Subject: LymeNet Newsletter vol#2 #09

From: [email-masked] (Marc Gabriel)
Date: Thu, 9 Jun 1994 20:13:57 EDT

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*                  The National Lyme Disease Network                  *
*                         LymeNet Newsletter                          *
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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-masked]>

        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-masked]>

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-masked]>

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-masked]>

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-masked]>

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.

=====*=====

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