort. This is unrelated to Borrelial infection; it's a response to tick antigens (what ticks do with their bodily wastes while feeding is unspeakable). There's some time delay before the EM rash appears. The incubation period (time interval between tick bite and onset of the erythema migrans) varies between about 3 days and 4 months, but is commonly 1-2 weeks. It's generally painless and nonpruritic but can be slightly raised from the surrounding skin. Weber and Neubert report 44% of patients had no symptoms other than redness; 33% had pruritus; 26% had pain or heat. 25% of patients had one or more lesions in the rash with ulceration, scaliness, blistering, or bleeding. The outer border of the rash is usually sharply demarcated and with a slightly irregular outline. The rash often advances outward and clears from the center, leaving the classic ring or "bullseye". Rashes occur most commonly on the legs, but anywhere on the body is possible; ticks like warm, moist areas, and usually the first rash appears at the bite site. - Summarized from Weber, Neubert, and Buchner, "Erythema Migrans and Early Signs and Symptoms", in _Aspects of Lyme Borreliosis_, Weber and Burgdorfer, ed., Springer-Verlag, 1993. =====*===== IV. Q&A: Lyme Transmittal Time (Q) ----------------------------------------- Sender: William Austin <[email protected]> How long, after an infected tick attaches to a person, does it take to transmit the Lyme disease producing, bacteria? Does this time differ for different types of ticks? Finally, are there other factors that determine disease transmittal time? =====*===== V. Q&A: Lyme Transmittal Time (A) ------------------------------------ Sender: Carl Brenner <[email protected]> The general consensus appears to be that an Ixodes tick has to be attached for about 48 hours before disease transmission can occur. There are a couple of factors that may facilitate faster transmission, however. If a tick is removed traumatically from a host, care must be taken to avoid squeezing the body of the tick, because such action can force spirochetes up from the tick's gut through its salivary glands and into the host. Also, recent research [1] has indicated that partially fed ticks that are removed from their hosts because of grooming or certain host-related immunologic factors can transmit a recently acquired infection much more quickly. The overwhelming majority of ticks that transmit B. burgdorferi to mammals, birds and reptiles are from the Ixodes genus, so transmission rates haven't been studied in depth in other ticks. I am not aware of any differences in transmission speed among the various Ixodes species. 1] Shih C-M, Spielman A. Accelerated transmission of Lyme disease spirochetes by partially fed vector ticks. Journal of Clinical Microbiology 1993;31:2878-81. =====*===== VI. HOW TO SUBSCRIBE, CONTRIBUTE AND GET BACK ISSUES ------------------------------------------------------ SUBSCRIPTIONS: Anyone with an Internet address may subscribe. Send a memo to: [email protected] in the body, type: subscribe LymeNet-L YourFirstName YourLastName DELETIONS: Send a memo to: [email protected] in the body, type: unsubscribe LymeNet-L CONTRIBUTIONS: Send all contributions to [email protected] or FAX them to 908-789-0028. All are encouraged to submit questions, news items, announcements, and commentaries. BACK ISSUES: Available via 3 methods: 1. 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