Volume: 6 Table of Contents: I. LDRC: Chronic Lyme study patients showing extraordinary debility II. LDRC: NIH looking for more patients for chronic neuroborreliosis study III. J INFECT DIS: Matrix metalloproteinases in the cerebrospinal fluid of patients with Lyme neuroborreliosis IV. ARCH INTERN MED: Erythema migrans-like rash illness at a camp in North Carolina: a new tick-borne disease? V. ABOUT THE LYMENET NEWSLETTER Newsletter: *********************************************************************** * The National Lyme Disease Network * * http://www.lymenet.org/ * * LymeNet Newsletter * *********************************************************************** Volume 6 / Number 05 / 20-MAY-98 INDEX I. LDRC: Chronic Lyme study patients showing extraordinary debility II. LDRC: NIH looking for more patients for chronic neuroborreliosis study III. J INFECT DIS: Matrix metalloproteinases in the cerebrospinal fluid of patients with Lyme neuroborreliosis IV. ARCH INTERN MED: Erythema migrans-like rash illness at a camp in North Carolina: a new tick-borne disease? V. ABOUT THE LYMENET NEWSLETTER QUOTE OF THE WEEK: "These [chronic lyme] patients are in a condition worse than patients with marked congestive heart failure. They are two and a half standard deviations from normal - among the most deviant of any chronic illness." -- Mark S. Klempner, MD, NIH Extramural Chronic Lyme Study Principal Investigator =====*===== I. LDRC: Chronic Lyme study patients showing extraordinary debility ---------------------------------------------------------------------- This article originally appeared in the January - March 1998 Issue of the Lyme Times Six months into the extramural arm of the NIH funded chronic Lyme disease study, the research team is making wonderful progress, according to principal investigator Mark S. Klempner, MD, of the New England Medical Center (NEMC) in Boston. While no conclusions are possible this early, they are receiving some very strong impressions from the patients they are seeing. Klempner shared some of those impressions in an interview with the Lyme Times. The study has five basic goals: to determine whether a specific treatment regimen benefits patients with chronic Lyme disease; to identify, if possible, evidence of ongoing infection; to investigate the possibility of coinfection; to find new diagnostic tests; and to determine whether there are specific markers which predict who will, and who will not, respond to the treatment regimen. Most remarkable, according to Klempner, is the extraordinary degree of debility they are seeing in this group of patients. Prior to this study, no one had profiled what chronic Lyme disease patients really complain about. The term "vague complaints" has been widely used as a pejorative to trivialize the patients' symptoms. Now, using a well established and professionally respected scale which measures health related quality of life, the NEMC doctors are discovering that patients do indeed experience striking limitations from chronic pain. "Their complaints are not 'vague,'"states Klempner, "but, on the contrary, are very quantifiable. These patients are in a condition worse than patients with marked congestive heart failure. They are two and a half standard deviations [a statistical term] from normal - among the most deviant of any chronic illness." He feels that this finding will remain important, even if other parts of the study are not as definitive. He expressed his confidence in the outcome measures the team has selected and expects to be able to detect any improvement over the course of treatment. Klempner took issue with the popular perception that Lyme disease patients are basically suffering from depression. From his early observations on the approximately 20 patients who have enrolled in the study so far, patients with chronic Lyme disease are not depressed. Their debility is not mental but physical. "They are absolutely normal mentally," he asserted. "What we see so clearly is the significant impact of their bodily pain. This has not been appreciated." An area of particular interest to Klempner is the search for better identifiers which will enable them to differentiate between patients who develop chronic disease and those who don't. He and his colleagues published the results of an earlier study in the February, 1998 issue of the Journal of Infectious Diseases detailing their search for matrix metalloprotease in the cerebrospinal fluid (CSF) of patients with acute neuroborreliosis (e.g. meningitis, facial palsy, positive PCR, culture). This protease is one of a group of enzymes which dissolves the extracellular matrix between cells in normal body tissues. Significantly, the researchers found a 78% incidence of the novel protease in the CSF of neuroborreliosis patients, compared with 6% in the general population or in patients with other neurologic diseases. "We are now looking for this enzyme in patients in