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Volume: 6
Issue: 05
Date: 20-May-98


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:

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                   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.    ABOUT THE LYMENET NEWSLETTER
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