the chronic Lyme disease study," explained Klempner. "Of the first 15 patients we tested, 14 have it." The study is on track with over twenty patients enrolled so far, and 60 more are being screened. They hope and expect to enroll a total of 70-80 patients in the first year. Patients are being enrolled both in Boston at New England Medical Center and in the New York area at New York Medical College in Westchester, NY (see box below). After the screening process, they are randomly assigned to a treatment group where they receive one month of intravenous antibiotics followed by two months of oral antibiotics, or to a placebo group. Neither doctors nor patients know which treatment is being given - this is known as a "double- blind, placebo-controlled" study. The codes will be broken after the trial is completed and then the data will be analyzed. Klempner is busy giving talks to explain the study and recruit patients. He is clearly impressed by the spirit of the people who are signing up even though they may only be getting months of a placebo. Over 450 of these chronically ill, debilitated patients have contacted the medical centers for information about the study. "No one is complaining about the treatment protocol, and only one patient has refused the spinal tap. People are really eager to help us and to help their community," he said. For information about the study contact Dr. Mark Klempner or Dr. Linden Hu at 1-888-LYME CTR (1-888-596-3287). New York residents may call the Lyme Research Office at New York Medical College, 914-594-4530. Study Description: http://www.niaid.nih.gov/recruit/phsiiip.htm =====*===== II. LDRC: NIH looking for more patients for chronic neuroborreliosis study ----------------------------------------------------- This article originally appeared in the January - March 1998 Issue of the Lyme Times The intramural arm of the NIH study on chronic Lyme disease is studying chronic neuroborreliosis, or Lyme disease of the central nervous system. They want to find out whether persistent signs and symptoms, especially neurologic ones, are due to ongoing active borrelial infection or other pathogenic mechanisms. According to principal investigator Adrianna Marques, MD, over 600 patients have requested information, but only 20% (120) have returned the paperwork. Of these, 71% were disqualified because they lacked serological confirmation of infection, or in some other way did not meet the eligibility criteria. Altogether, 28 people have been enrolled in the study so far, mostly from the northeast, and two from Florida. Patients who pass the initial screening must come to the NIH Clinical Center in Bethesda, Maryland, for an evaluation which includes a full clinical and neurological examination, routine laboratory tests, EIA or ELISA testing (with confirmatory immunoblot), Babesia and Ehrlichia screening, lumbar puncture, high-resolution MRI, audiologic evaluation, neuropsychological testing and leukapheresis for extensive immune system studies. The tests take approximately four days. All costs of the study and medical care at the NIH and travel to and from Bethesda are covered by the NIH. Marques says the patients are very interesting, although it's too early to see the bigger picture. "Each patient is different," she said. "We are just beginning to get an impression of the group." She performs the physical examination on each one before sending them to specialists for all the other tests. Patients are investigated for hearing abnormalities, and their T-cell responses are examined. Some patients present with a disease like multiple sclerosis; others have fibromyalgia or chronic arthritis. Marques wants to look more closely at how the patients respond to therapy and how their immune systems are functioning, to see if she can figure out a pattern. More patients are needed. To enroll, patients must: * Be seropositive for Lyme infection - that is, have a documented positive Lyme serology test, confirmed with Western Blot. * Have neurological symptoms of at least three month's duration. * Have no other disease that can explain the symptoms. * Be without antibiotic therapy for one month prior to the study. Patients who have evidence of persistent infection by PCR, antigen- capture assay or other assays will be offered four weeks of intravenous ceftriaxone therapy. The therapy will be given on an out-patient basis, ideally under the supervision of each referring physician. The subjects will then return to NIH for reevaluation at the end of treatment, three, six, and twelve months after therapy. NIH is also recruiting people for the control group. They are looking for men and women aged 18 to 65 in the following categories: * People diagnosed with Lyme arthritis, who have continuous joint swelling for more then three months with no other documented cause; * People who have had Lyme disease, according to the CDC Lyme Disease National Surveillance Case Definition, received accepted antibiotic treatment for Lyme disease, and are currently asymptomatic; * People who are seropositive for Lyme infection but are asymptomatic, recall no episodes of disease compatible with Lyme infection, and have not received antibiotic therapy for Lyme disease. People who have serious pre-existing or concurrent chronic medical or psychiatric illnesses are excluded from the study. "Research is a two-way road," said Marques. "It is important to think we are all partners in research. The patients make a big difference. It's their participation that makes it happen." If you are interested in more detailed information about this study, please send a self-addressed envelope to the following address: NIAID Chronic Lyme Disease Study Adriana Marques Building 10 Room 11C405 9000 Rockville Pike Bethesda MD 20892 Study Description: http://www.niaid.nih.gov/recruit/lyme.htm =====*===== III. J INFECT DIS: Matrix metalloproteinases in the cerebrospinal fluid of patients with Lyme neuroborreliosis ------------------------------------------------------------------ AUTHORS: Perides G, Charness ME, Tanner LM, Peter O, Satz N, Steere AC, Klempner MS ORGANIZATION: Tupper Research Institute, Tufts University School of Medicine, New England Medical Center, Boston, Massachusetts 02111, USA. REFERENCE: J Infect Dis 1998 Feb;177(2):401-8 ABSTRACT: Neurologic manifestations of Lyme disease include meningitis, encephalopathy, and cranial and peripheral neuropathy. There are no sensitive markers for neuroborreliosis, and diagnosis is often based on clinical presentation and cerebrospinal fluid (CSF) abnormalities, including intrathecal antibody production. Matrix metalloproteinase (MMP) activity in CSF was compared in patients with neuroborreliosis, patients with diverse neurologic disorders, and healthy controls. The CSF of 17 of 18 healthy subjects and 33 of 37 patients with neurologic symptoms and normal CSF and imaging studies contained only MMP2. The CSF of several patients with neurologic disorders contained MMP2, MMP9, and gelatinolytic activity at 130 and 250 kDa. The 130-kDa MMP was found without the 92-kDa MMP9 in the CSF of 11 (79%) of 14 patients with neuroborreliosis and only 7 (6%) of 118 control patients (P < .001). This pattern of CSF gelatinase activity may be a useful marker for neuroborreliosis. =====*===== IV. ARCH INTERN MED: Erythema migrans-like rash illness at a camp in North Carolina: a new tick-borne disease? -------------------------------------------------------------- AUTHORS: Kirkland KB, Klimko TB, Meriwether RA, Schriefer M Levin M, Levine J, Mac Kenzie WR, Dennis DT ORGANIZATION: Epidemic Intelligence Service, and Division of Field Epidemiology, Centers for Disease Control and Prevention, Atlanta, GA, USA. REFERENCE: Arch Intern Med 1997 Dec 8-22;157(22):2635-41 ABSTRACT: BACKGROUND: Borrelia burgdorferi, the causative agent of Lyme disease, has never been isolated from a patient thought to have acquired Lyme disease in any southeastern state. OBJECTIVE: To investigate 14 cases of an erythema migrans (EM)-like rash illness that occurred during 2 summers at an outdoor camp in central North Carolina in an effort to determine the etiologic, epidemiological, and clinical aspects of this illness. METHODS: Using active surveillance, we identified cases of clinically diagnosed EM in residents and staff of the camp. We collected clinical and demographic information; history of exposure to ticks; acute and convalescent serum antibodies to B. burgdorferi, Rickettsia rickettsii, and Ehrlichia chaffeensis; and cultures for spirochetes from biopsy specimens of skin lesions. Serum samples from a group of residents and staff who did not develop rashes were tested for the same antibodies. We speciated ticks removed from people and collected from vegetation. RESULTS: We identified 14 cases of EM-like rash illness during the 2 summers. Of the 14 case-patients, 10 had associated mild systemic symptoms and 1 had documented fever. All 14 case-patients had removed attached ticks, and 8 remembered having removed a tick from the site where the rash developed a median of 12 days earlier (range, 2-21 days). One tick removed from the site where a rash later developed was identified as Amblyomma americanum, the Lone Star tick; 97% of ticks collected from vegetation and 95% of ticks removed from people were A. americanum. No spirochetes were isolated from skin biopsy specimens. Paired serum samples from 13 case-patients did not show diagnostic antibody responses to B. burgdorferi or other tick-borne pathogens. CONCLUSIONS: This investigation suggests the existence of a new tick-associated rash illness. We suspect that the disease agent is carried by A. americanum ticks. In the southern United States, EM-like rash illness should no longer be considered definitive evidence of early Lyme disease. =====*===== V. 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